L-fucose, a sugary regulator of antitumor immunity and immunotherapies.

l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell-intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.

Women's preferences for cancer risk management strategies in Lynch syndrome.

OBJECTIVE: We assessed preferences for cancer risk management strategies for Lynch syndrome (LS) in LS-affected women. METHODS: Women with LS aged ≥25 years evaluated 9 cancer risk management strategies using a visual analog scale (VAS) and modified standard gamble (SG). For the VAS, women ranked each strategy ranging from 0 (least preferred) to 100 (most preferred). VAS scores were calculated by dividing the corresponding number by 100. Scores closer to 1.0 reflected more favorable strategies. For the SG, participants were asked to specify their expected threshold of lifetime risk of endometrial or colorectal cancer, ranging from 0 to 100%, at which they would consider undertaking each strategy. Strategies included chemoprevention, cancer screening, and preventive surgery. Cancer worry and perceived cancer risk measures were collected on a subset of participants. RESULTS: Sixty-one women completed preference assessments. By VAS, annual combined screening was the most preferred, followed by annual screenings and chemoprevention with oral contraceptives. By SG, women were the most willing to endorse oral contraceptives and biannual screening strategies at the lowest threshold of lifetime risk followed by annual screening strategies. Surgical interventions were the least preferred strategies using both VAS and SG. Women with a family history of gynecologic or colorectal cancer were less likely to consider prevention or screening options compared to women without a family history. Cancer worry was higher among women with a positive family history of LS cancer. CONCLUSION: Understanding women's preferences may facilitate optimal use and adherence to cancer risk management strategies.

Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome.

Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS.

Attitudes toward molecular testing for personalized cancer therapy.

BACKGROUND: This study assessed attitudes of breast cancer patients toward molecular testing for personalized therapy and research. METHODS: A questionnaire was given to female breast cancer patients presenting to a cancer center. Associations between demographic and clinical variables and attitudes toward molecular testing were evaluated. RESULTS: Three hundred eight patients were approached, and 100 completed the questionnaire (a 32% response rate). Most participants were willing to undergo molecular testing to assist in the selection of approved drugs (81%) and experimental therapy (59%) if testing was covered by insurance. Most participants were white (71%). Even if testing was financially covered, nonwhite participants were less willing to undergo molecular testing for the selection of approved drugs (54% of nonwhites vs 90% of whites, odds ratio [OR] = 0.13, P = .0004) or experimental drugs (35% vs 68%, OR = 0.26, P = .0072). Most participants (75%) were willing to undergo a biopsy to guide therapy, and 46% were willing to undergo research biopsies. Nonwhite participants were less willing to undergo research biopsies (17% vs 55%, OR = 0.17, P = .0033). Most participants wanted to be informed when research results had implications for treatment (91%), new cancer risk (90%), and other preventable/treatable diseases (87%). CONCLUSIONS: Most patients were willing to undergo molecular testing and minimally invasive procedures to guide approved or experimental therapy. There were significant differences in attitudes toward molecular testing between racial groups; nonwhites were less willing to undergo testing even if the results would guide their own therapy. Novel approaches are needed to prevent disparities in the delivery of genomically informed care and to increase minority participation in biomarker-driven trials. Cancer 2015;121:243-50. © 2014 American Cancer Society.

Patterns of family health history communication among older African American adults.

This qualitative study examined patterns of communication regarding family health history among older African American adults. The authors conducted 5 focus groups and 6 semi-structured interviews with African Americans aged 60 years and older (N = 28). The authors identified 4 distinct patterns of family health history communication: noncommunication, open communication, selective communication (communication restricted to certain people or topics), and one-way communication (communication not reciprocated by younger family members). In general, participants favored open family health history communication, often resulting from desires to change patterns of noncommunication in previous generations regarding personal and family health history. Some participants indicated that they were selective about what and with whom they shared health information in order to protect their privacy and not worry others. Others described family health history communication as one-way or unreciprocated by younger family members who appeared uninterested or unwilling to share personal and family health information. The communication patterns that the authors identified are consistent with communication privacy management theory and with findings from studies focused on genetic testing results for hereditary conditions, suggesting that individuals are consistent in their communication of health and genetic risk information. Findings may guide the development of health message strategies for African Americans to increase family health history communication.

Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome.

We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75-80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence.

The functional role of L-fucose on dendritic cell function and polarization.

Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.

Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families.

