Rebecca D. Pentz

Broad Consent for Research With Biological Samples: Workshop Conclusions.

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Centers Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

Therapeutic Misconception, Misestimation, and Optimism in Participants Enrolled in Phase 1 Trials

Ethical concerns about phase 1 trials persist. Important conceptual advances have been made in understanding concepts used to describe misunderstanding. However, a systematic, empirical evaluation of the frequency of misunderstanding incorporating recent developments is lacking.

The Return of Research Results to Participants: Pilot Questionnaire of Adolescents and Parents of Children with Cancer

The offer to return research results to participants is increasingly recognized as an ethical obligation, although few researchers routinely return results. We examined the needs and attitudes of parents of children with cancer and of adolescents with cancer to the return of research results.

Providing Research Results to Participants: Attitudes and Needs of Adolescents and Parents of Children With Cancer

PURPOSE There is an increasing demand for researchers to provide research results to participants. Our aim was to define an appropriate process for this, based on needs and attitudes of participants. METHODS A multicenter survey in five sites in the United States and Canada was offered to parents of children with cancer and adolescents with cancer. Respondents indicated their preferred mode of communication of research results with respect to implications; timing, provider, and content of the results; reasons for and against providing results; and barriers to providing results. RESULTS Four hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n = 385; 94.2%) felt that they had a strong right to research results. For positive results, most wanted a letter or e-mail summary (n = 238; 58.2%) or a phone call followed by a letter (n = 100; 24.4%). If the results were negative, phone call (n = 136; 33.3%) or personal visits (n = 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n = 341; 83.4%), effect on future treatments (n = 341; 83.4%), and subsequent research steps (n = 284; 69.5%). Understanding the researcher was a main concern about receiving results (n = 145; 35.5%). Parents felt that results provide information to support quality of life (n = 315; 77%) and raise public awareness of research (n = 282; 68.9%). Adolescents identified similar preferences. CONCLUSION Parents of children with cancer and adolescents with cancer feel strongly that they have a right to be offered research results and have specific preferences of how and what information should be communicated.

Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients

Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ∼2.35 × 106 motifs recovered from biopsies yielded a nonrandom distribution, indicating that systemic tissue targeting is feasible. High-throughput analysis by similarity search, protein arrays, and affinity chromatography revealed four native ligand-receptors, three of which were previously unrecognized. Two are shared among multiple tissues (integrin α4/annexin A4 and cathepsin B/apolipoprotein E3) and the other two have a restricted and specific distribution in normal tissue (prohibitin/annexin A2 in white adipose tissue) or cancer (RAGE/leukocyte proteinase-3 in bone metastases). These findings provide vascular molecular markers for biotechnology and medical applications.

Bioethical considerations of monoclonal B‐cell lymphocytosis: donor transfer after haematopoietic stem cell transplantation

Monoclonal B‐cell lymphocytosis (MBL) is a recently described laboratory finding in otherwise healthy individuals. In MBL, a light chain‐restricted, clonal B‐cell population, often with a chronic lymphocytic leukaemia (CLL) phenotype, is identified by flow cytometry. Although the prognostic significance remains unclear, there is an increased incidence in ageing populations and those with a family history of CLL. During the past decade of MBL study, three families have come to our attention in which prospective sibling haematopoietic stem cell donors were found to have an MBL. These families raise complex bioethical issues with regard to disclosure of research data, eligibility for clinical trials and potential donor transfer of MBL. These issues are explored in this report. Identification of MBL among prospective sibling transplant donors will become a common occurrence in transplant practice as transplantation is increasingly offered to older individuals and those with CLL.

Decision-making by Adolescents and Parents of Children with Cancer Regarding Health Research Participation

BACKGROUND: Low rates of participation of adolescents and young adults (AYAs) in clinical oncology trials may contribute to poorer outcomes. Factors that influence the decision of AYAs to participate in health research and whether these factors are different from those that affect the participation of parents of children with cancer. METHODS: This is a secondary analysis of data from validated questionnaires provided to adolescents (>12 years old) diagnosed with cancer and parents of children with cancer at 3 sites in Canada (Halifax, Vancouver, and Montreal) and 2 in the United States (Atlanta, GA, and Memphis, TN). Respondents reported their own research participation and cited factors that would influence their own decision to participate in, or to provide parental authorization for their child to participate in health research. RESULTS: Completed questionnaire rates for AYAs and parents were 86 (46.5%) of 185 and 409 (65.2%) of 627, respectively. AYAs (n = 86 [67%]) and parents (n = 409 [85%]) cited that they would participate in research because it would help others. AYAs perceived pressure by their family and friends (16%) and their physician (19%). Having too much to think about at the time of accrual was an impediment to both groups (36% AYAs and 47% parents). The main deterrent for AYAs was that research would take up too much time (45%). Nonwhite parents (7 of 56 [12.5%]) were more apt to decline than white parents (12 of 32 [3.7%]; P < .01). CONCLUSIONS: AYAs identified time commitment and having too much to think about as significant impediments to research participation. Addressing these barriers by minimizing time requirements and further supporting decision-making may improve informed consent and impact on enrollment in trials.

