Status of the Clinician Investigator in America: An Essential Healthcare Provider Driving Advances in Cancer Care.

BACKGROUND: Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC). METHODS: To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians. RESULTS: Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources. CONCLUSIONS: This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.

Status of Cancer Care at Network Sites of the Nation's Academic Cancer Centers.

BACKGROUND: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care. METHODS: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada. We analyzed the number and locations of network sites; access to electronic medical records (EMRs); clinical research support and participation at networks; use of patient navigators, care paths, and quality measures; and physician workforce. Responses were collected via Qualtrics software between September 2017 and December 2018. RESULTS: Of the 69 responding cancer centers, 74% were NCI-designated. Eighty-seven percent of respondents were part of a matrix health system, and 13% were freestanding. Fifty-six reported having network sites. Forty-three respondents use navigators for disease-specific populations, and 24 use them for all patients. Thirty-five respondents use ≥1 types of care path. Fifty-seven percent of networks had complete, integrated access to their main center's EMRs. Thirty-nine respondents said the main center provides funding for clinical research at networks, with 22 reporting the main center provides all funding. Thirty-five said the main center provided pharmacy support at the networks, with 15 indicating the main center provides 100% pharmacy support. Certification program participation varied extensively across networks. CONCLUSIONS: The data show academic cancer centers have extensive involvement in network cancer care, often extending into rural communities. Coordinating care through improved clinical trial access and greater use of patient navigation, care paths, coordinated EMRs, and quality measures is likely to improve patient outcomes. Although it is premature to draw firm conclusions, the survey results are appropriate for mapping next steps and data queries.

Perceptions of care coordination in cancer patient-family caregiver dyads.

PURPOSE: To examine cancer patients and their family caregivers' perspectives of care coordination (CC) using a dyadic research design. METHODS: In this pilot cross-sectional study, 54 patient-family caregiver dyads completed a validated care coordination instrument (CCI) and its parallel family caregiver instrument (CCICG) from June to September 2019. The sample available for analysis included data from 32 dyads, which included patients receiving active therapy for any cancer type and their primary family caregivers aged 18 years or older. Mixed regression models were used to examine dyadic differences. RESULTS: The overall family caregiver scores demonstrated a bimodal pattern; thus, we conducted analyses using aggregate data as well as by highCG and lowCG subgroups. Among dyads in the lowCG subgroup, family caregivers reported significantly lower scores than patients on the total CCI and the three CC domains: Communication, Navigation, and Operational. Caregiver gender, the absence of a patient navigator, and practice setting (hospital-based ambulatory) significantly predicted dyadic differences in the lowCG subgroup. In item-level analyses, family caregivers in the lowCG subgroup reported lower scores than patients on the items related to patient-physician communication. CONCLUSION: A subgroup of family caregivers reported poorer perception of CC than patients, suggesting that those family caregivers and providers may benefit from intervention. Further understanding of patient-family caregiver dyads' perspectives of CC can inform development of strategies to integrate family caregivers into the cancer care team, develop effective CC interventions for family caregivers, and contribute to improved quality and value of cancer care.

GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.

BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.

Development and psychometric evaluation of a questionnaire to measure cancer patients' perception of care coordination.

