Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells.

Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models.

PURPOSE: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC. EXPERIMENTAL DESIGN: The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells. RESULTS: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFß and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFß and nitric oxide. CONCLUSIONS: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.

Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells.

PURPOSE: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. EXPERIMENTAL DESIGN: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. RESULTS: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. CONCLUSIONS: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.

Experimental Evolution Generates Novel Oncolytic Vesicular Stomatitis Viruses with Improved Replication in Virus-Resistant Pancreatic Cancer Cells.

Vesicular stomatitis virus (VSV) based oncolytic viruses are promising agents against various cancers. We have shown that pancreatic ductal adenocarcinoma (PDAC) cell lines exhibit great diversity in susceptibility and permissibility to VSV. Here, using a directed evolution approach with our two previously described oncolytic VSV recombinants, VSV-p53wt and VSV-p53-CC, we generated novel oncolytic VSVs with an improved ability to replicate in virus-resistant PDAC cell lines. VSV-p53wt and VSV-p53-CC encode a VSV matrix protein (M) with a ΔM51 mutation (M-ΔM51) and one of two versions of a functional human tumor suppressor, p53, fused to a far-red fluorescent protein, eqFP650. Each virus was serially passaged 32 times (which accounts for more than 60 viral replication cycles) on either the SUIT-2 (moderately resistant to VSV) or MIA PaCa-2 (highly permissive to VSV) human PDAC cell lines. While no phenotypic changes were observed for MIA PaCa-2-passaged viruses, both SUIT-2-passaged VSV-p53wt and VSV-p53-CC showed improved replication in SUIT-2 and AsPC-1, another human PDAC cell line also moderately resistant to VSV, while remaining highly attenuated in nonmalignant cells. Surprisingly, two identical VSV glycoprotein (VSV-G) mutations, K174E and E238K, were identified in both SUIT-2-passaged viruses. Additional experiments indicated that the acquired G mutations improved VSV replication, at least in part due to improved virus attachment to SUIT-2 cells. Importantly, no mutations were found in the M-ΔM51 protein, and no deletions or mutations were found in the p53 or eqFP650 portions of virus-carried transgenes in any of the passaged viruses, demonstrating long-term genomic stability of complex VSV recombinants carrying large transgenes.IMPORTANCE Vesicular stomatitis virus (VSV)-based oncolytic viruses are promising agents against pancreatic ductal adenocarcinoma (PDAC). However, some PDAC cell lines are resistant to VSV. Here, using a directed viral evolution approach, we generated novel oncolytic VSVs with an improved ability to replicate in virus-resistant PDAC cell lines, while remaining highly attenuated in nonmalignant cells. Two independently evolved VSVs obtained 2 identical VSV glycoprotein mutations, K174E and E238K. Additional experiments indicated that these acquired G mutations improved VSV replication, at least in part due to improved virus attachment to SUIT-2 cells. Importantly, no deletions or mutations were found in the virus-carried transgenes in any of the passaged viruses. Our findings demonstrate long-term genomic stability of complex VSV recombinants carrying large transgenes and support further clinical development of oncolytic VSV recombinants as safe therapeutics for cancer.

Large Igneous Province thermogenic greenhouse gas flux could have initiated Paleocene-Eocene Thermal Maximum climate change.

Large Igneous Provinces (LIPs) are associated with the largest climate perturbations in Earth's history. The North Atlantic Igneous Province (NAIP) and Paleocene-Eocene Thermal Maximum (PETM) constitute an exemplar of this association. As yet we have no means to reconstruct the pacing of LIP greenhouse gas emissions for comparison with climate records at millennial resolution. Here, we calculate carbon-based greenhouse gas fluxes associated with the NAIP at sub-millennial resolution by linking measurements of the mantle convection process that generated NAIP magma with observations of the individual geological structures that controlled gas emissions in a Monte Carlo framework. These simulations predict peak emissions flux of 0.2-0.5 PgC yr-1 and show that the NAIP could have initiated PETM climate change. This is the first predictive model of carbon emissions flux from any proposed PETM carbon source that is directly constrained by observations of the geological structures that controlled the emissions.

Collaborating on Data, Science, and Infrastructure: The 20-Year Journey of the Cancer Research Network.

