Clinical Focus


  • Pediatric Hematology-Oncology
  • Leukemia
  • Relapsed leukemia
  • Infectious complication of oncology treatment
  • Fungal infections

Honors & Awards


  • Bertil Glader Award for Outstanding Teaching and Mentoring, Lucile Packard Children's Hospital (2019)
  • Early Career Clinical Excellence Award, Lucile Packard Children's Hospital (2019)
  • Stanford Society of Physician Scholars, Stanford University (2013-2014)
  • Innovations in Patient Care Award, Spectrum Child Health Research Institute (2012-2014)
  • Fellow, Rachleff Hem-Onc Pediatric Fellowship fund (2012-2013)
  • AOA, Medical Honor Society (2007)

Professional Education


  • Medical Education: Tufts University School of Medicine (2007) MA
  • Fellowship: Stanford University Pediatric Hematology Oncology Fellowship (2014) CA
  • Residency: Mass General Hospital for Children Pediatric Residency (2011) MA
  • Internship: Mass General Hospital for Children Pediatric Residency (2008) MA
  • Board Certification: American Board of Pediatrics, Pediatrics (2010)
  • Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (2015)
  • Chief Resident, Massachusetts General Hospital for Children, Pediatrics (2011)
  • Resident, Massachusetts General Hospital for Children, Pediatrics (2010)
  • Doctor of Medicine, Tufts University School of Medicine (2007)

Current Research and Scholarly Interests


I conduct clinical research on the prevention, early diagnosis, and treatment of infectious complications in pediatric patients with leukemia.

Clinical Trials


  • Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections Recruiting

    This study will establish a non-invasive diagnostic approach and evaluate clinical outcomes for children at high-risk for pulmonary invasive fungal infection (PIFI).

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  • Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies Recruiting

    This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

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  • Home Away From Home - Quality of Life Surveys Not Recruiting

    Treatment for pediatric acute myeloid leukemia (AML) involves intensive chemotherapy regimens that result in periods of profound neutropenia leaving patients susceptible to severe infectious complications. Infectious complications are the leading cause of treatment related mortality among AML patients, but there are little clinical data to inform whether management of neutropenia post AML chemotherapy should occur in an outpatient or inpatient setting. Further, no studies have been conducted that assess the impact of neutropenia management strategy on the quality of life of pediatric patients with AML and their caregivers.

    Stanford is currently not accepting patients for this trial.

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  • Symptom Screening Linked to Care Pathways Not Recruiting

    Most children with cancer survive because they are given intensive treatments, but unfortunately, these treatments are associated with distressing symptoms. To address this problem, we developed the Symptom Screening in Pediatrics Tool (SSPedi) so that children receiving cancer treatments can communicate their bothersome symptoms, and Supportive care Prioritization, Assessment and Recommendations for Kids (SPARK), a web-based application that links identified symptoms to supportive care guidelines for symptom management. To establish that these tools improve the lives of children newly diagnosed with cancer, we will conduct a trial that randomizes 20 pediatric cancer institutions and measures the impact of three times weekly symptom screening, symptom feedback to healthcare providers and the development of care pathways for symptom management to improve total symptom burden, fatigue and quality of life.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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All Publications


  • Plasma microbial cell-free DNA following chimeric antigen receptor T cell therapy in pediatric patients with relapsed/refractory leukemia. European journal of haematology Aftandilian, C., Bito, X. R., Berman, D., Zhang, A., Duttagupta, R., Davis, K. L. 2024

    Abstract

    Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (R/R B ALL). Cytokine release syndrome (CRS) is a common toxicity after CAR T cell therapy and fever is often the first symptom. Differentiating CRS from infection after CAR T cell therapy can be challenging. Plasma microbial cell free DNA (mcfDNA) is a novel diagnostic tool which allows for qualitative and quantitative assessment of over 1000 organisms. This pilot study sought to characterize mcfDNA results in pediatric patients with R/R B ALL in the first 2 months after CAR T cell therapy.

    View details for DOI 10.1111/ejh.14216

    View details for PubMedID 38658354

  • Household income and health-related quality of life in children receiving treatment for acute myeloid leukemia: Potential impact of selection bias in health equity research. Cancer medicine Newman, H., Li, Y., Huang, Y. V., Elgarten, C. W., Myers, R. M., Ruiz, J., Zheng, D. J., Leahy, A. B., Aftandilian, C., Arnold, S. D., Bona, K., Gramatges, M. M., Heneghan, M. B., Maloney, K. W., Modi, A. J., Mody, R. J., Morgan, E., Rubnitz, J., Winick, N., Wilkes, J. J., Seif, A. E., Fisher, B. T., Aplenc, R., Getz, K. D. 2024; 13 (7): e6966

    Abstract

    Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML).Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States.Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity.Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey.Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction.While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.

    View details for DOI 10.1002/cam4.6966

    View details for PubMedID 38572962

    View details for PubMedCentralID PMC10993703

  • Characterizing the limitations of using diagnosis codes in the context of machine learning for healthcare. BMC medical informatics and decision making Guo, L. L., Morse, K. E., Aftandilian, C., Steinberg, E., Fries, J., Posada, J., Fleming, S. L., Lemmon, J., Jessa, K., Shah, N., Sung, L. 2024; 24 (1): 51

    Abstract

    Diagnostic codes are commonly used as inputs for clinical prediction models, to create labels for prediction tasks, and to identify cohorts for multicenter network studies. However, the coverage rates of diagnostic codes and their variability across institutions are underexplored. The primary objective was to describe lab- and diagnosis-based labels for 7 selected outcomes at three institutions. Secondary objectives were to describe agreement, sensitivity, and specificity of diagnosis-based labels against lab-based labels.This study included three cohorts: SickKids from The Hospital for Sick Children, and StanfordPeds and StanfordAdults from Stanford Medicine. We included seven clinical outcomes with lab-based definitions: acute kidney injury, hyperkalemia, hypoglycemia, hyponatremia, anemia, neutropenia and thrombocytopenia. For each outcome, we created four lab-based labels (abnormal, mild, moderate and severe) based on test result and one diagnosis-based label. Proportion of admissions with a positive label were presented for each outcome stratified by cohort. Using lab-based labels as the gold standard, agreement using Cohen's Kappa, sensitivity and specificity were calculated for each lab-based severity level.The number of admissions included were: SickKids (n = 59,298), StanfordPeds (n = 24,639) and StanfordAdults (n = 159,985). The proportion of admissions with a positive diagnosis-based label was significantly higher for StanfordPeds compared to SickKids across all outcomes, with odds ratio (99.9% confidence interval) for abnormal diagnosis-based label ranging from 2.2 (1.7-2.7) for neutropenia to 18.4 (10.1-33.4) for hyperkalemia. Lab-based labels were more similar by institution. When using lab-based labels as the gold standard, Cohen's Kappa and sensitivity were lower at SickKids for all severity levels compared to StanfordPeds.Across multiple outcomes, diagnosis codes were consistently different between the two pediatric institutions. This difference was not explained by differences in test results. These results may have implications for machine learning model development and deployment.