BACKGROUND: Although the importance of care coordination (CC) is well-recognized, cancer patients often receive poorly coordinated care across varied care settings and different oncology providers. Efforts to improve cancer care are hampered by lack of adequate measures. In this two-part, mixed-method study, we describe the development, refinement, and validation of a new care coordination instrument (CCI) designed to assess cancer patients' perception of CC. METHODS: In Study 1, an initial CCI was developed incorporating questions based on literature review. The items were then modified following four field tests conducted in a large academic hospital with oncology nurses (n = 20) and cancer patients (n = 120). This modified instrument was used to determine whether the CCI was able to distinguish CC between two practices (30 GI and 30 myeloma patients) within the same hospital setting. In Study 2, 68 patients receiving community-based care participated in seven focus groups. Based on these discussions, the CCI items were again refined, and psychometric evaluation was conducted to assess the quality of the instrument. RESULTS: Based on field tests, 3 domains of the CCI, Communication, Navigation, and Operational, were defined as critical components of CC. The Operational domain evaluates efficiency of care and is unique to this CCI. The field test demonstrated that GI patients reported significantly better CC Overall and for the Communication and Navigation domains (all p < .05). In Study 2, patients expressed concordance with the CCI items and their CC experiences, establishing validity of the CCI. Qualitative analysis of the focus group discussions indicated that the items with the highest frequencies of participants' comments were related to the concepts of Navigator, Team, Survey, and Communication. Quantitative analysis identified items with a limited response range or high rates of "neutral" responses; accordingly, those items were removed. The final CCI survey is a 29 item, multiple-choice questionnaire with excellent reliability, Cronbach's α = .922. CONCLUSIONS: We developed a novel, patient-centered tool with excellent psychometric properties that can be utilized across varied practice settings to assess patients' perception of cancer care coordination. TRIAL REGISTRATION: Not required; retrospectively registered ClinicalTrials.gov NCT03594006 20 July 2018.

Gastric adenocarcinoma in young adult patients: patterns of care and survival in the United States.

BACKGROUND: Evidence regarding gastric cancer patients < 40 years old is limited. This study examines young adults with gastric adenocarcinoma in the National Cancer Database to describe demographics and treatment practices, and to develop a nomogram to predict survival. METHODS: The database was queried for adult patients diagnosed with gastric adenocarcinoma from 2004 to 2013. Patients were stratified into two age groups: <40 and ≥ 40 years. The database was analyzed to compare demographics, clinical characteristics, and treatments used for each group. Differences in survival were assessed using Kaplan-Meier curves and log-rank test. For adults < 40 years old, an accelerated failure time survival model was fitted for overall survival and a descriptive nomogram was constructed. RESULTS: Of 70,084 patients included, 2615 (4%) were < 40 years old and 67,469 (96%) were ≥ 40 years. Compared to older patients, adults < 40 years old were more likely to be female (46 vs. 35%), non-white (31 vs. 23%), Hispanic (32 vs. 11%), from the northeast (36 vs. 23%), and to present with stage IV disease (59 vs. 42%) and bone metastases (36 vs. 21%; p < 0.001 for all). The nomogram showed clinical stage as the strongest predictor of overall survival, followed by treatment, grade, race, Charlson-Deyo comorbidity score, and sex. CONCLUSIONS: Young adults with gastric adenocarcinoma are more likely to be Hispanic, female, from the northeast, and to present with metastases. Despite these differences, clinical stage, treatment, and tumor grade are most predictive of overall survival for young adult patients.

Predictors of Satisfaction With Doctor and Nurse Communication: A National Study.

Prior research indicates that effective communication between medical providers and patients is associated with a number of positive patient outcomes, yet little research has examined how ecological factors (e.g., hospital size, local demographics) influence patients' reported satisfaction with doctor and nurse communication. Given the current emphasis on improving patient satisfaction in hospitals across the United States, understanding these factors is critical to interpreting patient satisfaction and improving patient-centered communication, particularly in diverse and dense populations. As such, this study examined county-level data including population density, population diversity, and hospital structural factors as predictors of patient satisfaction with doctor and nurse communication. Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS), U.S. Census data, and number of hospital beds were obtained from publicly available Hospital Compare, U.S. Census, and American Hospital Directory websites, respectively. Multivariate regression modeling was performed for the individual dimensions of HCAHPS scores assessing doctor and nurse communication. Standardized partial regression coefficients were used to assess strengths of county-level predictors. County-level factors accounted for 30% and 16% of variability in patient satisfaction with doctor and nurse communication, respectively. College education (ß = 0.45) and White ethnicity (ß = 0.25) most strongly predicted a favorable rating of doctor and nurse communication, respectively. Primary language (non-English speaking; ß = -0.50) most strongly predicted an unfavorable rating of doctor communication, while number of hospital beds (ß = -0.16) and foreign-born (ß = -0.16) most strongly predicted an unfavorable rating of nurse communication. County-level predictors should be considered when interpreting patient satisfaction with doctor and nurse communication and designing multilevel patient-centered communication improvement strategies. Discordant findings with individual-level factors should be explored further.