The Cancer Research Network (CRN) is a consortium of 12 research groups, each affiliated with a nonprofit integrated health care delivery system, that was first funded in 1998. The overall goal of the CRN is to support and facilitate collaborative cancer research within its component delivery systems. This paper describes the CRN's 20-year experience and evolution. The network combined its members' scientific capabilities and data resources to create an infrastructure that has ultimately supported over 275 projects. Insights about the strengths and limitations of electronic health data for research, approaches to optimizing multidisciplinary collaboration, and the role of a health services research infrastructure to complement traditional clinical trials and large observational datasets are described, along with recommendations for other research consortia.

How patients with an intact immune system develop head and neck cancer.

Although the adaptive immune system can detect and eliminate malignant cells, patients with intact and fully functional immune systems develop head and neck cancer. How is this paradox explained? Manuscripts published in the English language from 1975 to 2018 were reviewed using search inputs related to tumor cell antigenicity and immunogenicity, immunodominance, cancer immunoediting and genomic alterations present within carcinomas. Early in tumor development, T cell responses to immunodominant antigens may lead to the elimination of cancer cells expressing these antigens and a tumor composed to tumor cells expressing only immunorecessive antigens. Conversely, other tumor cells may acquire genomic or epigenetic alterations that result in an antigen processing or presentation defect or other inability to be detected or killed by T cells. Such T cell insensitive tumor cells may also be selected for in a progressing tumor. Tumors harboring subpopulations of cells that cannot be eliminated by T cells may require non-T cell-based treatments, such as NK cell immunotherapies. Recognition of such tumor cell populations within a heterogeneous cancer may inform the selection of treatment for HNSCC in the future.

Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy.

Recruitment of myeloid-derived suppressor cells (MDSCs) into tumors induces local immunosuppression in carcinomas. Here, we assessed whether SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2, could block tumor MDSC recruitment and enhance T cell activation and antitumor immunity following multiple forms of immunotherapy. CXCR2+ neutrophilic MDSCs (PMN-MDSCs) were the most abundant myeloid cell subset within oral and lung syngeneic carcinomas. PMN-MDSCs demonstrated greater suppression of tumor-infiltrating lymphocyte killing of targets compared with macrophages. SX-682 significantly inhibited trafficking of PMN-MDSCs without altering CXCR2 ligand expression. Trafficking of CXCR1+ macrophages was unaltered, possibly due to coexpression of CSF1R. Reduced PMN-MDSC tumor infiltration correlated with enhanced accumulation of endogenous or adoptively transferred T cells. Accordingly, tumor growth inhibition or the rate of established tumor rejection following programed death-axis (PD-axis) immune checkpoint blockade or adoptive cell transfer of engineered T cells was enhanced in combination with SX-682. Despite CXCR1/2 expression on tumor cells, SX-682 appeared to have little direct antitumor effect on these carcinoma models. These data suggest that tumor-infiltrating CXCR2+ PMN-MDSCs may prevent optimal responses following both PD-axis immune checkpoint blockade and adoptive T cell transfer therapy. Abrogation of PMN-MDSC trafficking with SX-682 enhances T cell-based immunotherapeutic efficacy and may be of benefit to patients with MDSC-infiltrated cancers.

From Principles to Practice: Real-World Patient and Stakeholder Engagement in Breast Cancer Research.

The Patient-Centered Outcomes Research Institute (PCORI) in Washington, DC, has catalyzed a meaningful shift in the composition of research project teams since its initial research funding cycle in 2011. Despite the influx of funding in the research community for patient-centered research, research on how to effectively engage patients and stakeholders in the research process is still relatively nascent. Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle, WA, was an early recipient of PCORI research funding and, as of December 2017, has received 8 PCORI research awards totaling nearly $15 million. Anticipating the pivotal importance of PCORI's patient-focused approach, KPWHRI developed a set of 8 principles to guide how research teams should work with patients and other stakeholders to simultaneously achieve research aims and embrace this new paradigm in how research teams collaborate. With a goal of assisting other research teams, this article describes the genesis of the KPWHRI principles, their relevance to patient- and stakeholder-engaged research, and how these principles were brought to life in the context of a specific PCORI-funded project on surveillance imaging in women after a breast cancer diagnosis.

