Recombination map tailored to Native Hawaiians may improve robustness of genomic scans for positive selection.

Recombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map) and one based on individuals of enriched Polynesian ancestries (PNS map) with the potential to be used for less admixed Polynesian populations such as the Samoans. We found the recombination landscape to be less correlated with those from other continental populations (e.g. Spearman's rho = 0.79 between PNS and CEU (Utah residents with Northern and Western European ancestry) compared to 0.92 between YRI (Yoruba in Ibadan, Nigeria) and CEU at 50 kb resolution), likely driven by the unique demographic history of the Native Hawaiians. PNS also shared the fewest recombination hotspots with other populations (e.g. 8% of hotspots shared between PNS and CEU compared to 27% of hotspots shared between YRI and CEU). We found that downstream analyses in the Native Hawaiian population, such as local ancestry inference, imputation, and IBD segment and relatedness detections, would achieve similar efficacy when using the NH map compared to an omnibus map. However, for genome scans of adaptive loci using integrated haplotype scores, we found several loci with apparent genome-wide significant signals (|Z-score|> 4) in Native Hawaiians that would not have been significant when analyzed using NH-specific maps. Population-specific recombination maps may therefore improve the robustness of haplotype-based statistics and help us better characterize the evolutionary history that may underlie Native Hawaiian-specific health conditions that persist today.

Health care costs for adolescents and young adults with cancer: a Wisconsin community-based hospital study between 2005 and 2020.

INTRODUCTION: Adolescents and young adults (AYA) with cancer are at risk of high cumulative healthcare system costs potentially associated with poor health and financial outcomes. Although this has been studied at academic centers, little data on AYA costs at community-based practices exist. The goals of this study were to understand direct health care costs for AYA patients, identify factors for high costs, and assess how total health care costs may relate to survival. METHODS: AYA patients (15-39 years) treated at a community hospital in Wisconsin (USA) between 2005 and 2020 were identified. Patient demographics, cancer characteristics, therapies, support services, and all direct health care charges (including up to 1 year prior to diagnosis to capture any diagnostic workup) were collected. Logistic and Cox proportional hazard regression models identified factors associated with high costs and survival, respectively. RESULTS: The 388 AYA patients had a median follow-up of 9 years (97% survival). Most were 30-39 years (62%), female (61%), white (95%), diagnosed early-stage (85%), and underwent surgery (83%). Complete health care costs were available for 233 patients (60%). Median total costs per patient were $123 K (range, $73-$215 K). On adjusted analysis, higher direct health care costs (> $125 K) were associated with greater odds of hospital admissions (odds ratio [OR] = 1.7, 95% CI = 1.35-2.27), chemotherapy (OR = 4.1, 95% CI = 1.44-12.70), and breast cancer diagnosis (OR = 3.8, 95% CI = 1.07-14.70). Living farther from the hospital (OR = 0.1, 95% CI = 0.02-0.50), later year of diagnosis (OR = 0.7, 95% CI = 0.55-0.77), and uninsured/unknown insurance status (OR = 0.1, 95% CI = 0.01-0.57) were associated with decreased odds of having higher health care costs. On adjusted analysis, death was associated with greater odds of higher direct health care costs per $125 K (hazards ratio [HR] = 7.9, 95% CI = 2.22-27.80) and radiation (HR = 31.8, 95% CI = 3.15-321) but lower odds of hormone therapy (HR = 0.1, 95% CI = 0.01-0.72) and later year of diagnosis (HR = 0.3, 95% CI = 0.12-0.60). CONCLUSION: High direct health care costs among AYA patients are associated with hospital admissions, chemotherapy, breast cancer diagnosis, hospital proximity, and earlier year of diagnosis. Death was associated with high direct health care costs, earlier years of diagnosis, and radiation therapy. Total health care costs in community-based hospitals should be considered in the context of AYA patients with cancer.

Biologics and 30-Day Postoperative Complications After Abdominal Operations for Crohn's Disease: Are There Differences in the Safety Profiles?