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets.

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.

SW480 colorectal cancer cells that naturally express Lgr5 are more sensitive to the most common chemotherapeutic agents than Lgr5-negative SW480 cells.

Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) is a colorectal cancer (CRC) stem cell marker. The role of Lgr5-expressing stem cells in resistance to chemotherapy is controversial. The notion that Lgr5-expressing cells are more chemotherapy resistant is supported by some data; other data do not support this notion. We hypothesized that Lgr5-expressing cells would be more chemotherapy sensitive, as Lgr5 is usually a marker of dividing cells. We tested this hypothesis by exploiting two natural variants of SW480 CRC cells: the less-differentiated Lgr5-expressing floating fraction and the more-differentiated Lgr5-depleted attached fraction. We estimated chemotherapy sensitivity using an XTT Cell Proliferation Assay Kit. We confirmed that the detected chemotherapy sensitivity differences were Lgr5-driven by overexpressing Lgr5. SW480 CRC cells that naturally express Lgr5 are those that are floating, and they are more sensitive to the chemotherapeutic compounds irinotecan (maximum difference approximately two times, 0.0001

Effects of a grape-supplemented diet on proliferation and Wnt signaling in the colonic mucosa are greatest for those over age 50 and with high arginine consumption.

A diet rich in fruits and vegetables, and a grape-derived compound, resveratrol, have been linked to a reduced incidence of colon cancer. In vitro and in vivo, resveratrol suppresses Wnt signaling, a pathway constitutively activated in over 85 % of colon cancers.Thirty participants were placed on a low resveratrol diet and subsequently allocated to one of three groups ingesting 1/3-to-1 lb (0.15-0.45 kg) of grapes per day for 2 weeks. Dietary information was collected via 24-h recall. Colon biopsies for biomarker analysis were obtained pre- and post-grape and evaluated for the expression of Wnt pathway target genes and for markers of proliferation by RT-PCR and immunohistochemistry.Participants lost an average of 2 · 6 lb (1.2 kg, p = 0 · 0018) during the period of grape ingestion. The expression of CyclinD1 (p < 0 · 01), AXIN2, CD133 (p = 0 · 02) and Ki67 (p = 0 · 002) were all reduced after grape ingestion. Individuals over 50 years of age and those with high dietary arginine consumption had increased basal expression of CyclinD1, AXIN2, cMYC and CD133 (p value range 0 · 04 to <0 · 001) that, following grape ingestion, were reduced to levels seen in younger participants.The reduction in Wnt signaling and mucosal proliferation seen following short-term ingestion of 1/3-1 lb (0.15-0.45 kg) of grapes per day may reduce the risk of mutational events that can facilitate colon carcinogenesis. The potential benefit is most marked for high-risk older individuals and individuals whose diet is high in arginine intake. Dietary grape supplementation may play a role in colon cancer prevention for high-risk individuals.

Developing clinical research incentives for academic oncologists.

Incentive plans can be developed to promote clinical research activities for academic oncologists. Such plans encourage faculty to devote the necessary time and effort to enroll patients in clinical trials. It is crucial to decide what types of activities will be incentivized and to define expectations at the outset. An incentive program requires resources that should remain stable over time. A resource allocation ideally would be indexed to a level of clinical research activity so that, as activity increases, more funding is available for distribution as incentives. Most academic oncologists are familiar with incentive-based reimbursement for clinical activities; a similar structure for academic pursuits such as clinical research can be incorporated into, or used in conjunction with, a clinical incentive plan.

Patient reports of cancer care coordination in rural Hawaii.

