Research Spotlight

Mannon, R. B., M. Askar, A. M. Jackson, K. Newell and M. Mengel (2018). “Meeting report of the STAR-Sensitization in Transplantation Assessment of Risk: Naive Abdominal Transplant Organ subgroup focus on kidney transplantation.” Am J Transplant 18(9): 2120-2134.

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The development of de novo donor-specific HLA antibody (dnDSA) is a critical feature contributing to late allograft failure. The complexity of the issue is further complicated by organ-specific differences, detection techniques, reliance of tissue histopathology and changing diagnostic criteria, ineffective therapies, and lack of consensus. To tackle these issues, the Sensitization in Transplantation Assessment of Risk (STAR) 2017 was initiated as a collaboration of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics consisting of 8 working groups with the goal to provide guidelines on how to assess risk and risk stratify patients based on their potential alloimmune and DSA status. Herein is a summary of discussions by the Naive Abdominal Working Group, highlighting currently available data and identifying gaps in our knowledge on the development and impact of dnDSA following kidney transplantation.

Liu, E., S. Paulson, A. Gulati, J. Freudman, W. Grosh, S. Kafer, P. C. Wickremesinghe, R. R. Salem and L. Bodei (2018). “Assessment of NETest Clinical Utility in a U.S. Registry-Based Study.” Oncologist Aug 29. [Epub ahead of print].

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BACKGROUND: The clinical relevance of molecular biomarkers in oncology management has been recognized in breast and lung cancers. We evaluated a blood-based multigene assay for management of neuroendocrine tumors (NETs) in a real-world study (U.S. registry NCT02270567). Diagnostic accuracy and relationship to clinical disease status in two cohorts (treated and watch-and-wait) were evaluated. MATERIALS AND METHODS: Patients with NETs (n = 100) were followed for 6-12 months. Patients’ primary tumors were gastroenteropancreatic (68%), lung 20%, and of unknown origin (12%). Characteristics included well-differentiated, low-grade tumors (97%), stage IV disease (96%); treatment with surgery (70%); and drug treatment (56%). NETest was measured at each visit and disease status determined by RECIST. Scores categorized as low (NETest 14%-40%) or high (>/=80%) defined disease as stable or progressive. Multivariate analyses determined the strength of the association with progression-free survival (PFS). RESULTS: NETest diagnostic accuracy was 96% and concordant (95%) with image-demonstrable disease. Scores were reproducible (97%) and concordant with clinical status (98%). The NETest was the only feature linked to PFS (odds ratio, 6.1; p < .0001). High NETest correlated with progressive disease (81%; median PFS, 6 months), and low NETest correlated with stable disease (87%; median PFS, not reached). In the watch-and-wait cohort, low NETest was concordant with stable disease in 100% of patients, and high NETest was associated with management changes in 83% of patients. In the treated cohort, all low NETest patients (100%) remained stable. A high NETest was linked to intervention and treatment stabilization (100%). Use of NETest was associated with reduced imaging (biannual to annual) in 36%-38% of patients. CONCLUSION: Blood NETest is an accurate diagnostic and can be of use in monitoring disease status and facilitating management change in both watch-and-wait and treatment cohorts. IMPLICATIONS FOR PRACTICE: A circulating multigene molecular biomarker to guide neuroendocrine tumor (NET) management has been developed because current biomarkers have limited clinical utility. NETest is diagnostic (96%) and in real time defines the disease status (>95%) as stable or progressive. It is >90% effective in guiding treatment decisions in conjunction with diagnostic imaging. Monitoring was effective in watch-and-wait or treatment groups. Low levels supported no management change and reduced the need for imaging. High levels indicated the need for management intervention. Real-time liquid biopsy assessment of NETs has clinical utility and can contribute additional value to patient management strategies and outcomes.

Levy, M. Y., L. J. McGarry, H. Huang, S. Lustgarten, S. Chiroli and S. Iannazzo (2018). “Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.” Curr Med Res Opin Aug 24: 1-9. [Epub ahead of print].

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OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects’ baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) – complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

Kearns, N. T., M. B. Powers, W. T. Jackson, T. R. Elliott and T. Ryan (2018). “Posttraumatic stress disorder symptom clusters and substance use among patients with upper limb amputations due to traumatic injury.” Disabil Rehabil Sep 5: 1-8. [Epub ahead of print].