BACKGROUND: The evidence regarding the association of preoperative biologic exposure and postoperative outcomes remains controversial for both antitumor necrosis factor agents and vedolizumab and largely unknown for ustekinumab. OBJECTIVE: The purpose of this study was to determine differences in the rates of 30-day postoperative overall infectious complications and intra-abdominal septic complications among the 3 classes of biologic therapies as compared with no biologic therapy. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at an IBD referral center. PATIENTS: Adult patients with Crohn's disease who received an antitumor necrosis factor, vedolizumab, ustekinumab, or no biologic therapy within 12 weeks of a major abdominal operation between May 20, 2014, and December 31, 2017, were included. MAIN OUTCOMES MEASURES: Thirty-day overall postoperative infectious complications and intra-abdominal septic complications were measured. RESULTS: A total of 712 patients with Crohn's disease were included; 272 patients were exposed to an antitumor necrosis factor agents, 127 to vedolizumab, 38 to ustekinumab, and 275 to no biologic therapy within the 12 weeks before an abdominal operation. Patients exposed to a biologic were more likely to be taking a concurrent immunomodulator, but there was no difference in concurrent corticosteroid usage. The particular class of biologic was not independently associated with total overall infectious complications. Vedolizumab was associated with an increased rate of intra-abdominal sepsis on univariate analysis but not on multivariable analysis. Combination immunosuppression was associated with both an increased rate of overall postoperative infectious complications and intra-abdominal sepsis. LIMITATIONS: The study was limited by its retrospective design and single-center data. CONCLUSIONS: The overall rate of total infectious complications or intra-abdominal septic complications was not increased based on preoperative exposure to a particular class of biologic. Rates increased with combination immunosuppression of biologic therapy with corticosteroids and previous abdominal resection. See Video Abstract at http://links.lww.com/DCR/B24. BIOLÓGICOS Y COMPLICACIONES POSTOPERATORIAS DE 30 DÍAS DESPUÉS DE LAS OPERACIONES ABDOMINALES PARA LA ENFERMEDAD DE CROHN: ¿EXISTEN DIFERENCIAS EN LOS PERFILES DE SEGURIDAD?:: La evidencia sobre la asociación de la exposición biológica preoperatoria y los resultados postoperatorios sigue siendo controvertida controversial tanto para los agentes del factor de necrosis tumoral (anti-TNF) como para el vedolizumab, y en gran parte desconocida para el ustekinumab.Determinar las diferencias en las tasas de complicaciones infecciosas generales postoperatorias de 30 días y complicaciones sépticas intraabdominales entre las tres clases de terapias biológicas en comparación con ninguna terapia biológica.Revisión retrospectiva.centro de referencia de la enfermedad inflamatoria intestinal.Pacientes adultos con enfermedad de Crohn que recibieron un factor de necrosis antitumoral, vedolizumab, ustekinumab o ningún tratamiento biológico dentro de las 12 semanas de una operación abdominal mayor entre el 5/20/2014 y el 12/31/2017.Complicaciones infecciosas postoperatorias generales de 30 días, complicaciones sépticas intraabdominales.Se incluyeron setecientos doce pacientes con enfermedad de Crohn; 272 pacientes fueron expuestos a un anti-TNF, 127 a vedolizumab, 38 a ustekinumab y 275 a ninguna terapia biológica dentro de las 12 semanas previas a una operación abdominal. Los pacientes expuestos a un producto biológico tenían más probabilidades de tomar un inmunomodulador concurrente, pero no hubo diferencias en el uso simultáneo de corticosteroides. La clase particular de productos biológicos no se asoció de forma independiente con las complicaciones infecciosas totales. Vedolizumab se asoció con una mayor tasa de sepsis intraabdominal en el análisis univariable, pero no en el análisis multivariable. La inmunosupresión combinada se asoció tanto con una mayor tasa de complicaciones infecciosas postoperatorias generales como con sepsis intraabdominal.Diseño retrospectivo, datos de centro único.La tasa general de complicaciones infecciosas totales o complicaciones sépticas intraabdominales no aumentó en función de la exposición preoperatoria a una clase particular de productos biológicos. Las tasas aumentaron con la combinación de inmunosupresión de la terapia biológica con corticosteroides y resección abdominal previa. Vea el Resumen del Video en http://links.lww.com/DCR/B24.

Rising From Ruin-Revitalizing Native Hawaiian Health.

This Viewpoint offers insight into the health effects of the recent fires in Hawaiʻi and what culturally conscious approaches are needed to ensure the health of Native Hawaiians going forward.

Therapeutic Targeting of Epithelial Plasticity Programs: Focus on the Epithelial-Mesenchymal Transition.

Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into 3 groups: (1) extracellular inducers of EMT, (2) the transcription factors that orchestrate the EMT transcriptome, and (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT, such as the signal transduction pathways TGFß, EFGR, and Axl-Gas6. We emphasize in more detail pathways that we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways, and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only 1 EMT-related process will be unsuccessful or only transiently successful. We suggest that with greater understanding of epithelial plasticity regulation, such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes.

Racial Disparities in 30-day Readmissions after Surgery for Head and Neck Cancer.