PURPOSE: Rural residents experience disproportionate burdens of cancer, and poorer cancer health outcomes in rural populations are partly attributed to care delivery challenges. Cancer patients in rural areas often experience unique challenges with care coordination. In this study, we explored patient reports of care coordination among rural Hawaii patients with cancer and compared rural and urban patients' perceptions of cancer care coordination. METHODS: 80 patients receiving active treatment for cancer from rural Hawaii participated in a care coordination study in 2020-2021. Participants completed the Care Coordination Instrument, a validated oncology patient questionnaire. FINDINGS: Mean age of rural cancer patients was 63.0 (SD = 12.1), and 57.7% were female. The most common cancer types were breast and GI. Overall, rural and urban patients' perceptions of care coordination were comparable (p > 0.05). There were statistically significant differences between rural and urban patients' perceptions in communication and navigation aspects of care coordination (p = 0.02 and 0.04, respectively). Specific differences included a second opinion consultation, clinical trial considerations, and after-hours care. 43% of rural patients reported traveling by air for part or all of their cancer treatment. CONCLUSIONS: Findings suggest that while overall perceptions of care coordination were similar between rural and urban patients, differential perceptions of specific care coordination areas between rural and urban patients may reflect limited access to care for rural patients. Improving access to cancer care may be a potential strategy to enhance care coordination for rural patients and ultimately address rural-urban cancer health disparities.

Time to Diagnosis and Treatment Initiation During the COVID-19 Pandemic Among Rural Patients With Cancer.

Time to diagnosis (TTD) and treatment initiation (TTI) are important measures of access to and quality of cancer care. This study addressed the knowledge gap on the impact of the COVID-19 pandemic on TTD and TTI for rural cancer patients. Sixty-three cancer patients residing in rural areas of the state of Hawaii were surveyed in 2020 to 2021. Overall, 67.5% of participants reported TTD within one month of reporting symptoms to a health care provider. Mean TTI for the overall sample was 55.3 days, and among breast cancer patients, 57.9 days. Compared with pre-pandemic state registry data, mean TTI for the overall sample and breast cancer patients were significantly longer than the state registry null value of 40 days (P = .02 and P =.05, respectively). During the COVID-19 pandemic, cancer patients in rural Hawaii experienced substantial delays in TTI compared with pre-pandemic years.

Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment.

BACKGROUND: Wnt signaling in the colon cancer tumor microenvironment (TME) may affect cancer biologic properties including invasion and metastatic dissemination. Prior reports have suggested that the expression of select frizzled (Fz) receptors may be altered in cancers and in the TME. METHODS: Colon cancer, colonic adenoma and normal colonic mucosal specimens were obtained under institutional review board approval and analyzed for the expression of Fz1 and Fz2 by confocal fluorescent immunohistochemistry and Wnt-specific membrane array. In vitro, the effect of Wnt3a on Fz1 expression was examined in normal-derived NCM460 cells by qRT-PCR and immunohistochemistry. RESULTS: Fz1 was expressed in colon cancer and villous adenomas but not in more benign tubular adenomas. Fz1 expression was seen in normal colonic mucosa in close proximity to colon cancer, but not villous or tubular adenomas. Normal colonic mucosa distant from colon cancer did not express Fz1. Fz2 was expressed ubiquitously in cancer, adenomas and normal colonic mucosa. Fz1 expression was induced by Wnt3a in a normal colon mucosa-derived cell line in vitro. CONCLUSIONS: Fz1 is a Wnt responsive gene in colon-derived tissues. Fz1 expression exhibited increased expression in normal mucosa only in close proximity to colon cancer. This field effect was not seen with pre-malignant adenomas and may be due to Wnt/ß-catenin signaling within the TME. Fz1 may represent a new TME-directed therapeutic target for patients with colon cancer.

Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy.