Advancing Learning Health Systems Through Embedded Research: The 23rd Annual Conference of the Health Care Systems Research Network.

The 23rd annual conference of the Health Care Systems Research Network (HCSRN, formerly the HMO Research Network) was held in San Diego, California, March 21-23, 2017, attracting 387 attendees. As a consortium of 20 research organizations embedded in or affiliated with large health care delivery organizations, the HCSRN has held annual research conferences since 1994. The overall aim of the conferences is to bring researchers, project staff, research funders and other stakeholders together to share latest scientific findings and foster new research ideas and collaborations. The 2017 conference was hosted by the Palo Alto Medical Foundation Research Institute. Each host site takes responsibility for the content and structure of the conference, and the 2017 team introduced several new features. In particular, past conferences used concurrent sessions to present research results in different topical areas, such as chronic disease, cancer, health informatics, mental health or precision medicine. This year, concurrent sessions shifted to panel discussions about how research results were achieved, including the use of methods, partnerships and analytic approaches. The 35 panels were organized into tracks such as engagement, data and informatics, partnerships and research implementation. Scientific results from HCSRN projects were presented via 120 posters in two poster sessions. Plenary sessions included a town hall-style panel with different funding agency representatives, an opening presentation on the range of opportunities and benefits to studying health systems, and a concluding presentation on how researchers can apply design thinking in their work.

The Catabolite Repressor Protein-Cyclic AMP Complex Regulates csgD and Biofilm Formation in Uropathogenic Escherichia coli.

The extracellular matrix protects Escherichia coli from immune cells, oxidative stress, predation, and other environmental stresses. Production of the E. coli extracellular matrix is regulated by transcription factors that are tuned to environmental conditions. The biofilm master regulator protein CsgD upregulates curli and cellulose, the two major polymers in the extracellular matrix of uropathogenic E. coli (UPEC) biofilms. We found that cyclic AMP (cAMP) regulates curli, cellulose, and UPEC biofilms through csgD The alarmone cAMP is produced by adenylate cyclase (CyaA), and deletion of cyaA resulted in reduced extracellular matrix production and biofilm formation. The catabolite repressor protein (CRP) positively regulated csgD transcription, leading to curli and cellulose production in the UPEC isolate, UTI89. Glucose, a known inhibitor of CyaA activity, blocked extracellular matrix formation when added to the growth medium. The mutant strains ΔcyaA and Δcrp did not produce rugose biofilms, pellicles, curli, cellulose, or CsgD. Three putative CRP binding sites were identified within the csgD-csgB intergenic region, and purified CRP could gel shift the csgD-csgB intergenic region. Additionally, we found that CRP binded upstream of kpsMT, which encodes machinery for K1 capsule production. Together our work shows that cAMP and CRP influence E. coli biofilms through transcriptional regulation of csgD IMPORTANCE The catabolite repressor protein (CRP)-cyclic AMP (cAMP) complex influences the transcription of ∼7% of genes on the Escherichia coli chromosome (D. Zheng, C. Constantinidou, J. L. Hobman, and S. D. Minchin, Nucleic Acids Res 32:5874-5893, 2004, https://dx.doi.org/10.1093/nar/gkh908). Glucose inhibits E. coli biofilm formation, and ΔcyaA and Δcrp mutants show impaired biofilm formation (D. W. Jackson, J.W. Simecka, and T. Romeo, J Bacteriol 184:3406-3410, 2002, https://dx.doi.org/10.1128/JB.184.12.3406-3410.2002). We determined that the cAMP-CRP complex regulates curli and cellulose production and the formation of rugose and pellicle biofilms through csgD Additionally, we propose that cAMP may work as a signaling compound for uropathogenic E. coli (UPEC) to transition from the bladder lumen to inside epithelial cells for intracellular bacterial community formation through K1 capsule regulation.

Primary care physicians' willingness to disclose oncology errors involving multiple providers to patients.