BACKGROUND: Native Hawaiians and other Pacific Islanders (NHPI) patients with head and neck cancer are often aggregated with Asian individuals despite evidence of heterogeneous health outcomes and mortality. The aim of this study was to determine the association of race with unplanned 30-day hospital readmission rate after head and neck surgery across the five federally recognized racial categories. METHODS: This retrospective cohort study used a national hospital-based database and included patients ≥18 years old with diagnostically confirmed, nonmetastatic head and neck cancer of any subsite treated surgically between 2004 and 2017. The primary endpoint was unplanned readmission within 30 days of discharge after primary surgery. RESULTS: A total of 365,834 patients were included who were predominantly White (87%), treated at academic cancer centers (47%), lower income (63%), with early-stage disease (60%), and with thyroid (47%) or oral cavity (23%) cancers. Median follow-up duration was 47 months. Of the 10,717 (3%) readmissions, 5,845 (1.6%) were unplanned. Adjusted for confounders and compared with White patients, NHPI patients had the highest likelihood of unplanned (aOR 2.07, 95%CI 1.16-3.40, p = 0.008) readmissions. Within the NHPI group, patients with lower income (aOR 4.27, 95%CI 1.28-20.4, p = 0.035) and those residing in an urban or rural area (aOR 7.42, 95%CI 1.14-49.5, p = 0.034) were more likely to be readmitted. CONCLUSIONS: NHPI patients with head and neck cancers experience significantly higher 30-day readmissions following definitive surgical treatment. These results highlight the importance of racial disaggregation in clinical studies. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1282-1287, 2024.

Site-specific patterns of early-stage cancer diagnosis during the COVID-19 pandemic.

The COVID-19 pandemic caused widespread disruptions in cancer care. We hypothesized that the greatest disruptions in diagnosis occurred in screen-detected cancers. We identified patients (≥18 years of age) with newly diagnosed cancer from 2019 to 2020 in the US National Cancer Database and calculated the change in proportion of early-stage to late-stage cancers using a weighted linear regression. Disruptions in early-stage diagnosis were greater than in late-stage diagnosis (17% vs 12.5%). Melanoma demonstrated the greatest relative decrease in early-stage vs late-stage diagnosis (22.9% vs 9.2%), whereas the decrease was similar for pancreatic cancer. Compared with breast cancer, cervical, melanoma, prostate, colorectal, and lung cancers showed the greatest disruptions in early-stage diagnosis. Uninsured patients experienced greater disruptions than privately insured patients. Disruptions in cancer diagnosis in 2020 had a larger impact on early-stage disease, particularly screen-detected cancers. Our study supports emerging evidence that primary care visits may play a critical role in early melanoma detection.

Racial Disparities in Cancer Stage at Diagnosis and Survival for Adolescents and Young Adults.

Importance: There are limited studies assessing stage at diagnosis and risk of death among all 5 federally defined races in the US among adolescent and young adult (AYA) patients with cancer. Objective: To identify racial disparities in stage at diagnosis and survival among AYA patients with cancer. Design, Setting, and Participants: This retrospective cohort study used data from a US national hospital-based oncology database on AYA patients, aged 15 to 39 years, with the 10 deadliest cancers among AYA patients who received a diagnosis from January 1, 2004, to December 31, 2017, with 6 months or more of follow-up. Analyses by race were categorized by the 5 federally defined races in the US: American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific Islander, and non-Hispanic White (hereafter, White). White patients served as the majority reference group. Statistical analysis was performed from November 2022 to September 2023. Main Outcomes and Measures: The primary end points were late stage at diagnosis (logistic regression with adjusted odds ratios [AORs] and 95% CIs) and overall survival (log-rank tests and Cox proportional hazards regression with adjusted hazard ratios [AHRs] and 95% CIs). Results: A total of 291 899 AYA patients (median age, 33 years [IQR, 28-37 years]; 186 549 female patients [64%]; 189 812 [65%] with stage I or II cancers) were evaluated. The cohort included 1457 American Indian or Alaska Native patients (1%), 8412 Asian patients (3%), 40 851 Black patients (14%), 987 Native Hawaiian or Other Pacific Islander patients (0.3%), and 240 192 White patients (82%). Cancers included breast (n = 79 195 [27%]), lymphoma (n = 45 500 [16%]), melanoma (n = 36 724 [13%]), testis (n = 31 413 [11%]), central nervous system (n = 26 070 [9%]), colon or rectum (n = 22 545 [8%]), cervix (n = 20 923 [7%]), sarcoma (n = 14 951 [5%]), ovary (n = 8982 [3%]), and lung (n = 5596 [2%]). Risk of late-stage diagnosis was higher for Asian (AOR, 1.20; 95% CI, 1.14-1.26), Black (AOR, 1.40; 95% CI, 1.36-1.43), and Native Hawaiian or Other Pacific Islander (AOR, 1.34; 95% CI, 1.16-1.55) patients compared with White patients. Overall survival differed by race for all cancer sites, except cancers of the central nervous system and ovary. Risk of death was higher for American Indian or Alaska Native (AHR, 1.15; 95% CI, 1.02-1.30), Black (AHR, 1.22; 95% CI, 1.19-1.26), and Native Hawaiian or Other Pacific Islander (AHR, 1.25; 95% CI, 1.09-1.44) patients but lower for Asian patients (AHR, 0.90; 95% CI, 0.85-0.95) compared with White patients. Conclusions and Relevance: This cohort study of AYA patients suggests that stage at diagnosis and survival varied across races for the 10 deadliest AYA cancers. These results support the need for tailored interventions and informed public policy to achieve cancer care equity for all races.

