COVID-19 and Rates of Cancer Diagnosis in the US.

Importance: US cancer diagnoses were substantially lower than expected during the COVID-19 pandemic in 2020. A national study on the extent to which rates recovered in 2021 has not yet been conducted. Objective: To examine observed vs expected cancer rate trends for January 2020 to December 2021. Design, Setting, and Participants: This cross-sectional, population-based study of cancer incidence trends used the Surveillance, Epidemiology, and End Results 22 (SEER-22) Registries Database, which covers 47.9% of the US population. Included individuals were those with an invasive cancer diagnosis reported to registries included in SEER-22 between January 1, 2000, and December 31, 2021. Exposures: Age, sex, race and ethnicity, urbanicity, and stage at diagnosis. Main Outcomes and Measures: Expected cancer incidence rates were measured for the COVID-19 pandemic years of 2020 and 2021 from prepandemic trends using ensemble forecasting methods. Relative difference between observed and expected cancer incidence rates and numbers of potentially missed cases were measured. Results: The SEER-22 registries reported 1 578 697 cancer cases in 2020 and 2021, including 798 765 among male individuals (50.6%) and 909 654 among persons aged 65 years or older (57.6%). Observed all-sites cancer incidence rates were lower than expected by 9.4% in 2020 (95% prediction interval [PI], 8.5%-10.5%), lower than expected by 2.7% in 2021 (95% PI, 1.4%-3.9%), and lower than expected by 6.0% across both years combined (95% PI, 5.1%-7.1%), resulting in 149 577 potentially undiagnosed cancer cases (95% PI, 126 059-176 970). Of the 4 screening-detected cancers, only female breast cancer showed significant recovery in 2021, exceeding expected rates by 2.5% (95% PI, 0.1%-4.8%), while significant reductions remained for lung cancer (9.1% lower than expected; 95% PI, 6.4%-13.2%) and cervical cancer (4.5% lower than expected; 95% PI, 0.4%-8.0%), particularly for early stage at diagnosis. Rates of all-sites cancer incidence returned to prepandemic trends in 2021 among female individuals, persons aged younger than 65 years, and persons of non-Hispanic Asian and Pacific Islander race and ethnicity. Conclusions and Relevance: This population-based cross-sectional study of US cancer incidence trends found that rates of diagnosis improved in 2021 but continued to be lower than expected, adding to the existing deficit of diagnosed cases from 2020. Particular attention should be directed at strategies to immediately increase cancer screenings to make up lost ground.

NCI SEER-Linked Virtual Tissue Repository Pilot.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) Program with the National Cancer Institute tested whether population-based cancer registries can serve as honest brokers to acquire tissue and data in the SEER-Linked Virtual Tissue Repository (VTR) Pilot. METHODS: We collected formalin-fixed, paraffin-embedded tissue and clinical data from patients with pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC) for two studies comparing cancer cases with highly unusual survival (≥5 years for PDAC and ≤30 months for BC) to pair-matched controls with usual survival (≤2 years for PDAC and ≥5 years for BC). Success was defined as the ability for registries to acquire tissue and data on cancer cases with highly unusual outcomes. RESULTS: Of 98 PDAC and 103 BC matched cases eligible for tissue collection, sources of attrition for tissue collection were tissue being unavailable, control paired with failed case, second control that was not requested, tumor necrosis ≥20%, and low tumor cellularity. In total, tissue meeting the study criteria was obtained for 70 (71%) PDAC and 74 (72%) BC matched cases. For patients with tissue received, clinical data completeness ranged from 59% for CA-19-9 after treatment to >95% for margin status, whether radiation therapy and chemotherapy were administered, and comorbidities. CONCLUSIONS: The VTR Pilot demonstrated the feasibility of using SEER cancer registries as honest brokers to provide tissue and clinical data for secondary use in research. Studies using this program should oversample by 45% to 50% to obtain sufficient sample size and targeted population representation and involve subspecialty matter expert pathologists for tissue selection.

Frailty in patients with ovarian cancer and the role of healthcare access, race, and ethnicity.

OBJECTIVE: Ovarian cancer has poor 5-year survival, particularly among non-Hispanic (NH) Black patients. Efforts to identify patients at high-risk of functional limitations and frailty may improve outcomes. In this study, we examined how healthcare access (HCA) and race/ethnicity relate to frailty among patients with ovarian cancer. METHODS: We identified Hispanic, NH Black, and NH White patients diagnosed at ages ≥6 5 years with ovarian cancer between 2009 and 2015 using SEER-Medicare. Log-binomial regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between HCA and race/ethnicity with pre- or post-diagnosis frailty, adjusting for age and comorbidities. RESULTS: A total of 6041 patients with ovarian cancer were included, including 91.8% NH White, 6.6% NH Black, and 1.7% Hispanic. Pre-diagnosis, 14.7% of patients were defined as frail (NH White: 14.3%; NH Black: 17.9%; Hispanic: 20.8%). Post-diagnosis, frailty prevalence increased to 58.8% (NH White: 58.2%; NH Black: 65.2%; Hispanic: 70.2%). No statistically significant associations were observed between race/ethnicity and pre- or post-diagnosis frailty in fully adjusted models. After adjustment for patient characteristics and healthcare accessibility and availability, higher healthcare affordability was associated with a decreased prevalence of pre-diagnosis frailty (PR: 0.91, 95% CI: 0.8 5, 0.98). CONCLUSIONS: Patients with ovarian cancer have a high prevalence of frailty after diagnosis, particularly NH Black and Hispanic patients. Improving healthcare affordability may prevent or help manage frailty in Medicare patients, improve receipt of cancer treatment, and increase cancer survival.

Cancer research provides a model for advancing clinical trials in dementia in the era of disease-modifying Alzheimer's-type dementia therapies.

Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy's side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on "health-span" rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on "dementia worry" strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than "magic bullet") clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Scrotal Cancer Incidence Rates and Trends-United States, 1999-2020.

OBJECTIVE: To examine population-level scrotal cancer incidence rates and trends among adult men in the United States. METHODS: Data from the United States Cancer Statistics, covering approximately 96% of the United States population, were analyzed to calculate age-standardized incidence rates of scrotal cancer among men aged 18 years and older from 1999 to 2020. Trends in incidence rates were evaluated by age, race and ethnicity, Census region, and histology using joinpoint regression. RESULTS: Overall, 4669 men were diagnosed with scrotal cancer (0.20 per 100,000). Incidence rates were highest among men aged 70 years and older (0.82 per 100,000). Rates were higher among non-Hispanic Asian or Pacific Islander men (0.31 per 100,000) compared to other race and ethnicity groups. The most common histologic subtypes were squamous cell carcinoma (35.9%), extramammary Paget disease (20.8%), and sarcoma (20.5%). Incidence rates decreased by 2.9% per year from 1999 to 2019 for non-Hispanic Asian or Pacific Islander men, decreased by 8.1% per year from 1999 to 2006 for basal cell carcinomas, and increased by 1.8% per year from 1999 to 2019 for extramammary Paget disease; otherwise, rates remained stable for all other variables examined. CONCLUSION: While scrotal cancer incidence rates were higher than previously reported, rates were still low and stable over time.

Population-level incidence of human papillomavirus-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 were among individuals who ever smoked. The population-level incidence rate was higher among individuals who ever smoked than among those who never smoked for HPV-positive oropharyngeal (7.8 vs 2.1; adjusted incidence rate ratio = 2.6), cervical (13.7 vs 6.8; adjusted incidence rate ratio = 2.0), and anal (3.9 vs 1.6; adjusted incidence rate ratio = 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 individuals 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.

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.

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.

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.

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.