Psychological functioning in persons considering genetic counseling and testing for Li-Fraumeni syndrome

Objective: Li–Fraumeni syndrome (LFS) confers an increased risk of multiple types of cancer in both children and adults. Clinical genetic testing for deleterious germline p53 gene mutations can identify most LFS‐affected families. We evaluated factors associated with cancer‐specific distress and perceived self‐efficacy in coping with a positive genetic test result among persons at risk of having deleterious p53 mutations.

Evaluation of a decision aid for families considering p53 genetic counseling and testing.

Purpose: Li-Fraumeni syndrome (LFS) is associated with p53 germline mutations, and carriers are at increased risk for multiple primary cancers. We evaluated outcomes following the administration of a video-based decision aid (DA) prior to clinical p53 genetic counseling and testing among persons who had previously participated in cancer genetics research.Methods: Fifty-seven individuals at risk for a known p53 mutation completed baseline and post-DA measures of psychological outcomes, plus knowledge and attitudes regarding p53 genetic testing. Counseling and testing uptake also was recorded.Results: At baseline, multivariate analysis showed that greater testing intention was associated with lower decisional conflict (P < 0.01). Compared with baseline data, multivariate analyses of post-DA outcomes showed that knowledge about LFS and genetic testing increased and decisional conflict related to testing decreased (P < 0.001). Mean cancer worries scores decreased among all participants (P < 0.001), and mean depression scores decreased for males (P < 0.05). Thirty-nine (68%) completed pre-test genetic counseling and 23 (40%) subsequently gave a blood sample for clinical genetic testing.Conclusion: This intervention was useful as an initial outreach and educational method for families considering p53 genetic testing, and may improve knowledge about LFS as well as psychological outcomes.

Real-World Effectiveness of Systemic Agents Approved for Advanced Non-Small Cell Lung Cancer: A SEER–Medicare Analysis

OBJECTIVES Disparity exists between patients with lung cancer enrolled in clinical trials and patients treated in the community setting. This study assessed the real-world effectiveness of cytotoxic agents that became available for the treatment of non-small cell lung cancer (NSCLC) in the last 2 decades. METHODS We employed the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage IIIB/IV NSCLC between 1988 and 2005 to assess the effectiveness of newly approved agents. Effectiveness of specific agents was assessed at time periods immediately following the approval of the agent for NSCLC: baseline, 1988-1994; platinum, 1995-1999; docetaxel, 1999-2003; pemetrexed and bevacizumab, 2004-2005. Significant associations between specific drug treatment and survival improvement were determined using the Kaplan-Meier method, Cox proportional hazard model, and propensity score analyses. Significant differences were established by log-rank test. RESULTS This analysis employed data from 143,548 patients by sex (58% male, 42% female), cancer stage (35% stage IIIB, 65% stage IV), and age (12% 20-64 years, 22% 65-69 years, 45% 70-79 years, 22% 80 years and older). There was temporal improvement in survival for patients treated with newly approved chemotherapy (1-year survival rates: 32.41% in 1988-1994, 32.95% in 1995-1998, 37.40% in 1999-2003, and 39.55% in 2004-2005). Patients treated with a newly approved drug during the relevant treatment era had a significant reduction in the risk of death when compared with patients treated with chemotherapy other than the newly approved agent (hazard ratios [95% confidence interval] were 0.76 [0.71-0.81] for platinum, 0.73 [0.70-0.75] for docetaxel, 0.40 [0.37-0.44] for pemetrexed, and 0.33 [0.27-0.40] for bevacizumab; p < .001). Propensity score adjustment did not significantly alter these results. CONCLUSIONS Currently approved drugs for the treatment of advanced NSCLC are associated with improved survival in the U.S. Medicare patient population. Our findings support the effectiveness of these agents in the real-world oncology practice.