BACKGROUND: Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory. METHODS: Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322) in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle. There were no toxicities or adverse events reported. Blood was obtained before chemotherapy/GM-CSF administration and 24 hours following the final dose of GM-CSF and evaluated for circulating dendritic cells and adaptive immune cellular subsets by flow cytometry. Peripheral blood mononuclear cell (PBMC) expression of γ-interferon and T-bet transcription factor (Tbx21) by quantitative real-time PCR was performed as a measure of Th1 adaptive cellular immunity. Pre- and post-treatment (i.e., chemotherapy and GM-CSF) samples were evaluable for 16 patients, ranging from 1 to 5 cycles (median 3 cycles, 6 biologic sample time points). Dendritic cells were defined as lineage (-) and MHC class II high (+). RESULTS: 73% of patients had significant increases in circulating dendritic cells of ~3x for the overall group (5.8% to 13.6%, p = 0.02) and ~5x excluding non-responders (3.2% to 14.5%, p < 0.001). This effect was sustained over multiple cycles for approximately half of the responders, but tachyphylaxis over subsequent chemotherapy cycles was noted for the remainder. Treatment also led to a significant reduction in the proportion of circulating regulatory T-cells (Treg; p = 0.0042). PBMC Tbx21 levels declined by 75% following each chemotherapy cycle despite administration of GM-CSF (p = 0.02). PBMC γ-interferon expression, however was unchanged. CONCLUSIONS: This clinical trial confirms the suppressive effects of chemotherapy on Th1 cellular immunity in patients with metastatic colorectal cancer but demonstrates that mid-cycle administration of GM-CSF can significantly increase the proportion of circulating dendritic cells. As the role of dendritic cells in anti-tumor immunity becomes better defined, GM-CSF administration may provide a non-toxic intervention to augment this arm of the immune system for cancer patients receiving cytotoxic therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00257322.

Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer.

OBJECTIVE: Emerging evidence implicates the Wnt antagonist Dickkopf-3 (Dkk3) as a tumor suppressor and potential biomarker in solid tumors. We investigated whether Dkk3 plays an important role in the carcinogenesis of endometrial cancer (EC). METHODS: We analyzed Dkk3 mRNA expression via real-time RT-PCR in twenty-seven human primary EC tissues, and six matched normal endometrial controls. Dkk3 levels were correlated with various clinicopathologic characteristics. Additionally, enforced Dkk3 expression was examined in proliferation and tumorigenesis in vitro and in vivo, using MTT, soft agar assay, invasion assay, a xenograft mouse model, and a ß-catenin-responsive SuperTopFlash luciferase assay. RESULTS: Compared with matched normal endometrial cases, Dkk3 was down-regulated in EC (p<0.0001). Among cancer cases, Dkk3 expression was significantly reduced in patients with higher stage (p=0.002), positive pelvic lymph nodes (p=0.0004), non-endometrioid histology (p=0.02), and cytology-positive ECs (p=0.02). Enforced expression of Dkk3 in EC cell lines showed reduced proliferation (p<0.0001), anchorage-independent growth (p=0.005), invasion (p=0.02), and reduced TCF activity (p=0.04), confirming Dkk3 as a negative regulator of the ß-catenin/Wnt signaling pathway. Tumor growth in Dkk3-injected mice was not statistically different, though did plateau towards the end, and was associated with increased lymphoid infiltration and tumor necrosis. CONCLUSION: Dkk3 gene expression is frequently downregulated in endometrial cancer, and is associated with poor prognostic clinicopathologic markers. The results also identify a role for Dkk3 as a tumor suppressor in EC, affecting both proliferation and invasiveness. These findings may prove to be important in the design of novel biomarkers and treatment modalities for advanced EC.

Clinical Research Professional Providing Care Coordination Support: A Study of Hawaii Minority/Underserved NCORP Community Site Trial Participants.

