Research Spotlight

Smith, J. W., 2nd, S. Vukelja, A. D. Hoffman, V. E. Jones, K. McIntyre, E. Berrak, J. X. Song and J. O’Shaughnessy (2016). “Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer.” Clin Breast Cancer 16(1): 31-37.

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BACKGROUND: The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m(2) intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m(2) orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of >/= 85%, with a lower 95% confidence boundary > 70%. RESULTS: The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. CONCLUSION: Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m(2) on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation.

Strasser-Weippl, K., N. Horick, I. E. Smith, J. O’Shaughnessy, B. Ejlertsen, F. Boyle, A. U. Buzdar, P. Fumoleau, W. Gradishar, M. Martin, B. Moy, M. Piccart-Gebhart, K. I. Pritchard, D. Lindquist, E. Rappold, D. M. Finkelstein and P. E. Goss (2016). “Identification of early breast cancer patient cohorts who may benefit from lapatinib therapy.” Eur J Cancer 56: 85-92.

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In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial. To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors. Hormone receptor negative (HR-) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR- patients on placebo (hazard ratio 0.64, P=0.003). For patients with HR- disease, starting treatment with lapatinib less and or equal to 1 year from diagnosis improved DFS by 12.1% [2.1-22.1] at 2 years and 15.7% [4.1-27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients <1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA). In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR- patients are in range with those reported from up-front adjuvant trastuzumab trials.

O’Leary, J. G., J. Cai, R. Freeman, N. Banuelos, B. Hart, M. Johnson, L. W. Jennings, H. Kaneku, P. I. Terasaki, G. B. Klintmalm and A. J. Demetris (2016). “Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts.” Am J Transplant 16(2): 603-614.

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Donor-specific alloantibodies (DSA) can cause acute antibody-mediated rejection (AMR) in all solid organ allografts. However, long-term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA- positive [DSA+; mean florescence intensity (MFI) >/=10 000] and -negative (DSA-) recipients of a primary liver-only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA- patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near-normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross-validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10-year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.

Warren, A. M., M. Reynolds, M. L. Foreman, M. M. Bennett, R. J. Weddle, J. D. Austin, K. Roden-Foreman and L. B. Petrey (2016). “Validation of a brief, two-question depression screen in trauma patients.” J Trauma Acute Care Surg 80(2): 318-323.

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BACKGROUND: Increasingly, depression following traumatic injury is recognized as a complication of injury. Unlike mandated screening for risky alcohol use in trauma centers, screening for psychological risks is not required by the American College of Surgeons’ Committee on Trauma. Limited resources and time constraints are commonly given reasons against routine screening. The purpose of this study was to determine if a two-item screen was as valid as an eight-question screen for depression. METHODS: A total of 421 patients were given the Patient Health Questionnaire 8 (PHQ-8) during initial hospitalization to assess depression in a prospective study at a Level I trauma center. A cutoff score of 10 or higher (possible range, 0-24) on the PHQ-8 is used as diagnostic for depression. The PHQ-2 (possible range, 0-6) is derived from the first two questions of the PHQ-8 and contains items assessing sad mood and loss of interest/pleasure during the previous 2 weeks. A cutoff score of 3 or higher was considered to be a positive screen result. Discriminatory ability of the PHQ-2 was calculated. RESULTS: The sample was predominantly male (65%) and white (67%). The majority (85%) sustained a blunt trauma, and the primary cause of injury was motor vehicle collision (37%), with a mean Injury Severity Score (ISS) of 11.6. A total of 142 patients (34%) were positive for depression on the PHQ-8. When comparing the PHQ-2 with the PHQ-8, a sensitivity of 76.1 and a specificity of 92.8 were found, as well as a positive predictive value of 84.4. CONCLUSION: The result of our study confirms that depression is a frequent condition (34%) among individuals who sustain physical injury. The PHQ-2 seems to have acceptable sensitivity and specificity to identify depression in this population. The use of a two-item screening questionnaire is a minimal addition to the evaluation of patients after injury, allowing for earlier intervention and better outcomes. LEVEL OF EVIDENCE: Diagnostic study, level IV; prognostic/epidemiologic study, level III.

Monden, K. R., Z. Trost, W. Scott, K. R. Bogart and S. Driver (2016). “The unfairness of it all: Exploring the role of injustice appraisals in rehabilitation outcomes.” Rehabil Psychol 61(1): 44-53.

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OBJECTIVE: A fundamental principle of rehabilitation psychology is that individual appraisals of the social and physical environment-including injury itself-have profound consequences for coping and adjustment. When core assumptions of a just and predictable world are violated and accompanied by ostensibly undeserved suffering and loss, perceptions of injustice can arise. Given the role of appraisal processes in adjustment to disability, mounting empirical support, and absence of targeted interventions, the current article considers perceptions of injustice regarding personal injury/disability as a fundamental appraisal affecting rehabilitation outcomes. RESEARCH METHOD: The authors review theory underpinning the relevance of injustice appraisals and critically examine existing literature regarding the impact of perceived injustice and related constructs (i.e., attribution of blame, anger, and belief in a just world) on adjustment following injury. RESULTS: The authors bring attention to perceptions of injustice regarding personal injury/disability as a fundamental appraisal affecting rehabilitation outcomes. Dimensions of the social environment that have not received substantial attention in current research on condition-related injustice appraisals are highlighted. IMPLICATIONS: Perceived injustice is a potentially central appraisal process to physical and psychological outcomes in the context of rehabilitation. Research regarding the role of perceived injustice, related constructs, and potential social/environmental modulators of injustice perception is still in its infancy. Guided buy its foundational principles, the field of rehabilitation psychology can broaden and shape inquiry regarding perceived injustice. This article aims to guide future research, offer concepts for key areas of discourse, and consider potential interventions in the rehabilitation psychology domain.