Population-level incidence of HPV-positive oropharyngeal, cervical, and anal cancers by smoking status.

We estimated the population-level incidence of human papillomavirus (HPV) positive oropharyngeal, cervical, and anal cancers by smoking status. We combined HPV DNA genotyping data from the Centers for Disease Control and Prevention's Cancer Registry Sentinel Surveillance System with data from the Kentucky Cancer Registry and Behavioral Risk Factor Surveillance System across smoking status. During 2004-2005 and 2014-2015 in Kentucky, most cases of oropharyngeal (63.3%), anal (59.7%), and cervical (54.9%) cancer cases were among persons who ever smoked. Population-level incidence rate was higher among persons who ever smoked than never smoked for HPV-positive oropharyngeal (7.8 vs 2.1; adjusted incidence rate ratio [RRadj] = 2.6), cervical (13.7 vs 6.8; RRadj = 2.0), and anal (3.9 vs 1.6; RRadj = 2.5) cancers. These findings indicate that smoking is associated with increased risk of HPV-positive oropharyngeal, cervical, and anal cancers, and the population-level burden of these cancers is higher among persons who ever smoked.

Undiagnosed Cancer Cases in the US During the First 10 Months of the COVID-19 Pandemic.

Importance: The COVID-19 pandemic disrupted the normal course of cancer screening and detection in the US. A nationwide analysis of the extent of this disruption using cancer registry data has not been conducted. Objective: To assess the observed and expected cancer rate trends for March through December 2020 using data from all 50 US states and the District of Columbia. Design, Settings, and Participants: This was a population-based cross-sectional analysis of cancer incidence trends using data on cases of invasive cancer diagnosis reported to the US Cancer Statistics from January 1, 2018, through December 31, 2020. Data analyses were performed from July 6 to 28, 2023. Exposure(s): Age, sex, race, urbanicity, and state-level response to the COVID-19 pandemic at the time of cancer diagnosis. Main Outcomes and Measures: Used time-series forecasting methods to calculate expected cancer incidence rates for March 1 through December 31, 2020, from prepandemic trends (January 2018-February 2020). Measured relative difference between observed and expected cancer incidence rates and numbers of potentially missed cancer cases. Results: This study included 1 297 874 cancer cases reported in the US from March 1 through December 31, 2020, with an age-adjusted incidence rate of 326.5 cases per 100 000 population. Of the observed cases, 657 743 (50.7%) occurred in male patients, 757 106 (58.3%) in persons 65 years or older, and 1 066 566 (82.2%) in White individuals. Observed rates of all-sites cancer incidence in the US were 28.6% (95% prediction interval [PI], 25.4%-31.7%) lower than expected during the height of the COVID-19 pandemic response (March-May 2020); 6.3% (95% PI, 3.8%-8.8%) lower in June to December 2020; and overall, 13.0% (95% PI, 11.2%-14.9%) lower during the first 10 months of the pandemic. These differences indicate that there were potentially 134 395 (95% PI, 112 544-156 680) undiagnosed cancers during that time frame. Prostate cancer accounted for the largest number of potentially missed cases (22 950), followed by female breast (16 870) and lung (16 333) cancers. Screenable cancers saw a total rate reduction of 13.9% (95% PI, 12.2%-15.6%) compared with the expected rate. The rate of female breast cancer showed evidence of recovery to previous trends after the first 3 months of the pandemic, but levels remained low for colorectal, cervical, and lung cancers. From March to May 2020, states with more restrictive COVID-19 responses had significantly greater disruptions, yet by December 2020, these differences were nonsignificant for all sites except lung, kidney, and pancreatic cancer. Conclusions and Relevance: This cross-sectional analysis of cancer incidence trends found a substantial disruption to cancer diagnoses in the US during the first 10 months of the COVID-19 pandemic. The overall and differential findings can be used to inform where the US health care system should be looking to make up ground in cancer screening and detection.

Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

Influence of depression on breast cancer treatment and survival: A Kentucky population-based study.