    View details for DOI 10.1186/s12911-024-02449-8

    View details for PubMedID 38355486

    View details for PubMedCentralID PMC10868117

  • Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Zhao, Z., Patel, P. A., Slatnick, L., Sitthi-Amorn, A., Bielamowicz, K. J., Nunez, F. A., Walsh, A. M., Hess, J., Rossoff, J., Elgarten, C., Myers, R., Saab, R., Basbous, M., Mccormick, M., Aftandilian, C., Richards, R., Nessle, C. N., Tribble, A. C., Sheth Bhutada, J. K., Coven, S. L., Runco, D., Wilkes, J., Gurunathan, A., Guinipero, T., Belsky, J. A., Lee, K., Wong, V., Malhotra, M., Armstrong, A., Jerkins, L. P., Cross, S. J., Fisher, L., Stein, M. T., Wu, N. L., Yi, T., Orgel, E., Haeusler, G. M., Wolf, J., Demedis, J. M., Miller, T. P., Esbenshade, A. J. 2023: JCO2301814

    Abstract

    The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation.Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration.In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics.The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

    View details for DOI 10.1200/JCO.23.01814

    View details for PubMedID 38060973

  • Racial and Ethnic Differences in Acuity and Cumulative Frontline Organ Toxicity at the Time of Relapse in Pediatric Acute Myeloid Leukemia Zheng, D. J., Li, Y., Huang, Y. V., Aftandilian, C., Bona, K., Caywood, E., Collier, A. B., Gramatges, M., Heneghan, M. M., Henry, M., Lotterman, C., Maloney, K., Miller, T. P., Modi, A., Mody, R., Morgan, E., Winick, N. J., Wilkes, J. J., Wong, V., Gathers, C., Newman, H., Moore, R. H., Myers, R. M., Elgarten, C. W., Seif, A. E., Fisher, B. T., Aplenc, R., Getz, K. D. AMER SOC HEMATOLOGY. 2023
  • Survival Disparities By Frontline Clinical Trial Enrollment Status for Treatment of Pediatric Acute Myeloid Leukemia Zheng, D. J., van der Mei, E., Li, Y., Huang, Y. V., Aftandilian, C., Bona, K., Caywood, E., Collier, A. B., Gramatges, M., Heneghan, M. M., Henry, M., Lotterman, C., Maloney, K., Miller, T. P., Modi, A., Mody, R., Morgan, E., Winick, N. J., Wilkes, J. J., Wong, V., Newman, H., Myers, R. M., Elgarten, C. W., Seif, A. E., Fisher, B. T., Aplenc, R., Getz, K. D. AMER SOC HEMATOLOGY. 2023
  • ASPARAGINASE-ASSOCIATED TOXICITY AND HYPERSENSITIVITY REACTIONS IN DOWN SYNDROME CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA Van Huynh, Phillips, C., August, K., Guest, E., Morales, S., Aftandilian, C., Winger, B., Agrawal, A., Lin, C. WILEY. 2023
  • Self-supervised machine learning using adult inpatient data produces effective models for pediatric clinical prediction tasks. Journal of the American Medical Informatics Association : JAMIA Lemmon, J., Guo, L. L., Steinberg, E., Morse, K. E., Fleming, S. L., Aftandilian, C., Pfohl, S. R., Posada, J. D., Shah, N., Fries, J., Sung, L. 2023

    Abstract

    Development of electronic health records (EHR)-based machine learning models for pediatric inpatients is challenged by limited training data. Self-supervised learning using adult data may be a promising approach to creating robust pediatric prediction models. The primary objective was to determine whether a self-supervised model trained in adult inpatients was noninferior to logistic regression models trained in pediatric inpatients, for pediatric inpatient clinical prediction tasks.This retrospective cohort study used EHR data and included patients with at least one admission to an inpatient unit. One admission per patient was randomly selected. Adult inpatients were 18 years or older while pediatric inpatients were more than 28 days and less than 18 years. Admissions were temporally split into training (January 1, 2008 to December 31, 2019), validation (January 1, 2020 to December 31, 2020), and test (January 1, 2021 to August 1, 2022) sets. Primary comparison was a self-supervised model trained in adult inpatients versus count-based logistic regression models trained in pediatric inpatients. Primary outcome was mean area-under-the-receiver-operating-characteristic-curve (AUROC) for 11 distinct clinical outcomes. Models were evaluated in pediatric inpatients.When evaluated in pediatric inpatients, mean AUROC of self-supervised model trained in adult inpatients (0.902) was noninferior to count-based logistic regression models trained in pediatric inpatients (0.868) (mean difference = 0.034, 95% CI=0.014-0.057; P < .001 for noninferiority and P = .006 for superiority).Self-supervised learning in adult inpatients was noninferior to logistic regression models trained in pediatric inpatients. This finding suggests transferability of self-supervised models trained in adult patients to pediatric patients, without requiring costly model retraining.

    View details for DOI 10.1093/jamia/ocad175

    View details for PubMedID 37639620

  • Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice from a Multicenter Cohort Study Conducted by the Pediatric Fungal Network. Journal of the Pediatric Infectious Diseases Society Wattier, R. L., Bucayu, R. F., Boge, C. L., Ross, R. K., Yildirim, I., Zaoutis, T. E., Palazzi, D. L., Vora, S. B., Castagnola, E., Avilés-Robles, M., Danziger-Isakov, L., Tribble, A. C., Sharma, T. S., Arrieta, A. C., Maron, G., Berman, D. M., Yin, D. E., Sung, L., Green, M., Roilides, E., Belani, K., Romero, J., Soler-Palacin, P., López-Medina, E., Nolt, D., Bin Hussain, I. Z., Muller, W. J., Hauger, S. B., Halasa, N., Dulek, D., Pong, A., Gonzalez, B. E., Abzug, M. J., Carlesse, F., Huppler, A. R., Rajan, S., Aftandilian, C., Ardura, M. I., Chakrabarti, A., Hanisch, B., Salvatore, C. M., Klingspor, L., Knackstedt, E. D., Lutsar, I., Santolaya, M. E., Shuster, S., Johnson, S. K., Steinbach, W. J., Fisher, B. T. 2023

    Abstract

    Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown.Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days -17 years with invasive candidiasis (predominantly candidemia) from 2014-2017. Ophthalmologic examination, abdominal imaging, echocardiogram, neuroimaging, and lumbar puncture were performed per clinician discretion. aDS performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed effects logistic regression.In 662 pediatric candidemia episodes, 490 (74%) underwent abdominal imaging, 450 (68%) ophthalmologic examination, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) lumbar puncture; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing ophthalmologic examination, abdominal imaging, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing abdominal imaging (aOR 2.38; 95% CI 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive ophthalmologic examination was reported in 15 (3%), abdominal imaging in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%) and lumbar puncture in 3 (4%).Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