BACKGROUND: Full disclosure of harmful errors to patients, including a statement of regret, an explanation, acceptance of responsibility and commitment to prevent recurrences is the current standard for physicians in the USA. OBJECTIVE: To examine the extent to which primary care physicians' perceptions of event-level, physician-level and organisation-level factors influence intent to disclose a medical error in challenging situations. DESIGN: Cross-sectional survey containing two hypothetical vignettes: (1) delayed diagnosis of breast cancer, and (2) care coordination breakdown causing a delayed response to patient symptoms. In both cases, multiple physicians shared responsibility for the error, and both involved oncology diagnoses. SETTING: The study was conducted in the context of the HMO Cancer Research Network Cancer Communication Research Center. PARTICIPANTS: Primary care physicians from three integrated healthcare delivery systems located in Washington, Massachusetts and Georgia; responses from 297 participants were included in these analyses. MAIN MEASURES: The dependent variable intent to disclose included intent to provide an apology, an explanation, information about the cause and plans for preventing recurrences. Independent variables included event-level factors (responsibility for the event, perceived seriousness of the event, predictions about a lawsuit); physician-level factors (value of patient-centred communication, communication self-efficacy and feelings about practice); organisation-level factors included perceived support for communication and time constraints. KEY RESULTS: A majority of respondents would not fully disclose in either situation. The strongest predictors of disclosure were perceived personal responsibility, perceived seriousness of the event and perceived value of patient-centred communication. These variables were consistently associated with intent to disclose. CONCLUSION: To make meaningful progress towards improving disclosure; physicians, risk managers, organisational leaders, professional organisations and accreditation bodies need to understand the factors which influence disclosure. Such an understanding is required to inform institutional policies and provider training.

Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli.

UNLABELLED: Uropathogenic Escherichia coli (UPEC) is the primary cause of community-acquired urinary tract infections (UTIs). UPEC bind the bladder using type 1 pili, encoded by the fim operon in nearly all E. coli. Assembled type 1 pili terminate in the FimH adhesin, which specifically binds to mannosylated glycoproteins on the bladder epithelium. Expression of type 1 pili is regulated in part by phase-variable inversion of the genomic element containing the fimS promoter, resulting in phase ON (expressing) and OFF (nonexpressing) orientations. Type 1 pili are essential for virulence in murine models of UTI; however, studies of urine samples from human UTI patients demonstrate variable expression of type 1 pili. We provide insight into this paradox by showing that human urine specifically inhibits both expression and function of type 1 pili. Growth in urine induces the fimS phase OFF orientation, preventing fim expression. Urine also contains inhibitors of FimH function, and this inhibition leads to a further bias in fimS orientation toward the phase OFF state. The dual effect of urine on fimS regulation and FimH binding presents a potential barrier to type 1 pilus-mediated colonization and invasion of the bladder epithelium. However, FimH-mediated attachment to human bladder cells during growth in urine reverses these effects such that fim expression remains ON and/or turns ON. Interestingly, FimH inhibitors called mannosides also induce the fimS phase OFF orientation. Thus, the transduction of FimH protein attachment or inhibition into epigenetic regulation of type 1 pilus expression has important implications for the development of therapeutics targeting FimH function. IMPORTANCE: Urinary tract infections (UTIs) are extremely common infections, frequently caused by uropathogenic Escherichia coli (UPEC), that are treated with antibiotics but often recur. Therefore, UTI treatment both is complicated by and contributes to bacterial antibiotic resistance. Thus, it is important to understand UTI pathogenesis to devise novel strategies and targets for prevention and treatment. Based on evidence from disease epidemiology and mouse models of infection, UPEC relies heavily on type 1 pili to attach to and invade the bladder epithelium during initial stages of UTI. Here, we demonstrate that the negative effect of planktonic growth in human urine on both the function and expression of type 1 pili is overcome by attachment to bladder epithelial cells, representing a strategy to subvert this alternative innate defense mechanism. Furthermore, this dually inhibitory action of urine is a mechanism shared with recently developed anti-type 1 pilus molecules, highlighting the idea that further development of antivirulence strategies targeting pili may be particularly effective for UPEC.

Pilicide ec240 disrupts virulence circuits in uropathogenic Escherichia coli.

UNLABELLED: Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240's inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE: CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.

Providers' perceptions of communication breakdowns in cancer care.