BACKGROUND: Depression is common among breast cancer patients and can affect concordance with guideline-recommended treatment plans. Yet, the impact of depression on cancer treatment and survival is understudied, particularly in relation to the timing of the depression diagnosis. METHODS: The Kentucky Cancer Registry data was used to identify female patients diagnosed with primary invasive breast cancer who were 20 years of age or older in 2007-2011. Patients were classified as having no depression, depression pre-cancer diagnosis only, depression post- cancer diagnosis only, or persistent depression. The impact of depression on receiving guideline-recommended treatment and survival was examined using multivariable logistic regression and Cox regression, respectively. RESULTS: Of 6054 eligible patients, 4.1%, 3.7%, and 6.2% patients had persistent depression, depression pre-diagnosis only, and depression post-diagnosis only, respectively. A total of 1770 (29.2%) patients did not receive guideline-recommended cancer treatment. Compared to patients with no depression, the odds of receiving guideline-recommended treatment were decreased in patients with depression pre-diagnosis only (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.54-1.04) but not in patients with post-diagnosis only or persistent depression. Depression post-diagnosis only (hazard ratio, 1.51; 95% CI, 1.24-1.83) and depression pre-diagnosis only (hazard ratio, 1.26; 95% CI, 0.99-1.59) were associated with worse survival. No significant difference in survival was found between patients with persistent depression and patients with no depression (p > .05). CONCLUSIONS: Neglecting depression management after a breast cancer diagnosis may result in poorer cancer treatment concordance and worse survival. Early detection and consistent management of depression is critical in improving patient survival.

Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients.

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.

Global survival trends for brain tumors, by histology: Analysis of individual records for 67,776 children diagnosed in 61 countries during 2000-2014 (CONCORD-3).

INTRODUCTION: Tumors of the central nervous system are among the leading causes of cancer-related death in children. Population-based cancer survival reflects the overall effectiveness of a health care system in managing cancer. Inequity in access to care world-wide may result in survival disparities. METHODS: We considered children (0-14 years) diagnosed with a brain tumor during 2000-2014, regardless of tumor behavior. Data underwent a rigorous, three-phase quality control as part of CONCORD-3. We implemented a revised version of the International Classification of Childhood Cancer (third edition) to control for under-registration of non-malignant astrocytic tumors. We estimated net survival using the unbiased nonparametric Pohar Perme estimator. RESULTS: The study included 67,776 children. We estimated survival for 12 histology groups, each based on relevant ICD-O-3 codes. Age-standardized 5-year net survival for low-grade astrocytoma ranged between 84% and 100% world-wide during 2000-2014. In most countries, 5-year survival was 90% or more during 2000-2004, 2005-2009, and 2010-2014. Global variation in survival for medulloblastoma was much wider, with age-standardized 5-year net survival between 47% and 86% for children diagnosed during 2010-2014. CONCLUSIONS: To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors in children, by histology. We devised an enhanced version of ICCC-3 to account for differences in cancer registration practices world-wide. Our findings may have public health implications, because low-grade glioma is 1 of the 6 index childhood cancers included by WHO in the Global Initiative for Childhood Cancer.

Human Papillomavirus Detection in Scrotal Squamous Cell Carcinoma: Case Series from a Population-Based Cancer Registry.

Introduction: Scrotal squamous cell carcinomas (SCCs) are rare malignancies that are not considered to be associated with the human papillomavirus (HPV) by the International Agency for Research on Cancer. However, recent studies have detected HPV in these cancers. We sought to determine the presence of HPV types among scrotal cancer cases identified through population-based cancer registries. Methods: Primary scrotal SCCs diagnosed from 2014 to 2015 were identified, and tissue sections from formalin-fixed, paraffin-embedded tissue blocks were obtained for laboratory testing. A pathology review was performed to confirm morphology. HPV testing was performed using L1 consensus polymerase chain reaction analysis. Immunohistochemistry was used to evaluate p16INK4a (p16) expression. Results: Five cases of scrotal SCC were identified from 1 cancer registry. Age at diagnosis ranged from 34 to 75 years (median, 56 years). Four cases were non-Hispanic White, and 1 was non-Hispanic Black. The morphologic subtype of 4 cases was keratinizing (usual), and 1 case was verrucous (warty) histologic subtype. Two of the usual cases of SCC were HPV-negative and p16-negative, and 2 were positive for HPV16 and p16. The verrucous (warty) SCC subtype case was HPV6-positive and p16-negative. Conclusions: The presence of HPV16 and p16 overexpression in the examined tissue specimens lends additional support for the role of HPV in the etiology of scrotal SCC.

Virtual Replicas of Real Places: Experimental Investigations.

As virtual reality (VR) technology becomes cheaper, higher-quality, and more widely available, it is seeing increasing use in a variety of applications including cultural heritage, real estate, and architecture. A common goal for all these applications is a compelling virtual recreation of a real place. Despite this, there has been very little research into how users perceive and experience such replicated spaces. This article reports the results from a series of three user studies investigating this topic. Results include that the scale of the room and large objects in it are most important for users to perceive the room as real and that non-physical behaviors such as objects floating in air are readily noticeable and have a negative effect even when the errors are small in scale.