    View details for DOI 10.1093/jpids/piad057

    View details for PubMedID 37589394

  • Outcomes in pediatric relapsed/refractory anaplastic large cell lymphoma: A multi-institutional retrospective analysis Marks, L., Ritter, V., Schultz, L. M., Lowe, E. J., Aftandilian, C., Relapsed ALCL Real Consortium LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Child and family perceptions of satisfaction with neutropenia management in pediatric acute myeloid leukemia. Pediatric blood & cancer Szymczak, J. E., Getz, K. D., Madding, R., Shuster, S., Aftandilian, C., Arnold, S. D., Collier, A. B., Gramatges, M. M., Henry, M., Hijiya, N., Mian, A., Raetz, E., Fisher, B. T., Aplenc, R. 2023: e30420

    Abstract

    Chemotherapy for pediatric acute myeloid leukemia (AML) is very intensive and many, but not all centers, require extended hospitalization until neutrophil recovery. Child and family preferences, beliefs, and experiences around hospitalization have not been systematically assessed.We recruited children with AML and their parents from nine pediatric cancer centers across the United States for a qualitative interview about their experiences of neutropenia management. Interviews were analyzed using a conventional content analysis approach.Of 116 eligible individuals, 86 (74.1%) agreed to participate. Interviews were conducted with 32 children and 54 parents from 57 families. Of these 57 families, 39 were cared for as inpatients and 18 were managed as outpatients. A very high proportion of respondents in both groups reported satisfaction with the discharge management strategy recommended by the treating institution: 86% (57 individuals) of respondents who experienced inpatient management and 85% (17 individuals) of respondents who experienced outpatient management expressed satisfaction. Respondent perceptions associated with satisfaction related to safety (access to emergency interventions, infection risk, close monitoring) and psychosocial concerns (family separation, low morale, social support). Respondents believed it could not be assumed that all children would have the same experience due to varied life circumstances.Children with AML and their parents express a very high degree of satisfaction with the discharge strategy recommended by their treating institution. Respondents saw a nuanced tradeoff between patient safety and psychosocial concerns that was mediated by a child's life circumstances.

    View details for DOI 10.1002/pbc.30420

    View details for PubMedID 37194639

  • Symptom management care pathway adaptation process and specific adaptation decisions. BMC cancer Vettese, E., Sherani, F., King, A. A., Yu, L., Aftandilian, C., Baggott, C., Agarwal, V., Nagasubramanian, R., Kelly, K. M., Freyer, D. R., Orgel, E., Bradfield, S. M., Kyono, W., Roth, M., Klesges, L. M., Beauchemin, M., Grimes, A., Tomlinson, G., Dupuis, L. L., Sung, L. 2023; 23 (1): 350

    Abstract

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

    View details for DOI 10.1186/s12885-023-10835-0

    View details for PubMedID 37069510

  • Evaluation of Feature Selection Methods for Preserving Machine Learning Performance in the Presence of Temporal Dataset Shift in Clinical Medicine. Methods of information in medicine Lemmon, J., Guo, L. L., Posada, J., Pfohl, S. R., Fries, J., Fleming, S. L., Aftandilian, C., Shah, N., Sung, L. 2023

    Abstract

    BACKGROUND: Temporal dataset shift can cause degradation in model performance as discrepancies between training and deployment data grow over time. The primary objective was to determine whether parsimonious models produced by specific feature selection methods are more robust to temporal dataset shift as measured by out-of-distribution (OOD) performance, while maintaining in-distribution (ID) performance.METHODS: Our dataset consisted of intensive care unit patients from MIMIC-IV categorized by year groups (2008-2010, 2011-2013, 2014-2016, and 2017-2019). We trained baseline models using L2-regularized logistic regression on 2008-2010 to predict in-hospital mortality, long length of stay (LOS), sepsis, and invasive ventilation in all year groups. We evaluated three feature selection methods: L1-regularized logistic regression (L1), Remove and Retrain (ROAR), and causal feature selection. We assessed whether a feature selection method could maintain ID performance (2008-2010) and improve OOD performance (2017-2019). We also assessed whether parsimonious models retrained on OOD data performed as well as oracle models trained on all features in the OOD year group.RESULTS: The baseline model showed significantly worse OOD performance with the long LOS and sepsis tasks when compared with the ID performance. L1 and ROAR retained 3.7 to 12.6% of all features, whereas causal feature selection generally retained fewer features. Models produced by L1 and ROAR exhibited similar ID and OOD performance as the baseline models. The retraining of these models on 2017-2019 data using features selected from training on 2008-2010 data generally reached parity with oracle models trained directly on 2017-2019 data using all available features. Causal feature selection led to heterogeneous results with the superset maintaining ID performance while improving OOD calibration only on the long LOS task.CONCLUSIONS: While model retraining can mitigate the impact of temporal dataset shift on parsimonious models produced by L1 and ROAR, new methods are required to proactively improve temporal robustness.

    View details for DOI 10.1055/s-0043-1762904

    View details for PubMedID 36812932

  • Survival Outcomes of Children with Relapsed or Refractory Myeloid Leukemia Associated with Down syndrome. Blood advances Raghuram, N., Nakashima, K., Ab Rahman, S., Antoniou, E., Skajaa, T., Merli, P., Verma, A., Rabin, K. R., Aftandilian, C., Kotecha, R. S., Cheuk, D. K., Jahnukainen, K., Kolenova, A., Balwierz, W., Norton, A., O'Brien, M. M., Cellot, S., Chopek, A., Arad-Cohen, N., Goemans, B. F., Rojas-Vasquez, M., Ariffin, H., Bartram, J., Kolb, E. A., Locatelli, F., Hasegawa, D., Klusmann, J., Hasle, H., McGuire, B., Sung, L., Hitzler, J. K. 2023

    Abstract

    Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between 2000-2021. Median time from diagnosis to relapse was 6.8 (range 1.1 - 45.5) months. Three-year event-free (EFS) and overall survival (OS) were 20.9±5.3% and 22.1±5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (HR 0.28), duration of first complete remission (CR1) (HR 0.31 for > 12 months) and attainment of remission after relapse (HR 4.03). Patients who achieved CR prior to HSCT, had an improved OS and EFS of 56.0±11.8% and 50.5±11.9% respectively, compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0±9.5%). Treatment failure after HSCT was predominantly due to disease recurrence (52%) followed by treatment related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.

    View details for DOI 10.1182/bloodadvances.2022009381

    View details for PubMedID 36735769

  • Role of peripheral blood MRD and 18F-FDG PET in the post-CAR relapse setting: a case study of discordant peripheral blood and bone marrow MRD. Journal for immunotherapy of cancer Schultz, L., Davis, K. L., Walkush, A., Baggott, C., Erickson, C., Ramakrishna, S., Aftandilian, C., Lacayo, N., Nadel, H. R., Oak, J., Mackall, C. L. 2023; 11 (2)

    Abstract

    Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse.Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD <0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling.We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patient's post-CAR relapse. Clinical/Biologic Insight: In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary and/or EM disease, peripheral blood MRD and/or whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling.

