The molecular diversity of receptors in human blood vessels remains largely unexplored. We developed a selection method in which peptides that home to specific vascular beds are identified after administration of a peptide library. Here we report the first in vivo screening of a peptide library in a patient. We surveyed 47,160 motifs that localized to different organs. This large-scale screening indicates that the tissue distribution of circulating peptides is nonrandom. High-throughput analysis of the motifs revealed similarities to ligands for differentially expressed cell-surface proteins, and a candidate ligand-receptor pair was validated. These data represent a step toward the construction of a molecular map of human vasculature and may have broad implications for the development of targeted therapies.

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 NIH Clinical Center’s 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, 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. The manuscript describes areas of agreement as well as 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.

Context Most children diagnosed as having leukemia become research subjects in randomized clinical trials (RCTs), but little is known about how randomization is explained to or understood by parents. Objective To investigate physicians' explanation and parental understanding of randomization in childhood leukemia RCTs. Design and Setting A multisite study of the informed consent communication process for RCTs of childhood leukemia. Consecutive cases were recruited from pediatric oncology inpatient wards at 6 US children's hospitals associated with major academic medical centers from July 1, 1999, until December 31, 2001. The informed consent conferences were observed and audiotaped, and the information obtained was coded and analyzed. Parents were interviewed shortly after the conference to ascertain their understanding. Participants Parents and members of the health care team who participated in 137 informed consent conferences for children with newly diagnosed acute leukemia. Main Outcome Measures Observed explanations of randomization and parental understanding of randomization after the consent conference. Results Randomization was explained by physicians in 83% of cases and a consent document was presented during the conference in 95% of cases. Interviews after the conference demonstrated that 68 (50%) of 137 parents did not understand randomization. Parents of racial minority and lower socioeconomic status were less likely to understand randomization (PϽ.001 for each). Discussion of specific clinical trial details and the presence of a nurse during the conference were associated with understanding. Eighty-four percent of children were enrolled in a leukemia trial. Conclusions Despite oral and written explanation, half of the parents in this study did not understand randomization for childhood leukemia trials. To make informed consent more effective, future research must seek to improve communication during this critical interchange.

Minority U.S. populations are underrepresented in cancer clinical trials. This review appraises the impact of the disparity in clinical trial participation by minority patients in the current era of cancer immunotherapy. Enrollment on pivotal trials leading to U.S. regulatory approval of immune checkpoint inhibitors showed poor representation of minority ethnic groups. Specifically, we found that black patients constitute less than 4% of all patients enrolled across multiple trials that supported the approval of immune checkpoint inhibitors for the treatment of lung cancer. Similar underrepresentation was observed for trials conducted in renal cell carcinoma and other tumor types. Since efficacy of immunotherapy is only observed in a subset of patients, the use of predictive biomarkers to identify responders along with new strategies to expand the benefit to a larger subset of patients are current areas of active investigation. The inadequate representation of minority patients on immunotherapy clinical trials could perpetuate outcome disparity because the unique biology of the host and the tumors from this subpopulation is not accounted for as new treatment algorithms to guide optimal use of immunotherapy are developed for use in the real world.

Background Ethical concerns about Phase I 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. Methods We queried 95 Phase I subjects to provide a more sophisticated estimate of the proportion who had therapeutic misconception (TM) - misunderstands the research purpose or how research differs from individualized care - and therapeutic misestimation (TMis) -misestimates the chance of research trial benefit as >20% or underestimates risk as 0%. Results 65/95 (68.4%) respondents had TM, associated in a multivariate analysis with lower education and family income (p= 0.008, p = 0.001), but TM was not associated with the vulnerability of having hardly any treatment options. 89/95 (94%) had TMis, though only 18% reported this was a factual estimate. Although risks of investigational agents and those exacerbated by research, such as uncertain outcomes, were mentioned (39%, 41% respondents respectively), risks novel to research, such as research biopsies, were rarely mentioned (3%). Although most of these respondents thought their chance of benefit was higher and risk lower than the population chance (optimists) (54.6%), a substantial minority (37.6%) were pessimists. Conclusions TM continues to be prevalent. Estimates of personal benefit were not usually meant to report facts so it is unknown whether respondents had TMis. Although not more vulnerable, Phase I participants need improved understanding of key TM concepts, with attention to risks not found in standard of care.

Proposals on consent for research with biological samples should be informed by empirical studies of individuals' views. Studies to date queried mostly white research subjects. The aim of this study was to compare the views of two groups of patients: cancer patients at a university clinic (Winship Cancer Institute at Emory Healthcare) and cancer patients at an inner city county hospital (Grady) who were given the option of tissue banking. Overall, 315/452 (70%) patients completed the survey. The Grady cohort was 86% African American; the Winship cohort was 82% White. The vast majority (95%) of individuals in both cohorts agreed to provide a biological sample for future research. Both cohorts were willing for their samples to be used to study cancer and other diseases, including Alzheimer disease. Few participants preferred to control the disease to be studied (10%) or wished to be contacted again for consent for each future research project (11%). In our sample, almost all clinical patients, regardless of site of care, ethnicity or socioeconomic status, were willing to provide a biological sample for research purposes and allow investigators to determine the research to be done without contacting the patients again. These findings support the recommendation to offer individuals a simplified consent with a one-time binary choice whether to provide biological samples for future research.

A B S T R A C T PurposeThere 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. MethodsA 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. ResultsFour hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n ϭ 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 ϭ 238; 58.2%) or a phone call followed by a letter (n ϭ 100; 24.4%). If the results were negative, phone call (n ϭ 136; 33.3%) or personal visits (n ϭ 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n ϭ 341; 83.4%), effect on future treatments (n ϭ 341; 83.4%), and subsequent research steps (n ϭ 284; 69.5%). Understanding the researcher was a main concern about receiving results (n ϭ 145; 35.5%). Parents felt that results provide information to support quality of life (n ϭ 315; 77%) and raise public awareness of research (n ϭ 282; 68.9%). Adolescents identified similar preferences. ConclusionParents 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.

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 × 10 6 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. To discover or analyze functional ligand-receptor interactions in blood vessels under disease conditions, we have used combinatorial screenings based on phage display, which has enabled the targeted delivery of agents to specific vascular beds (8,9). This approach allows the selection of homing peptides to specific organs in vivo after systemic administration of random peptide libraries (10, 11). We have isolated ligand peptides and identified their tissue-specific receptors in rodents and in a patient, and have developed a ligand-receptor in prostate cancer (12, 13) that serves as the basis for an ongoing first-in-man trial.Over the past few years we have developed a tripartite approach to enable serial combinatorial selections to humans. First, we established an ethical framework to ensure respectful research in patients who were brain-dead or whose families decided to terminate life support (14,15). Second, we adapted techniques that were validated in rodents (16) to enable synchronous selection of ligands to multiple organs. Third, we integrated genomic tools, in which recovery of 10 6 peptides is ∼1;000-fold faster and ∼250-fold cheaper (17). Here, these quantitative and qualitative methods enabled refined combinatorial selections in patients and identified unique ligand-receptors.