BACKGROUND: Communication breakdowns in cancer care are common and represent a failure in patient-centered care. While multiple studies have elicited patients' perspectives on these breakdowns, little is known about cancer care providers' attitudes regarding the causes and potential solutions. OBJECTIVE: To examine providers' (1) perceptions of the nature and causes of communication breakdowns with patients in cancer care and (2) suggestions for managing and preventing breakdowns. DESIGN: Qualitative study of nine focus groups held at three sites (Massachusetts, Georgia and Washington). PARTICIPANTS: Fifty-nine providers: 33% primary care physicians, 14% oncologists, 36% nurses, and 17% nurse practitioners, physician assistants, and others. APPROACH: Directed content analysis of focus group transcripts. KEY RESULTS: Providers' perceptions of the causes of communication breakdowns fell into three categories: causes related to patients, providers, or healthcare systems. Providers perceived that patients sometimes struggle to understand cancer and health-related information, have unrealistic expectations, experience emotional and psychological distress that interferes with information exchange; and may be reticent to share their confusion or concerns. Providers described their own and colleagues' contributions to these breakdowns as sharing inaccurate, conflicting, or uncoordinated information. Providers also described the difficulty in balancing hope with reality in discussions of prognosis. System issues named by providers included insufficient time with patients, payment systems, and changing protocols that inhibit communication and coordination of care. Potential solutions included greater patient engagement, team coordination, and systems that promote patient feedback. CONCLUSIONS: Providers described multiple causes for communication breakdowns at the patient, provider, and system level. Multi-level interventions that coordinate care and encourage feedback may help to address or prevent communication breakdowns.

Informed choice about breast cancer prevention: randomized controlled trial of an online decision aid intervention.

INTRODUCTION: Tamoxifen and raloxifene are chemopreventive drugs that can reduce women's relative risk of primary breast cancer by 50%; however, most women eligible for these drugs have chosen not to take them. The reasons for low uptake may be related to women's knowledge or attitudes towards the drugs. We aimed to examine the impact of an online breast cancer chemoprevention decision aid (DA) on informed intentions and decisions of women at high risk of breast cancer. METHODS: We conducted a randomized clinical trial, assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention. Women (n = 585), 46- to 74-years old old, completed online baseline, post-test, and three-month follow-up questionnaires. Participants were randomly assigned to either an intervention group, a standard control group that answered questions about chemoprevention at baseline, or a three-month control group that did not answer questions about chemoprevention at baseline. The main outcome measures were whether women's intentions and decisions regarding chemoprevention drugs were informed, and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA, using a dichotomous composite variable 'informed choice' (yes/no) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman's decision and relevant attitudes. RESULTS: Analyses showed that more intervention than standard control participants (52.7% versus 5.9%) made informed decisions at post-test, P <0.001. At the three-month follow-up, differences in rates of informed choice between intervention (16.9%) and both control groups (11.8% and 8.0%) were statistically non-significant, P = 0.067. CONCLUSIONS: The DA increased informed decision making about breast cancer chemoprevention, although the impact on knowledge diminished over time. This study was not designed to determine how much knowledge decision makers must retain over time. Examining informed decisions increases understanding of the impact of DAs. A standard for defining and measuring sufficient knowledge for informed decisions is needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00967824

Patients' and family members' views on patient-centered communication during cancer care.

OBJECTIVES: To explore patients' and family members' views on communication during cancer care and to identify those aspects of clinician-patient communication which were most important to patients and family members. METHODS: We conducted a secondary data analysis of qualitative data from 137 patients with cancer and family members of patients with cancer. We used a modified version of the constant comparative method and coding paradigm of grounded theory. RESULTS: Patients want sensitive, caring clinicians who provide information that they need, when they need it, in a way that they can understand; who listen and respond to questions and concerns, and who attempt to understand the patient's experience. Effective information exchange and a positive interpersonal relationship with the clinician were of fundamental importance to patients and family members. These were interrelated; for instance, failure to provide information a patient needed could damage the relationship, whereas excellent listening could foster the relationship. Information exchange and relationship were also integral to decision-making, managing uncertainty, responding to emotions, and self-management. Clinicians who were responsive to patients' needs beyond the immediate medical encounter were valued. CONCLUSIONS: The complexity of cancer care today suggests that efforts to improve communication must be multilevel, acknowledging and addressing patient, clinician, organizational and policy barriers, and facilitators. Measurement tools are needed to assess cancer patients' and family members' experiences with communication over the course of cancer care to provide meaningful, actionable feedback to those seeking to optimize their effectiveness in communicating with patients with cancer.