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PURPOSE: Examining the relationship between posttraumatic stress disorder and posttraumatic stress disorder symptom clusters (re-experiencing, avoidance, hyperarousal, emotional numbing) on three substance use measures among individuals with upper limb amputation due to traumatic injury – an understudied population with high rates of posttraumatic stress disorder. METHODS: Multi-site, cross-sectional design. Participants (N = 236) were recruited from seven prosthetic rehabilitation centres across the USA and completed measures of PTSD, alcohol use, prescription medication overuse, and illicit drug use. RESULTS: Twenty-six percent of participants screened positive for posttraumatic stress disorder, 39% for problematic alcohol use, 12% for prescription medication overuse, and 7% for illicit drug use. No association was found between posttraumatic stress disorder or posttraumatic stress disorder symptoms clusters on problematic alcohol use. However, hyperarousal symptoms increased odds of overusing prescription medication (odds ratio = 3.30); further, a positive screen for posttraumatic stress disorder increased odds of illicit drug use (odds ratio = 2.95). CONCLUSIONS: These findings demonstrate the importance of assessing psychological well-being and a variety of substance use behaviours following amputation from traumatic injury. These findings may also provide clinically-relevant targets for prevention and intervention regarding prescription medication and illicit substance use, such as incorporating evidence-based treatment for posttraumatic stress disorder hyperarousal symptoms (e.g., prolonged exposure) and/or integrated treatment for posttraumatic stress-substance misuse (e.g., Seeking Safety) into patients’ long-term inpatient/outpatient rehabilitation plans. Implications for rehabilitation Posttraumatic stress disorder hyperarousal symptoms increased odds of overusing prescription medication among individuals with upper limb amputation due to traumatic injury; a positive screen for posttraumatic stress disorder increased odds of illicit drug use. Psychological assessments should be incorporated into treatment and rehabilitation plans following amputation from traumatic injury. Rehabilitation specialists should consider adding or integrating evidence-based treatment for posttraumatic stress disorder into patients’ long-term rehabilitation plan to reduce risk for problematic substance use. Findings support calls by the Centre for Disease Control and Prevention to overhaul prescription medication guidelines, including the need to assess risk and address harms concerning overuse of prescription medication.

Kearns, N. T., J. K. Peterson, L. Smurr Walters, W. T. Jackson, J. M. Miguelez and T. Ryan (2018). “Development and Psychometric Validation of Capacity Assessment of Prosthetic Performance for the Upper Limb (CAPPFUL).” Arch Phys Med Rehabil 99(9): 1789-1797.

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OBJECTIVES: (1) To develop a performance-based measure for adult upper limb (UL) prosthetic functioning through broad (ie, overall performance) and functional domain-specific (eg, control skills) assessment of commonplace activities; (2) to conduct initial psychometric evaluation of the Capacity Assessment of Prosthetic Performance for the Upper Limb (CAPPFUL). DESIGN: Internal consistency of CAPPFUL and interrater reliability for task, functional domain, and full-scale (sub)scores among 3 independent raters were estimated. Known-group validity was examined comparing scores by amputation level. Convergent validity was assessed between CAPPFUL and 2 hand dexterity or function tests; discriminant validity was assessed against self-reported disability. SETTING: Six prosthetic rehabilitation centers across the United States. PARTICIPANTS: Subjects (N=60) with UL amputation using a prosthesis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Interrater reliability was excellent for scoring on the task, domain, and full-scale scores (intraclass correlation coefficients=.88-.99). Internal consistency was good (alpha=.79-.82). Generally, subjects with higher UL amputation levels scored lower (worse) than subjects with lower UL amputation levels. CAPPFUL demonstrated strong correlations with measures of hand dexterity or functioning (rs=-.58 to .72) and moderate correlation with self-reported disability (r=-.35). CONCLUSIONS: CAPPFUL was designed as a versatile, low-burden measure of prosthesis performance for any UL functional prosthetic device type and any UL amputation level. CAPPFUL assesses overall performance and 5 functional performance domains during completion of 11 tasks that require movement in all planes while manipulating everyday objects requiring multiple grasp patterns. Psychometric evaluation indicates good interrater reliability, internal consistency, known-group validity, and convergent and discriminant validity.