Exceptional Survival Among Kentucky Stage IV Non-small Cell Lung Cancer Patients: Appalachian Versus Non-Appalachian Populations.

PURPOSE: To determine differences in exceptional survival (ES)-survival of 5 years or more past diagnosis-between stage IV non-small cell lung cancer (NSCLC) patients residing in the Appalachian versus non-Appalachian regions of Kentucky. METHODS: This was a population-based, retrospective case-control study of Kentucky patients, diagnosed with stage IV NSCLC between January 1, 2000, and December 31, 2011. The data were drawn from the Kentucky Cancer Registry. FINDINGS: Findings from the multivariable logistic regression revealed no significant differences in the odds of ES between patients who resided in Appalachian versus non-Appalachian Kentucky. Being female and undergoing surgery only as the first course of treatment were associated with higher odds of ES. Increasing age, unspecified histology, having poorly differentiated or undifferentiated carcinomas, and receiving radiation therapy only as the first course of treatment were associated with decreased odds of ES. CONCLUSION: Differences in the odds of ES among stage IV NSCLC patients were not related to residence in Appalachian versus non-Appalachian Kentucky. ES was associated with other nongenetic and treatment factors that warrant further investigations.

Population-Based Cancer Survival in Canada and the United States by Socioeconomic Status: Findings from the CONCORD-2 Study.

Background: Population-based cancer survival provides insight into the effectiveness of health systems to care for all residents with cancer, including those in marginalized groups. Methods: Using CONCORD-2 data, we estimated 5-year net survival among patients diagnosed 2004-2009 with one of 10 common cancers, and children diagnosed with acute lymphoblastic leukemia (ALL), by socioeconomic status (SES) quintile, age (0-14, 15-64, ≥65 years), and country (Canada or United States). Results: In the lowest SES quintile, survival was higher among younger Canadian adults diagnosed with liver (23% vs 15%) and cervical (78% vs 68%) cancers and with leukemia (62% vs 56%), including children diagnosed with ALL (92% vs 86%); and higher among older Americans diagnosed with colon (62% vs 56%), female breast (87% vs 80%), and prostate (97% vs 85%) cancers. In the highest SES quintile, survival was higher among younger Americans diagnosed with stomach cancer (33% vs 27%) and younger Canadians diagnosed with liver cancer (31% vs 23%); and higher among older Americans diagnosed with stomach (27% vs 22%) and prostate (99% vs 92%) cancers. Conclusions: Among younger Canadian cancer patients in the lowest SES group, greater access to health care may have resulted in higher cancer survival, while higher screening prevalence and access to health insurance (Medicare) among older Americans during the period of this study may have resulted in higher survival for some screen-detected cancers. Higher survival in the highest SES group for stomach and liver may relate to treatment differences. Survival differences by age and SES between Canada and the United States may help inform cancer control strategies.

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

Discovery and characterization of novel peptide inhibitors of the NRF2/MAFG/DNA ternary complex for the treatment of cancer.

Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).

Prevalence of human papillomavirus genotypes in high-grade cervical precancer and invasive cervical cancer from cancer registries before and after vaccine introduction in the United States.

BACKGROUND: US population-based cancer registries can be used for surveillance of human papillomavirus (HPV) types found in HPV-associated cancers. Using this framework, HPV prevalence among high-grade cervical precancers and invasive cervical cancers were compared before and after HPV vaccine availability. METHODS: Archived tissue from 2 studies of cervical precancers and invasive cervical cancers diagnosed from 1993-2005 (prevaccine) were identified from 7 central cancer registries in Florida; Hawaii; Iowa; Kentucky; Louisiana; Los Angeles County, California; and Michigan; from 2014 through 2015 (postvaccine) cases were identified from 3 registries in Iowa, Kentucky, and Louisiana. HPV testing was performed using L1 consensus polymerase chain reaction analysis. HPV-type-specific prevalence was examined grouped by hierarchical attribution to vaccine types: HPV 16, 18, HPV 31, 33, 45, 52, 58, other oncogenic HPV types, and other types/HPV negative. Generalized logit models were used to compare HPV prevalence in the prevaccine study to the postvaccine study by patient age, adjusting for sampling factors. RESULTS: A total of 676 precancers (328 prevaccine and 348 postvaccine) and 1140 invasive cervical cancers (777 prevaccine and 363 postvaccine) were typed. No differences were observed in HPV-type prevalence by patient age between the 2 studies among precancers or invasive cancers. CONCLUSIONS: The lack of reduction in vaccine-type prevalence between the 2 studies is likely explained by the low number of cases and low HPV vaccination coverage among women in the postvaccine study. Monitoring HPV-type prevalence through population-based strategies will continue to be important in evaluating the impact of the HPV vaccine.