The purpose of this study was to examine colonoscopy adherence and attitudes toward colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation negative and 26 mutation positive). While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. To conclude, adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence.

Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy.

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that L-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma.

Developing the Future End-of-Life Health Care Workforce: Lessons Learned From a Survey of Advanced Health Professions Students.

OBJECTIVE: To examine health professions trainees' end-of-life (EOL) care knowledge, attitudes, and intentions. METHODS: IRB-approved online survey of 346 students/5 universities in final training years-public health, pharmacy, physician, physician assistant, occupational therapy, and physical therapy (April-May 2016). Queried knowledge, attitudes, and intentions toward EOL care. RESULTS: Sufficient knowledge of palliative care was reported by 25% while sufficient knowledge of advance care planning (ACP) was 17%. Ninety-six percent thought it important to discuss EOL issues in training; 92% believed their professions played important roles in EOL care. Managing pain was chosen as the best example of palliative care by 93.6% and designating healthcare proxies was reported as the best example of ACP (5.8%). Pharmacy, public health, and rehabilitation therapy students were less likely than physician and physician assistant trainees to report intent to work in EOL care. Among those who want to work in EOL care, 65% reported having clinical experience with seriously ill or dying patients/clients. We discuss other findings related to perceptions of didactic preparation in palliative care, palliative care knowledge access/function, death/dying attitudes, and intentions toward seriously illness care. DISCUSSION: There is interest in and knowledge of palliative care, including EOL care, among multiple health professions. Provides guidance for how we train health professionals to improve population health by optimizing EOL care.

Assessing Advance Care Planning in Individuals with Lynch Syndrome.

Lynch syndrome (LS) is a hereditary cancer syndrome characterized by an increased risk of multiple cancers, predominantly endometrial and colorectal, at a younger age (typically < 50). In prior research, high death anxiety and a lack of provider-initiated communication about advance care planning (ACP) have been shown to decrease a patient's likelihood of having advance directives. Providers often have gaps in knowledge and are uncomfortable with these conversations. We used a mixed methods approach (quantitative survey with a follow-up telephone interview) to assess knowledge, preferences, and attitudes regarding ACP in individuals with LS (n = 20). This study also assessed which ACP documents individuals already had in place and which persons (providers, family, or friends) an individual made aware of the documentation and/or preferences. These data were analyzed to determine patient preferences for who is responsible for initiating these conversations, identify motivating factors and barriers to these conversations, and determine whether the current conversations are adequate to meet the needs of this patient population. Participants recognized the importance of ACP and expressed interest in creating these documents. However, knowledge and confidence about these topics were lacking, with many participants attributing this to their young age and lack of experience. Although uncomfortable, many patients want to have ACP discussions with their providers, but frequently patients were only asked if these documents are completed with no further discussion. These findings can inform educational efforts to improve knowledge of ACP and interventional research to increase use of ACP by individuals with LS.

Strategies for Success: Landing Your First Academic Position and Navigating the Early Years-A Report from the American Society of Preventive Oncology's Early Career Investigator Special Interest Group.

As part of the 2019 American Society of Preventative Oncology (ASPO) annual meeting, the Early Career Investigator Special Interest Group organized a session entitled "Strategies for Success: Landing Your First Academic Position and Navigating the Early Years."* This session was designed to provide senior doctoral students and postdoctoral fellows with strategies for preparing successful faculty job applications. Furthermore, strategies and best practices to help guide early career faculty through the initial years of their academic positions were also discussed. This report summarizes the main themes of the session, including advice and recommendations from the panelists.

Perceptions of Forgetfulness in Adulthood.

In two experiments, we examined younger and older participants' appraisals of memory failures in fictitious characters portrayed as younger (in their 20's to 30's) or older (in their 60's to 70's) adults. Participants read vignettes where forgetful behavior had minor or more severe consequences for the target character (Experiment 1) or for the character and others in the social environment (Experiment 2). Participants rated potential causes of the forgetfulness and opinions concerning the target character's cognitive health. In Experiment 1, an age-based double standard was observed, where both age groups rated ability as a cause of forgetting more often for older than younger characters. Ratings of forgetfulness as a sign of mental difficulty, need for memory training, and professional evaluation were also higher for older compared to younger characters. In Experiment 2, the Attribution Type by Target Age interaction effect was replicated. Ability and effort contributed to the significance of the interaction, confirming the reliability and generalizability of the age-based double standard. Forgetfulness was rated as a sign of mental difficulty more often for the older than younger characters, replicating Experiment 1. In both experiments, the consequences of the forgetting had a large impact on the attribution and opinion ratings for younger and older forgetful characters. These data suggest that people of all ages evaluate forgetful characters in light of situational outcomes as well as ageist presumptions of cognitive frailty in later life.