    View details for DOI 10.1136/jitc-2022-004851

    View details for PubMedID 36849202

    View details for PubMedCentralID PMC9972424

  • Development of clinical pathways to improve multidisciplinary care of high-risk pediatric oncology patients. Frontiers in oncology Reschke, A., Richards, R. M., Smith, S. M., Long, A. H., Marks, L. J., Schultz, L., Kamens, J. L., Aftandilian, C., Davis, K. L., Gruber, T., Sakamoto, K. M. 2022; 12: 1033993

    Abstract

    Clinical pathways are evidence-based tools that have been integrated into many aspects of pediatric hospital medicine and have proven effective at reducing in-hospital complications from a variety of diseases. Adaptation of similar tools for specific, high-risk patient populations in pediatric oncology has been slower, in part due to patient complexities and variations in management strategies. There are few published studies of clinical pathways for pediatric oncology patients. Pediatric patients with a new diagnosis of leukemia or lymphoma often present with one or more "oncologic emergencies" that require urgent intervention and deliberate multidisciplinary care to prevent significant consequences. Here, we present two clinical pathways that have recently been developed using a multidisciplinary approach at a single institution, intended for the care of patients who present with hyperleukocytosis or an anterior mediastinal mass. These clinical care pathways have provided a critical framework for the immediate care of these patients who are often admitted to the pediatric intensive care unit for initial management. The goal of the pathways is to facilitate multidisciplinary collaborations, expedite diagnosis, and streamline timely treatment initiation. Standardizing the care of high-risk pediatric oncology patients will ultimately decrease morbidity and mortality associated with these diseases to increase the potential for excellent outcomes.

    View details for DOI 10.3389/fonc.2022.1033993

    View details for PubMedID 36523979

    View details for PubMedCentralID PMC9744920

  • Perspective Toward Machine Learning Implementation in Pediatric Medicine: Mixed Methods Study. JMIR medical informatics Alexander, N., Aftandilian, C., Guo, L. L., Plenert, E., Posada, J., Fries, J., Fleming, S., Johnson, A., Shah, N., Sung, L. 2022; 10 (11): e40039

    Abstract

    BACKGROUND: Given the costs of machine learning implementation, a systematic approach to prioritizing which models to implement into clinical practice may be valuable.OBJECTIVE: The primary objective was to determine the health care attributes respondents at 2 pediatric institutions rate as important when prioritizing machine learning model implementation. The secondary objective was to describe their perspectives on implementation using a qualitative approach.METHODS: In this mixed methods study, we distributed a survey to health system leaders, physicians, and data scientists at 2 pediatric institutions. We asked respondents to rank the following 5 attributes in terms of implementation usefulness: the clinical problem was common, the clinical problem caused substantial morbidity and mortality, risk stratification led to different actions that could reasonably improve patient outcomes, reducing physician workload, and saving money. Important attributes were those ranked as first or second most important. Individual qualitative interviews were conducted with a subsample of respondents.RESULTS: Among 613 eligible respondents, 275 (44.9%) responded. Qualitative interviews were conducted with 17 respondents. The most common important attributes were risk stratification leading to different actions (205/275, 74.5%) and clinical problem causing substantial morbidity or mortality (177/275, 64.4%). The attributes considered least important were reducing physician workload and saving money. Qualitative interviews consistently prioritized implementations that improved patient outcomes.CONCLUSIONS: Respondents prioritized machine learning model implementation where risk stratification would lead to different actions and clinical problems that caused substantial morbidity and mortality. Implementations that improved patient outcomes were prioritized. These results can help provide a framework for machine learning model implementation.

    View details for DOI 10.2196/40039

    View details for PubMedID 36394938

  • Plasma Microbial Cell-Free DNA to Characterize Infection Vs Cytokine Release Syndrome in Pediatric Patients with B ALL after CAR T Cell Therapy Aftandilian, C., Bito, X., Berman, D. M., Duttagupta, R., Davis, K. L. AMER SOC HEMATOLOGY. 2022: 4681-4683
  • Influence of Household Income on Health-Related Quality of Life in Children with Acute Myeloid Leukemia Newman, H., Li, Y., Huang, Y., Elgarten, C. W., Myers, R. M., Ruiz, J., Leahy, A., Aftandilian, C., Arnold, S. D., Bona, K. O., Heneghan, M. M., Gramatges, M., Maloney, K. W., Modi, A. J., Mody, R., Winick, N. J., Morgan, E., Wilkes, J. J., Seif, A. E., Fisher, B. T., Aplenc, R., Getz, K. D. AMER SOC HEMATOLOGY. 2022: 11001-11003
  • CLOSTRIDIODES DIFFICILE INFECTION IN PEDIATRIC PATIENTS WITH CANCER AND HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS Loves, R., Haeusler, G., Lehrnbecher, T., Agyeman, P., Castagnola, E., Groll, A., Van De Wetering, M., Aftandilian, C., Phillips, B., Chirra, K., Schneider, C., Dupuis, L., Sung, L. WILEY. 2022
  • Management of Chronic Myeloid Leukemia in Children and Young Adults. Current hematologic malignancy reports Ford, M., Mauro, M., Aftandilian, C., Sakamoto, K. M., Hijiya, N. 2022

    Abstract

    PURPOSE OF REVIEW: Due to lack of pediatric-specific data, the management of chronic myeloid leukemia (CML) in pediatric, adolescents, and young adults is guided by adult CML evidence-based recommendations. Pediatric CML presents differently than adult CML and is often a more aggressive disease with different biological and host factors, yet there is sparse literature on how to address those differences.RECENT FINDINGS: Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the way CML is treated. There are currently three FDA-approved TKIs (imatinib, dasatinib, and nilotinib) for pediatric patients. When choosing which TKI to begin treatment with, there are many factors that should be considered on a case-to-case basis to obtain optimal outcomes. The safety profiles for long-term TKI use in pediatrics require further study. Unlike adults, children are still actively growing during TKI use, and the effect on development can be detrimental. TKI therapy is not recommended during pregnancy with variable but significant risk of fetal abnormalities and miscarriage, warranting counseling for young female patients prior to beginning TKIs. Attempts for treatment-free remission (TFR) by planned TKI cessation in eligible adult patients in deep and sustained molecular remission are now done as a standard of practice. However, data is sparse in the pediatric population. There is currently an ongoing Children's Oncology Group (COG) study to determine the feasibility of TFR as a treatment goal. Further research and additional pediatric trials are needed to characterize the unique aspects of CML in children and adolescents and optimize outcomes.