PURPOSE: Although effective care coordination (CC) is recognized as a vital component of a patient-centered, high-quality cancer care delivery system, CC experiences of patients who enroll and receive treatment through clinical trials (CTs) are relatively unknown. Using mixed methods, we examined perceptions of CC among patients enrolled onto therapeutic CTs through the Hawaii Minority/Underserved National Cancer Institute Community Oncology Research Program. METHODS: The Care Coordination Instrument, a validated instrument, was used to measure patients' perceptions of CC among CT participants (n = 45) and matched controls (n = 45). Paired t-tests were used to compare overall and three CC domain scores (Communication, Navigation, and Operational) between the groups. Semistructured focus group interviews were conducted virtually with 14 CT participants in 2020/2021. RESULTS: CT participants reported significantly higher total CC scores than non-CT participants (P = .0008). Similar trends were found for Navigation and Operational domain scores (P = .007 and .001, respectively). Twenty-nine percent of CT participants reported receiving high-intensity CC assistance from their clinical research professionals (CRPs). Content analysis of focus group discussions revealed that nearly half of the focus group discussions centered on CRPs (47%), including CC support provided by CRPs (26%). Other key themes included general CT experiences (22%) and CRP involvement as an additional benefit to CT participation (15%). CONCLUSION: Our results show that patients on CTs in this study had a more positive CC experience. This may be attributable in part to CC support provided by CRPs. These findings highlight both the improved experience of treatment for patients participating in a trial and the generally unrecognized yet integral role of CRPs as part of a cancer CT care team.

Wnt signaling and colon carcinogenesis: beyond APC.

Activation of the Wnt signaling pathway via mutation of the adenomatous polyposis coli gene (APC) is a critical event in the development of colon cancer. For colon carcinogenesis, however, constitutive signaling through the canonical Wnt pathway is not a singular event. Here we review how canonical Wnt signaling is modulated by intracellular LEF/TCF composition and location, the action of different Wnt ligands, and the secretion of Wnt inhibitory molecules. We also review the contributions of non-canonical Wnt signaling and other distinct pathways in the tumor micro environment that cross-talk to the canonical Wnt pathway and thereby influence colon cancer progression. These 'non-APC' aspects of Wnt signaling are considered in relation to the development of potential agents for the treatment of patients with colon cancer. Regulatory pathways that influence Wnt signaling highlight how it might be possible to design therapies that target a network of signals beyond that of APC and ß-catenin.

WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells.

Epigenetic silencing of secreted wingless-type (Wnt) antagonists through hypermethylation is associated with tobacco smoking and with invasive bladder cancer. The secreted Wnt inhibitory factor-1 (WIF1) has shown consistent growth-inhibitory effect on various cancer cell lines. Therefore, we assessed the mechanisms of action of WIF1 by either restoring WIF1 expression in invasive bladder cancer cell lines (T24 and TSU-PR1) or using a recombinant protein containing functional WIF1 domain. Both ectopic expression of WIF1 and treatment with WIF1 domain protein resulted in cell growth inhibition via G(1) arrest. The G(1) arrest induced by WIF1 is associated with down-regulation of SKP2 and c-myc and up-regulation of p21/WAF1 and p27/Kip1. Conversely, reexpression of SKP2 in WIF1-overexpressing TSU-PR1 cells attenuated the WIF1-induced G(1) arrest. Furthermore, inhibition of nuclear Wnt signaling by either dominant-negative LEF1 or short hairpin RNA of TCF4 also reduced SKP2 expression. The human SKP2 gene contains two TCF/LEF1 consensus binding sites within the promoter. Chromatin immunoprecipitation/real-time PCR analysis revealed that both WIF1 and dominant-negative LEF1 expression decreased the in vivo binding of TCF4 and beta-catenin to the SKP2 promoter. Together, our results suggest that mechanisms of WIF1-induced G(1) arrest include (a) SKP2 down-regulation leading to p27/Kip1 accumulation and (b) c-myc down-regulation releasing p21/WAF1 transcription. Additionally, we show that WIF1 inhibits in vivo bladder tumor growth in nude mice. These observations suggest a mechanism for transformation of bladder epithelium on loss of WIF1 function and provide new targets such as SKP2 for intervention in WIF1-deficient bladder cancer.