Potential Role of Community-Based Healthcare System Data in Research on Survivors of Adolescent and Young Adult Cancer.

PURPOSE: We sought to examine issues of generalizability in research on adolescent and young adult (AYA) cancer survivorship that relies on using community-based healthcare delivery system data. METHODS: Individuals aged 15 to 39 diagnosed with cancer between 1992 and 2006 were identified using data from community-based healthcare systems in California and Seattle. Loss to follow-up was defined as the first disenrollment (the end) of membership in the healthcare systems after cancer. Censoring occurred at death or study end (2009). We used Kaplan-Meier analysis to quantify follow-up, and multiple Cox regression to examine the association of follow-up loss with demographic and cancer characteristics. RESULTS: Of 6828 eligible AYAs, most (93%) were aged between 20 and 39 years at diagnosis; 62% were female and 39% were non-White. Solid tumors accounted for 81% of diagnoses. The majority (89%) of patients continued to be members of the healthcare systems and available for follow-up 1 year after diagnosis. Approximately 60% remained enrolled 5 years after diagnosis. Loss to follow-up was associated with younger age at diagnosis, male gender, and African American or Hispanic race/ethnicity. CONCLUSION: Data from community-based healthcare delivery systems offer an efficient way to identify large and diverse samples of AYA-onset cancer survivors. Differential loss to follow-up can threaten the generalizability of results from these studies and should be assessed quantitatively. Healthcare system data offer an alternative to studies requiring direct contact with participants.

Belief in numbers: When and why women disbelieve tailored breast cancer risk statistics.

OBJECTIVE: To examine when and why women disbelieve tailored information about their risk of developing breast cancer. METHODS: 690 women participated in an online program to learn about medications that can reduce the risk of breast cancer. The program presented tailored information about each woman's personal breast cancer risk. Half of women were told how their risk numbers were calculated, whereas the rest were not. Later, they were asked whether they believed that the program was personalized, and whether they believed their risk numbers. If a woman did not believe her risk numbers, she was asked to explain why. RESULTS: Beliefs that the program was personalized were enhanced by explaining the risk calculation methods in more detail. Nonetheless, nearly 20% of women did not believe their personalized risk numbers. The most common reason for rejecting the risk estimate was a belief that it did not fully account for personal and family history. CONCLUSIONS: The benefits of tailored risk statistics may be attenuated by a tendency for people to be skeptical that these risk estimates apply to them personally. PRACTICE IMPLICATIONS: Decision aids may provide risk information that is not accepted by patients, but addressing the patients' personal circumstances may lead to greater acceptance.

Results from a randomized trial of a web-based, tailored decision aid for women at high risk for breast cancer.

OBJECTIVE: To assess the impact of Guide to Decide (GtD), a web-based, personally-tailored decision aid designed to inform women's decisions about prophylactic tamoxifen and raloxifene use. METHODS: Postmenopausal women, age 46-74, with BCRAT 5-year risk ≥ 1.66% and no prior history of breast cancer were randomized to one of three study arms:intervention (n=690), Time 1 control (n=160), or 3-month control (n=162). Intervention participants viewed GtD prior to completing a post-test and 3 month follow-up assessment. Controls did not. We assessed the impact of GtD on women's decisional conflict levels and treatment decision behavior at post-test and at 3 months, respectively. RESULTS: Intervention participants had significantly lower decisional conflict levels at post-test (p<0.001) and significantly higher odds of making a decision about whether or not to take prophylactic tamoxifen or raloxifene at 3-month follow-up (p<0.001) compared to control participants. CONCLUSION: GtD lowered decisional conflict and helped women at high risk of breast cancer decide whether to take prophylactic tamoxifen or raloxifene to reduce their cancer risk. PRACTICE IMPLICATIONS: Web-based, tailored decision aids should be used more routinely to facilitate informed medical decisions, reduce patients' decisional conflict, and empower patients to choose the treatment strategy that best reflects their own values.