Factors Impacting the Decision of an Individual With Lynch Syndrome to Terminate a Health Care Provider Relationship.

Lynch syndrome (LS) is a genetic cancer syndrome that puts affected individuals at a significantly higher risk of developing multiple cancers. Participants (n = 57) were recruited through social media. Data were collected through online surveys and phone interviews; the interview data (n = 55) were analyzed to identify provider terminations and the factors that motivated these decisions. Results indicate that individuals with LS terminated their patient-provider relationships due to lack of provider LS knowledge, poor interactions, or a combination of both factors. Findings from this study suggest a need for better interactions between LS patients and providers and increased knowledge of LS-specific care.

Health and lifestyle behaviors in colorectal cancer survivors with and without Lynch syndrome.

Lynch syndrome (LS), a hereditary cancer syndrome, accounts for approximately 3% of colorectal cancers (CRC). Positive health behaviors and surveillance are preventive strategies, but research on whether recommended behavioral guidelines are followed by individuals with LS is limited. Additional health education and promotion could be beneficial to the improved survivorship of CRC survivors. Explore health and lifestyle behaviors in CRC survivors with and without LS. We conducted a case-control study of CRC survivors with and without LS using a mailed questionnaire. Recruitment was conducted via patient registries at The University of Texas MD Anderson Cancer Center (cases n = 33; controls n = 75) and through social media (cases n = 42). CRC survivors with and without LS in our study had substantially lower smoking prevalence (5.5% and 2.7%) compared to national prevalence (18.0%). However, they had higher levels of alcohol consumption (36.8% and 10.3% for male and female LS survivors, respectively, and 35.8% and 22.0% for male and female sporadic survivors, respectively) compared to national prevalence of 13.88% for males and 6.02% for females. Both groups of CRC survivors participate in negative health behaviors that impact survivorship. More research is needed to examine the relationship between personal engagement in preventive behaviors and patient-provider relationships to improve health behaviors and explore strategies for intervention. Additionally, better health education and lifestyle change recommendations would promote and reinforce positive health outcomes in the CRC population and especially in LS survivors.

Syncytia Formation in Oncolytic Virotherapy.

Oncolytic virotherapy uses replication-competent virus as a means of treating cancer. Whereas this field has shown great promise as a viable treatment method, the limited spread of these viruses throughout the tumor microenvironment remains a major challenge. To overcome this issue, researchers have begun looking at syncytia formation as a novel method of increasing viral spread. Several naturally occurring fusogenic viruses have been shown to possess strong oncolytic potential and have since been studied to gain insight into how this process benefits oncolytic virotherapy. Whereas these naturally fusogenic viruses have been beneficial, there are still challenges associated with their regular use. Because of this, engineered/recombinant fusogenic viruses have also been created that enhance nonfusogenic oncolytic viruses with the beneficial property of syncytia formation. The purpose of this review is to examine the existing body of literature on syncytia formation in oncolytics and offer direction for potential future studies.

Impact of Induced Syncytia Formation on the Oncolytic Potential of Myxoma Virus.

INTRODUCTION: Cancer has become one of the most critical health issues of modern times. To overcome the ineffectiveness of current treatment options, research is being done to explore new therapeutic modalities. One such novel treatment is oncolytic virotherapy (OV) which uses tumor tropic viruses to specifically target and kill malignant cells. While OV has shown significant promise in recent clinical trials, the therapeutic use of viruses poses a number of unique challenges. In particular, obtaining effective viral spread throughout the tumor microenvironment remains problematic. Previous work has suggested this can be overcome by forcing oncolytic viruses to induce syncytia formation. METHODS: In the current work, we generated a series of recombinant myxoma viruses expressing exogenous fusion proteins from other viral genomes and examined their therapeutic potential in vitro and in vivo. RESULTS: Similar to previous studies, we observed that the expression of these fusion proteins during myxoma infection induced the formation of multinucleated syncytia which increased viral spread and lytic potential compared to non-fusogenic controls. Contrary to expectations, however, the treatment of established tumors with these viruses resulted in decreased therapeutic efficacy which corresponded with reduced viral persistence. DISCUSSION: These findings indicate that enhanced viral spread caused by syncytia formation can actually reduce the efficacy of OV and supports a number of previous works suggesting that the in vitro properties of viruses frequently fail to predict their in vivo efficacy.