    View details for DOI 10.1007/s11899-022-00673-5

    View details for PubMedID 35920965

  • Risk of bacterial bloodstream infection does not vary by central-line type during neutropenic periods in pediatric acute myeloid leukemia. Infection control and hospital epidemiology Elgarten, C. W., Otto, W. R., Shenton, L., Stein, M. T., Horowitz, J., Aftandilian, C., Arnold, S. D., Bona, K. O., Caywood, E., Collier, A. B., Gramatges, M. M., Henry, M., Lotterman, C., Maloney, K., Modi, A. J., Mian, A., Mody, R., Morgan, E., Raetz, E. A., Verma, A., Winick, N., Wilkes, J. J., Yu, J. C., Aplenc, R., Fisher, B. T., Getz, K. D. 2022: 1-8

    Abstract

    BACKGROUND: Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy.OBJECTIVE: To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML.METHODS: We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics.RESULTS: The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75-1.32) and TIC IRR = 0.83 (95% CI, 0.49-1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar.CONCLUSIONS: In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.

    View details for DOI 10.1017/ice.2022.82

    View details for PubMedID 35465865

  • Breakthrough Trichosporon asahii in a Patient With New Diagnosis B-ALL on Echinocandin Prophylaxis: A Case Report. Journal of pediatric hematology/oncology Mahoney, D., Aftandilian, C. 2022; 44 (2): e514-e517

    Abstract

    Invasive fungal disease is a difficult to diagnose complication of therapy in patients with hematologic malignancy. Antifungal prophylaxis is recommended in high-risk populations, but its use in other populations is less clear. This brief report describes a patient with Trisomy 21 on caspofungin prophylaxis who died of disseminated Trichosporon asahii during induction therapy for new diagnosis low-risk B-cell acute lymphoblastic leukemia, accompanied by a review of similar cases in the literature. Her case highlights the utility of relatively novel diagnostic modalities and reinforces the need for caution in placing patients on antifungal prophylaxis.

    View details for DOI 10.1097/MPH.0000000000002339

    View details for PubMedID 35200226

  • Neutropenia and Infection Prophylaxis in Childhood Cancer. Current oncology reports Villeneuve, S., Aftandilian, C. 2022

    Abstract

    PURPOSE OF REVIEW: Pediatric oncology patients frequently experience episodes of prolonged neutropenia which puts them at high risk for infection with significant morbidity and mortality. Here, we review the data on infection prophylaxis with a focus on both pharmacologic and ancillary interventions. This review does not include patients receiving hematopoietic stem cell transplantation.RECENT FINDINGS: Patients with hematologic malignancies are at highest risk for infection. Bacterial and fungal prophylaxis decrease the risk of infection in certain high-risk groups. Ancillary measures such as ethanol locks, chlorhexidine gluconate baths, GCSF, IVIG, and mandatory hospitalization do not have enough data to support routine use. There is limited data on risk of infection and role of prophylaxis in patients receiving immunotherapy and patients with solid tumors. Patients with Down syndrome and adolescent and young adult patients may benefit from additional supportive care measures and protocol modifications. Consider utilizing bacterial and fungal prophylaxis in patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. More research is needed to evaluate other supportive care measures and the role of prophylaxis in patients receiving immunotherapy.

    View details for DOI 10.1007/s11912-022-01192-5

    View details for PubMedID 35230594

  • Evaluation of domain generalization and adaptation on improving model robustness to temporal dataset shift in clinical medicine. Scientific reports Guo, L. L., Pfohl, S. R., Fries, J., Johnson, A. E., Posada, J., Aftandilian, C., Shah, N., Sung, L. 2022; 12 (1): 2726

    Abstract

    Temporal dataset shift associated with changes in healthcare over time is a barrier to deploying machine learning-based clinical decision support systems. Algorithms that learn robust models by estimating invariant properties across time periods for domain generalization (DG) and unsupervised domain adaptation (UDA) might be suitable to proactively mitigate dataset shift. The objective wasto characterize the impact of temporal dataset shift on clinical prediction models and benchmark DG and UDA algorithms on improving model robustness. In this cohort study, intensive care unit patients from the MIMIC-IV database were categorized by year groups (2008-2010, 2011-2013, 2014-2016 and 2017-2019). Tasks were predicting mortality, long length of stay, sepsis and invasive ventilation. Feedforward neural networks were used as prediction models. The baseline experiment trained models using empirical risk minimization (ERM) on 2008-2010 (ERM[08-10]) and evaluated them on subsequent year groups. DG experiment trained models using algorithms that estimated invariant properties using 2008-2016 and evaluated them on 2017-2019. UDA experiment leveraged unlabelled samples from 2017 to 2019 for unsupervised distribution matching. DG and UDA models were compared to ERM[08-16] models trained using 2008-2016. Main performance measures were area-under-the-receiver-operating-characteristic curve (AUROC), area-under-the-precision-recall curve and absolute calibration error. Threshold-based metrics including false-positives and false-negatives were used to assess the clinical impact of temporal dataset shift and its mitigation strategies. In the baseline experiments, dataset shift was most evident for sepsis prediction (maximum AUROC drop, 0.090; 95% confidence interval (CI), 0.080-0.101). Considering a scenario of 100 consecutively admitted patients showed that ERM[08-10] applied to 2017-2019 was associated with one additional false-negative among 11 patients with sepsis, when compared to the model applied to 2008-2010. When compared with ERM[08-16], DG and UDA experiments failed to produce more robust models (range of AUROC difference, -0.003 to 0.050). In conclusion,DG and UDA failed to produce more robust models compared to ERM in the setting of temporal dataset shift. Alternate approaches are required to preserve model performance over time in clinical medicine.

    View details for DOI 10.1038/s41598-022-06484-1

    View details for PubMedID 35177653

  • Comparison of the Transcriptomic Signatures in Pediatric and Adult CML. Cancers Youn, M., Smith, S. M., Lee, A. G., Chae, H., Spiteri, E., Erdmann, J., Galperin, I., Jones, L. M., Donato, M., Abidi, P., Bittencourt, H., Lacayo, N., Dahl, G., Aftandilian, C., Davis, K. L., Matthews, J. A., Kornblau, S. M., Huang, M., Sumarsono, N., Redell, M. S., Fu, C. H., Chen, I., Alonzo, T. A., Eklund, E., Gotlib, J., Khatri, P., Sweet-Cordero, E. A., Hijiya, N., Sakamoto, K. M. 1800; 13 (24)

    Abstract

    Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.

    View details for DOI 10.3390/cancers13246263

    View details for PubMedID 34944883

  • Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia. JAMA network open Getz, K. D., Szymczak, J. E., Li, Y., Madding, R., Huang, Y. V., Aftandilian, C., Arnold, S. D., Bona, K. O., Caywood, E., Collier, A. B., Gramatges, M. M., Henry, M., Lotterman, C., Maloney, K., Mian, A., Mody, R., Morgan, E., Raetz, E. A., Rubnitz, J., Verma, A., Winick, N., Wilkes, J. J., Yu, J. C., Fisher, B. T., Aplenc, R. 2021; 4 (10): e2128385

    Abstract

    Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management.Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML.Design, Setting, and Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020.Exposures: Discharge to outpatient vs inpatient neutropenia management.Main Outcomes and Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome.Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P=.08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P=.03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P=.03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P=.59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management.Conclusions and Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.