Pathology Laboratory Policies and Procedures for Releasing Diagnostic Tissue for Cancer Research.

CONTEXT.­: The Surveillance, Epidemiology, and End Results (SEER) cancer registry program is currently evaluating the use of archival, diagnostic, formalin-fixed, paraffin-embedded (FFPE) tissue obtained through SEER cancer registries, functioning as honest brokers for deidentified tissue and associated data. To determine the feasibility of this potential program, laboratory policies for sharing tissue for research needed to be assessed. OBJECTIVE.­: To understand the willingness of pathology laboratories to share archival diagnostic tissue for cancer research and related policies. DESIGN.­: Seven SEER registries administered a 27-item questionnaire to pathology laboratories within their respective registry catchment areas. Only laboratories that processed diagnostic FFPE specimens and completed the questionnaire were included in the analysis. RESULTS.­: Of the 153 responding laboratories, 127 (83%) responded that they process FFPE specimens. Most (n = 88; 69%) were willing to share tissue specimens for research, which was not associated with the number of blocks processed per year by the laboratories. Most laboratories retained the specimens for at least 10 years. Institutional regulatory policies on sharing deidentified tissue varied considerably, ranging from requiring a full Institutional Review Board review to considering such use exempt from Institutional Review Board review, and 43% (55 of 127) of the laboratories did not know their terms for sharing tissue for research. CONCLUSIONS.­: This project indicated a general willingness of pathology laboratories to participate in research by sharing FFPE tissue. Given the variability of research policies across laboratories, it is critical for each SEER registry to work with laboratories in their catchment area to understand such policies and state legislation regulating tissue retention and guardianship.

Improving the Quality of Cancer Care in Community Hospitals.

BACKGROUND: Cancer patients treated in community hospitals receive less guideline-recommended care and experience poorer outcomes than those treated in academic medical centers or National Cancer Institute-Designated Cancer Centers. The Markey Cancer Center Affiliate Network (MCCAN) was designed to address this issue in Kentucky, the state with the highest cancer incidence and mortality rates in the U.S. METHODS: Using data obtained from the Kentucky Cancer Registry, the study evaluated the impact of patients treated in MCCAN hospitals on four evidence-based Commission on Cancer (CoC) quality measures using a before-and-after matched-cohort study design. Each group included 13 hospitals matched for bed size, cancer patient volume, community population, and region (Appalachian vs. non-Appalachian). Compliance with quality measures was assessed for the 3 years before the hospital joined MCCAN (T1) and the 3 years afterward (T2). RESULTS: In T1, the control hospitals demonstrated greater compliance with two quality measures than the MCCAN hospitals. In T2, the MCCAN hospitals achieved greater compliance in three measures than the control hospitals. From T1 to T2, the MCCAN hospitals significantly increased compliance on three measures (vs. 1 measure for the control hospitals). Although most of the hospitals were not accredited by the CoC in T1, 92% of the MCCAN hospitals had achieved accreditation by the end of T2 compared with 23% of the control hospitals. CONCLUSION: After the MCCAN hospitals joined the Network, their compliance with quality measures and achievement of CoC accreditation increased significantly compared with the control hospitals. The unique academic/community-collaboration model provided by MCCAN was able to make a significant impact on improvement of cancer care. Future research is needed to adapt and evaluate similar interventions in other states and regions.

Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein-protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.

EGFR testing and erlotinib use in non-small cell lung cancer patients in Kentucky.

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.

Making the Invisible Visible: Illuminating the Hidden Histories of the World War I Tunnels at Vauquois Through a Hybridized Virtual Reality Exhibition.

Visualizing History: Tunnels of Vauquois is an educational immersive virtual reality (VR) exhibit that makes the invisible history of World War I soldiers' experiences in the tunnels of Vauquois, France, visible to contemporary audiences. The exhibit presents the visitor with both discrete knowledge and the opportunity for emotional awareness. The virtual environment is recreated from scanned data of the original site. Visitors traverse the tunnel through the use of a head-mounted display, redirected walking, passive haptics, aligned physical and virtual environments, interactive tracked props, and narration. In this article, we describe the motivation and rationale for creating an immersive exhibit for informal learning environments, such as museums, libraries, and school VR laboratories. We also describe how the current exhibit functions and our iterative design process informed by observational feedback from pilot testing.