For Women, Lynch Syndrome Is About More than Colon Cancer.

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, has historically been characterized by a predisposition to colorectal cancer; however, for women with Lynch syndrome, the risks for gynecologic cancers pose an equal or greater risk than colorectal cancer. In addition, the gynecologic cancer is often the first cancer that presents in these patients. Also of importance to women with Lynch syndrome is the efficacy of gynecologic cancer screening being significantly lower than colorectal cancer screening, leading to inconsistency in provider recommendations for gynecologic screening and surveillance. We had the chance to listen to women with Lynch syndrome, in their own words, discuss their health care experiences as they relate to gynecologic cancer risk, and identified several important themes. They describe feeling confused about their screening and surveillance options while also being heavily reliant on their health care providers for guidance. In addition, women with Lynch syndrome discuss attempting to balance medical management of Lynch syndrome with their reproductive choices. Finally, they believe that increased awareness by women and their providers about the gynecologic cancer risks associated with Lynch syndrome should be a higher priority. We view the words of these women as a call to action for Lynch syndrome patients, clinicians, researchers, and advocates.

Oncolytic myxoma virus synergizes with standard of care for treatment of glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive form of brain cancer which is associated with poor prognosis. A variety of oncolytic viruses have previously shown positive efficacy against GBM, potentially offering new treatment options for patients. One such oncolytic virus is Myxoma virus (MYXV), a rabbit-specific poxvirus that has been shown to be efficacious against a variety of tumor models including GBM. PURPOSE: The purpose of this study was to test the efficacy of MYXV combined with current treatment regimens for GBM in both established cell lines as well as patient biopsy samples. MATERIALS AND METHODS: U118 gliobastoma cell lines were treated under various standard of care combinations (untreated, radiation and chemotherapeutic) prior to infection with MYXV. Infection was then monitored for differences in rate of infection, titer and rate of spread. Cellular death was measured by MTT assay and Caspase-3 colorimetric assay. Patient biopsies were harvested and treated under similar treatment conditions. RESULTS: The addition of GBM standard of care to MYXV infection resulted in an increased rate of spread compared to single treatment with either radiation or chemotherapeutic alone. SOC did not alter viral replication or infection rates. Similar effects were seen in ex vivo patient biopsies. Cellular viability was significantly decreased with the combination therapy of SOC and MYXV infection compared to any other treatment outcome. Caspase-3 activity was also significantly increased in samples treated with combination therapy when compared to any other treatment combination. CONCLUSION: Our results show that the combination of MYXV with current SOC results in both increased killing of GBM cells compared to either treatment regime alone as well as increased spread of MYXV infection. These findings lay the foundation for future in vivo studies on combining MYXV with GBM SOC.

The Use of Social Media to Recruit Participants With Rare Conditions: Lynch Syndrome as an Example.

BACKGROUND: Social media is increasingly being used as a means of recruiting participants, particularly for investigators whose areas of interest involve rare conditions or hard-to-reach populations. However, much of the literature to date has focused on paid advertisement recruitment. OBJECTIVE: We used Lynch syndrome (LS), a rare hereditary cancer syndrome, as a model to demonstrate the successful partnership between researchers and a Web-based patient education and advocacy organization to facilitate participant recruitment. METHODS: Recruitment was undertaken in partnership with Lynch Syndrome International (LSI), an advocacy organization with a strong social media presence. After LSI published our study information, participants followed up via email or phone call. Following prescreening and consent, interested and eligible participants were then sent a secure survey link. RESULTS: Within 36 hours of a single Facebook post by the site administrators for LSI, over 150 individuals responded via phone or email. Sixty-five individuals were sent the survey link and 57 individuals completed the survey (88% response rate). Of note, these 57 individuals were geographically diverse within the Unites States, representing LS patients from 26 different states. CONCLUSIONS: This approach has several advantages, including recruitment through a trusted source outside of a clinical setting, higher response rates, and cost-effectiveness with a small research team in a relatively short amount of time. Overall, social media recruitment with a trusted online partner can be highly effective in hard-to-reach clinical populations, such as patients with LS. However, this approach requires additional effort for eligibility screening.