    View details for DOI 10.1001/jamanetworkopen.2021.28385

    View details for PubMedID 34709389

  • Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents. Journal of the Pediatric Infectious Diseases Society Fisher, B. T., Zaoutis, T. E., Xiao, R., Wattier, R. L., Castagnola, E., Pana, Z. D., Fullenkamp, A., Boge, C. L., Ross, R. K., Yildirim, I., Palazzi, D. L., Danziger-Isakov, L., Vora, S. B., Arrieta, A., Yin, D. E., Aviles-Robles, M., Sharma, T., Tribble, A. C., Maron, G., Berman, D., Green, M., Sung, L., Romero, J., Hauger, S. B., Roilides, E., Belani, K., Nolt, D., Soler-Palacin, P., Lopez-Medina, E., Muller, W. J., Halasa, N., Dulek, D., Hussain, I. Z., Pong, A., Hoffman, J., Rajan, S., Gonzalez, B. E., Hanisch, B., Aftandilian, C., Carlesse, F., Abzug, M. J., Huppler, A. R., Salvatore, C. M., Ardura, M. I., Chakrabarti, A., Santolaya, M. E., Localio, A. R., Steinbach, W. J. 2021

    Abstract

    BACKGROUND: Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis.METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups.RESULTS: Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was -7.1% points (95% CI: -13.1% to -2.4%), favoring echinocandins. The risk difference was -0.4% (95% CI: -7.5% to 6.7%) at 30 days.CONCLUSIONS: In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents.CLINICAL TRIALS REGISTRATION: NCT01869829.

    View details for DOI 10.1093/jpids/piab024

    View details for PubMedID 34374424

  • Systematic Review of Approaches to Preserve Machine Learning Performance in the Presence of Temporal Dataset Shift in Clinical Medicine. Applied clinical informatics Guo, L. L., Pfohl, S. R., Fries, J., Posada, J., Fleming, S. L., Aftandilian, C., Shah, N., Sung, L. 2021; 12 (4): 808-815

    Abstract

    OBJECTIVE: The change in performance of machine learning models over time as a result of temporal dataset shift is a barrier to machine learning-derived models facilitating decision-making in clinical practice. Our aim was to describe technical procedures used to preserve the performance of machine learning models in the presence of temporal dataset shifts.METHODS: Studies were included if they were fully published articles that used machine learning and implemented a procedure to mitigate the effects of temporal dataset shift in a clinical setting. We described how dataset shift was measured, the procedures used to preserve model performance, and their effects.RESULTS: Of 4,457 potentially relevant publications identified, 15 were included. The impact of temporal dataset shift was primarily quantified using changes, usually deterioration, in calibration or discrimination. Calibration deterioration was more common (n=11) than discrimination deterioration (n=3). Mitigation strategies were categorized as model level or feature level. Model-level approaches (n=15) were more common than feature-level approaches (n=2), with the most common approaches being model refitting (n=12), probability calibration (n=7), model updating (n=6), and model selection (n=6). In general, all mitigation strategies were successful at preserving calibration but not uniformly successful in preserving discrimination.CONCLUSION: There was limited research in preserving the performance of machine learning models in the presence of temporal dataset shift in clinical medicine. Future research could focus on the impact of dataset shift on clinical decision making, benchmark the mitigation strategies on a wider range of datasets and tasks, and identify optimal strategies for specific settings.

    View details for DOI 10.1055/s-0041-1735184

    View details for PubMedID 34470057

  • Psychosocial impacts of the COVID-19 pandemic on young adult cancer survivors and parents of children with cancer. Smith, S. M., Kumar, D., Benedict, C., Heathcote, L. C., Aftandilian, C., Bondy, M., Schapira, L. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia. Haematologica Hecht, A., Meyer, J. A., Behnert, A., Wong, E., Chehab, F., Olshen, A., Hechmer, A., Aftandilian, C., Bhat, R., Choi, S. W., Chonat, S., Farrar, J. E., Fluchel, M., Frangoul, H., Han, J. H., Kolb, E. A., Kuo, D. J., MacMillan, M. L., Maese, L., Maloney, K. W., Narendran, A., Oshrine, B., Schultz, K. R., Sulis, M. L., Van Mater, D., Tasian, S. K., Hofmann, W., Loh, M. L., Stieglitz, E. 2020; Online ahead of print

    Abstract

    Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

    View details for DOI 10.3324/haematol.2020.270595

    View details for PubMedID 33375775

  • Paraneoplastic Neurologic Symptoms in a Pediatric Patient with Hodgkin Lymphoma. Cancer investigation Baniel, C. C., Donaldson, S. S., Aftandilian, C., Hiniker, S. M. 2020: 1–7

    Abstract

    Neurological paraneoplastic syndromes are exceedingly rare, and often difficult to recognize clinically. Paraneoplastic achalasia is a condition characterized by new onset dysphagia that is unrelated to tumor burden, most often due to the development of auto-immune antibodies targeting esophageal tissue. Due to the rarity of this condition, diagnosis is often delayed, leading to increased time to treatment. Here we report a case of a rare paraneoplastic achalasia in a female child with EBV+Hodgkin lymphoma, review literature describing paraneoplastic achalasia, and discuss treatment strategies for improving clinical outcome in these patients.

    View details for DOI 10.1080/07357907.2020.1852412

    View details for PubMedID 33191790

  • Summary of COVID-19 clinical practice adjustments across select institutions PEDIATRIC BLOOD & CANCER Schultz, L., Link, M. P., Rheingold, S., Hawkins, D. S., Dome, J. S., Wickiser, J., Kung, A. L., Henderson, T. O., Aftandilian, C. 2020

    View details for DOI 10.1002/pbc.28411

    View details for Web of Science ID 000549825100001

  • Summary of COVID-19 clinical practice adjustments across select institutions. Pediatric blood & cancer Schultz, L., Link, M. P., Rheingold, S., Hawkins, D. S., Dome, J. S., Wickiser, J., Kung, A. L., Henderson, T. O., Aftandilian, C. 2020: e28411

    View details for DOI 10.1002/pbc.28411

    View details for PubMedID 32779834

  • Home or Away from Home: A Multi-Institution Study Comparing Medical Outcomes, Patient Perspectives, and Health-Related Quality of Life for Outpatient Versus Inpatient Management after Chemotherapy for Pediatric Acute Myeloid Leukemia Getz, K. D., Li, Y., Szymczak, J. E., Aftandilian, C., Arnold, S. D., Bona, K. O., Caywood, E., Collier, A. B., Gramatges, M., Henry, M., Lotterman, C., Maloney, K., Mian, A., Mody, R., Raetz, E. A., Rubnitz, J., Verma, A., Winick, N., Wilkes, J. J., Yu, J. C., Fisher, B. T., Aplenc, R. AMER SOC HEMATOLOGY. 2019
  • CONTINUATION OF TYROSINE KINASE INHIBITORS AFTER CHEMOTHERAPY IN PH plus ACUTE LYMPHOBLASTIC LEUKEMIA Smith, S., Aftandilian, C. WILEY. 2019
  • CHROMATIN REMODELING THERAPY AND CAPIZZI METHOTREXATE IN TREATMENT-RELATED MDS/AML Aftandilian, C., Sakamoto, K., Davis, K., Dahl, G., Lacayo, N. WILEY. 2019
  • Mucormycosis diagnosed during induction chemotherapy in five pediatric patients with acute lymphoblastic leukemia. Pediatric blood & cancer Aftandilian, C., Eguiguren, L., Mathew, R., Messner, A. 2019: e27834

    Abstract

    Mucormycosis in pediatric oncology patients is a rare invasive fungal infection associated with significant morbidity and mortality. We describe five patients diagnosed with mucormycosis during induction chemotherapy for acute lymphoblastic leukemia at our institution. All of the patients in our series survived, some in spite of having disseminated disease. Most of the patients' chemotherapy was modified with the aim of controlling their leukemia while minimizing immunosuppression until their fungal infection was under control. Although mucormycosis is frequently fatal, rapid diagnosis and a multidisciplinary approach can lead to excellent outcomes, even in patients undergoing intensive chemotherapy.

    View details for DOI 10.1002/pbc.27834

    View details for PubMedID 31131954

  • Chromation Remodeling Therapy and Capizzi Methotrexate in Treatment-Related MDS/AML Aftandilian, C., Sakamoto, K. M., Davis, K. L., Dahl, G., Lacayo, N. J. AMER SOC HEMATOLOGY. 2018
  • Comparison of the Transcriptomic Signature of Pediatric Vs. Adult CML and Normal Bone Marrow Stem Cells Chae, H., Murphy, L. C., Donato, M., Lee, A. G., Sweet-Cordero, E., Abidi, P., Bittencourt, H., Lacayo, N. J., Dahl, G., Aftandilian, C., Davis, K. L., Huang, M., Sumarsono, N., Redell, M., Fu, C. H., Chen, I. L., Alonzo, T. A., Eklund, E. A., Gotlib, J. R., Khatri, P., Hijiya, N., Sakamoto, K. M. AMER SOC HEMATOLOGY. 2018
  • Multisite external validation of a risk prediction model for the diagnosis of blood stream infections in febrile pediatric oncology patients without severe neutropenia (vol 123, pg 3781, 2017) CANCER Esbenshade, A. J., Zhao, Z., Aftandilian, C. 2018; 124 (8): 1841-1844

    View details for DOI 10.1002/cncr.31306

    View details for Web of Science ID 000429411900027

  • Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia PEDIATRIC BLOOD & CANCER Szymczak, J. E., Getz, K. D., Madding, R., Fisher, B., Raetz, E., Hijiya, N., Gramatges, M. M., Henry, M., Mian, A., Arnold, S. D., Aftandilian, C., Collier, A. B., Aplenc, R. 2018; 65 (4)

    View details for DOI 10.1002/pbc.26927

    View details for Web of Science ID 000425642100028

  • Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia. Pediatric blood & cancer Szymczak, J. E., Getz, K. D., Madding, R., Fisher, B., Raetz, E., Hijiya, N., Gramatges, M. M., Henry, M., Mian, A., Arnold, S. D., Aftandilian, C., Collier, A. B., Aplenc, R. 2018; 65 (4)

    Abstract

    Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.

    View details for DOI 10.1002/pbc.26927

    View details for PubMedID 29286570

  • Multisite external validation of a risk prediction model for the diagnosis of blood stream infections in febrile pediatric oncology patients without severe neutropenia. Cancer Esbenshade, A. J., Zhao, Z., Aftandilian, C., Saab, R., Wattier, R. L., Beauchemin, M., Miller, T. P., Wilkes, J. J., Kelly, M. J., Fernbach, A., Jeng, M., Schwartz, C. L., Dvorak, C. C., Shyr, Y., Moons, K. G., Sulis, M., Friedman, D. L. 2017

    Abstract

    Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness.A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables.From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI.The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017. © 2017 American Cancer Society.

    View details for DOI 10.1002/cncr.30792

    View details for PubMedID 28542918

  • Pediatric Oncology Discharges With Febrile Neutropenia: Variation in Location of Care JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Alvarez, E., Chamberlain, L. J., Aftandilian, C., Saynina, O., Wise, P. 2017; 39 (1): E1-E7

    Abstract

    We examined the use of Pediatric Cancer Specialty Centers (PCSCs) over time and the length of stay (LOS) in pediatric oncology patients with a diagnosis of febrile neutropenia. PCSCs were defined as Children's Oncology Group and California Children's Services designated centers. We performed a retrospective analysis on all discharges of pediatric (0 to 18) oncology patients with febrile neutropenia in California (1983 to 2011) using the private Office of Statewide Health Planning and Development database. We examined influence of age, sex, race/ethnicity, payer, income, distance, tumor type, and complications on utilization of PCSCs and LOS (SAS 9.2). Analysis of 24,559 pediatric oncology febrile neutropenia discharges showed hospitalizations in PCSCs increasing from 48% in 1983 to 94% in 2011. The adjusted regression analysis showed decreased PCSC utilization for ages 15 to 18, Hispanic patients, and those living >40 miles away. The median PCSC LOS was 9 days compared with 7 days at a non-PCSC (P<0.0001). Discharge from a PCSC was associated with a LOS >8 days after controlling for complications. Inpatient PCSC care for febrile neutropenia in California has increased since 1983. Receiving care at a PCSC is influenced by age, tumor type, ethnicity, geography, and complications.

    View details for DOI 10.1097/MPH.0000000000000716

    View details for Web of Science ID 000391634100001

    View details for PubMedID 27918351

  • Invasive Fungal Disease in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Aftandilian, C., Weinberg, K., Willert, J., Kharbanda, S., Porteus, M., Maldonado, Y., Agarwal, R. 2016; 38 (7): 574-580
  • Invasive Fungal Disease in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant. Journal of pediatric hematology/oncology Aftandilian, C., Weinberg, K., Willert, J., Kharbanda, S., Porteus, M., Maldonado, Y., Agarwal, R. 2016; 38 (7): 574-580

    Abstract

    Invasive fungal disease (IFD) remains a major cause of morbidity and mortality in pediatric patients after allogeneic hematopoietic stem cell transplant (HSCT). We analyzed the outcome of 152 consecutive pediatric patients who underwent allogeneic HSCT from 2005 to 2012: 126 of these without a history of IFD and 26 with IFD before HSCT. Antifungal prophylaxis agent was determined by the primary transplant attending. The rate of IFD after HSCT among patients with or without prior IFD was similar (7.7% with and 7.1% without a history of fungal disease before transplant). Mortality in these 2 populations did not differ (35% vs. 28%, P=0.48, χ). Patients deemed at higher risk for IFD were generally placed on voriconazole prophylaxis; however, this did not affect rates of posttransplant IFD. All-cause mortality in patients with posttransplant IFD was significantly higher than those without posttransplant IFD (67% vs. 21%, P<0.0001,χ). Identifying risk factors for posttransplant IFD remains a high priority to improve outcome of HSCT.

    View details for DOI 10.1097/MPH.0000000000000629

    View details for PubMedID 27658021

  • Evaluation of Febrile, Nonneutropenic Pediatric Oncology Patients with Central Venous Catheters Who Are Not Given Empiric Antibiotics JOURNAL OF PEDIATRICS Bartholomew, F., Aftandilian, C., Andrews, J., Gutierrez, K., Luna-Fineman, S., Jeng, M. 2015; 166 (1): 157-162

    Abstract

    To evaluate the practice of empiric antibiotics for febrile, nonneutropenic pediatric oncology patients with a central venous catheter (CVC) in place.Episodes of fever without neutropenia (absolute neutrophil count [ANC] ≥500 cells/mm(3)) were reviewed retrospectively in pediatric oncology patients with a CVC undergoing chemotherapy. Characteristics and symptoms were compared between patients with bacteremia and patients without bacteremia.A total of 392 episodes of nonneutropenic fever in 138 subjects (52 females; 38%) were reviewed. In this cohort, the median age at an episode was 7 years, and the majority of patients had a diagnosis of acute leukemia (54%). Median ANC was 3100 cells/mm(3) (IQR, 1570-5980 cells/mm(3)). Median temperature was 38.7°C (IQR, 38.3-39.2°C). Twenty-four infectious episodes (6%) occurred in 18 subjects, and 5 CVCs required removal; all patients requiring removal admitted and received antibiotics owing to chills. There were no significant difference in age, sex, or ANC between patients with bacteremia and those without bacteremia; however, mean temperature was higher in the patients with bacteremia (39.4°C vs 38.7°C; P = .003). No deaths due to sepsis occurred, and no CVCs were removed because antibiotics were not administered empirically.Our practice of observing pediatric oncology patients undergoing chemotherapy with CVCs who are not neutropenic does not appear to lead to increased serious adverse outcomes and avoids antibiotic exposure for >90% of patients without a bacterial infection.

    View details for DOI 10.1016/j.jpeds.2014.09.008

    View details for PubMedID 25444524

  • Incidence and Mortality of Invasive Fungal Disease in Pediatric Patients after Allogeneic Stem Cell Transplant Aftandilian, C., Agarwal, R., Kharbanda, S., Weinberg, K. I. ELSEVIER SCIENCE INC. 2014: S165
  • Outcome in Pediatric Patients with a History of Fungal Disease Prior to Allogeneic Stem Cell Transplant Aftandilian, C., Agarwal, R., Kharbanda, S., Weinberg, K. I. ELSEVIER SCIENCE INC. 2014: S165
  • The Neutropenic Diet ... Still Ageless? C. Aftandilian Article Reviewed ONCOLOGY-NEW YORK Aftandilian, C. C., Milotich, C., Sakamoto, K. M. 2012; 26 (6): 586-589
  • The neutropenic diet... still ageless? Oncology (Williston Park, N.Y.) Aftandilian, C. C., Milotich, C., Sakamoto, K. M. 2012; 26 (6): 586-?

    View details for PubMedID 22870544

  • Burkitt Lymphoma With Pancreatic Involvement JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Aftandilian, C. C., Friedmann, A. M. 2010; 32 (8): E338-E340

    Abstract

    A 10-year-old boy was referred to our clinic for tonsillectomy and was found to have a large mass within his oropharynx. Intraoperative biopsies confirmed Burkitt lymphoma. Further imaging and biopsy revealed pancreatic involvement. He was treated with multiagent chemotherapy. He remains disease-free 6 years later. Review of the literature demonstrates other cases of non-Hodgkin lymphoma with pancreatic involvement with good outcomes. Pancreatic involvement is a relatively rare occurrence in childhood lymphoma.

    View details for DOI 10.1097/MPH.0b013e3181ed1178

    View details for Web of Science ID 000283538300021

    View details for PubMedID 20930650

  • Group therapy for substance use disorders: What do we know? HARVARD REVIEW OF PSYCHIATRY Weiss, R. D., Jaffee, W. B., de Menil, V. P., Cogley, C. B. 2004; 12 (6): 339-350

    Abstract

    Although group therapy is the most prevalent treatment modality for substance use disorders, an up-to-date review of treatment outcome literature does not exist. A search of the literature yielded 24 treatment outcome studies comparing group therapy to other treatment conditions. These studies fell into one of six research design categories: (1) group therapy versus no group therapy; (2) group therapy versus individual therapy; (3) group therapy plus individual therapy versus group therapy alone; (4) group therapy plus individual therapy versus individual therapy alone; (5) group therapy versus another group therapy with different content or theoretical orientation; and (6) more group therapy versus less group therapy. In general, treatment outcome studies did not demonstrate differences between group and individual modalities, and no single type of group therapy reliably demonstrated greater efficacy than others. Unique methodological and logistical hurdles encountered in research on group therapy for substance use disorders, as well as considerations for future research, are also discussed.

    View details for DOI 10.1080/1067322049095723

    View details for Web of Science ID 000226593100004

    View details for PubMedID 15764469

  • Requiring remission of undue influence of weight and shape on self-evaluation in the definition of recovery for bulimia nervosa Annual Conference of the Academy-for-Eating-Disorders Cogley, C. B., Keel, P. K. JOHN WILEY & SONS INC. 2003: 200–210

    Abstract

    The current study evaluated the concurrent validity of requiring remission of undue influence of weight and shape on self-evaluation (undue influence) in defining recovery from bulimia nervosa (BN).Three groups completed the Beck Depression Inventory, the Mood and Anxiety Symptom Questionnaire, the Body Shape Questionnaire, and the Social Adjustment Scale: 31 women were fully recovered from BN (FR), 28 women had no behavioral symptoms of BN (partially recovered [PR]), and 59 matched non-eating-disordered controls (MC).The PR group had more pathologic scores on depression, anxiety, body dissatisfaction, and social adjustment compared with both the FR and MC groups, which did not differ from each other.These findings suggest that including remission of cognitive symptoms in a standardized definition of recovery may prove to be clinically useful in establishing reliable prognostic indicators. Future research should evaluate the role played by cognitive symptoms in triggering relapse.

    View details for DOI 10.1002/eat.10187

    View details for Web of Science ID 000184510900003

    View details for PubMedID 12898556