Race and Ethnicity Representation in Phase 2/3 Oncology Clinical Trial Publications: A Systematic Review.

Importance: The five 1997 Office of Management and Budget races in the US include American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, and White, with Hispanic ethnicity. Despite the Affordable Care Act mandating Office of Management and Budget-based collecting and reporting standards, race and ethnicity publishing in medical journals is inconsistent, despite being necessary to achieve health equity. Objective: To quantify race and ethnicity reporting rates and calculate representation quotients (RQs) in published oncology clinical trials. Evidence Review: In this systematic review, PubMed and Embase were queried for phase 2/3 clinical trials of the 6 most common noncutaneous solid cancers, published between January 1, 2012, and December 31, 2022, in 4 high-impact journals. Trial characteristics were recorded. The RQs for each race and ethnicity were calculated by dividing the percent of representation in each clinical trial publication by the percent of year-matched, site-specific incident cancers in the US, compared with Kruskal-Wallis tests with Bonferroni correction (BC). Reporting was compared between journal publications and ClinicalTrials.gov. Findings: Among 1202 publications evaluated, 364 met inclusion criteria: 16 JAMA, 241 Journal of Clinical Oncology, 19 Lancet, and 88 New England Journal of Medicine. Publications included 268 209 patients (171 132 women [64%]), with a median of 356 (IQR, 131-800) patients per publication. Reported race and ethnicity included American Indian or Alaska Native in 52 (14%) publications, Asian in 196 (54%), Black or African American in 215 (59%), Hispanic in 67 (18%), Native Hawaiian or Other Pacific Islander in 28 (8%), and White in 254 (70%). Median RQ varied across race (P < .001 BC), with 1.04 (IQR, 0.09-4.77) for Asian, 0.98 (IQR, 0.86-1.06) for White, 0.42 (IQR, 0.12-0.75) for Black or African American, and 0.00 (IQR, 0.00-0.00) for both American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander patients. Sensitivity analyses showed similar findings on subset analysis for US-only clinical trials. There was significantly less race and ethnicity reporting in the clinical trial publications compared with ClinicalTrials.gov documentation for American Indian or Alaska Native (14% vs 45%; P < .001 per McNemar χ2 test with continuity correction [MC]) and Native Hawaiian or Other Pacific Islander (8% vs 43%; P < .001 MC). Conclusions and Relevance: While most phase 2/3 oncology clinical trials published in high-impact journals report race and ethnicity, most did not report American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander racial categories. Our findings support a call to action for consistent journal policies and transparent race and ethnicity reporting, in alignment with Affordable Care Act-concordant race and ethnicity federal reporting requirements.

A Lung Cancer Mouse Model Database.

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

Peroxiredoxin overexpression in MCF-7 breast cancer cells and regulation by cell proliferation and oxidative stress.

Peroxiredoxins are thiol-specific antioxidant proteins that protect cells from ROS-induced cell death and are elevated in several cancers. We found that five of the six mammalian peroxiredoxins are overexpressed in MCF-7 breast cancer cells at the mRNA and protein levels, compared to noncancerous MCF-10A cells. Inhibition of MCF-7 proliferation reduced the levels of several peroxiredoxins. In contrast, all six proteins were strongly and transiently induced in MCF-7 cells by H2O2. These data suggest that coordinate overexpression of peroxiredoxins may be an important cancer cell adaptation, and that these proteins can be regulated by cell proliferation and oxidative stress.

Diversity in Cancer Care: Current Challenges and Potential Solutions to Achieving Equity in Clinical Trial Participation.

ABSTRACT: Access to and participation in cancer clinical trials determine whether such data are applicable, feasible, and generalizable among populations. The lack of inclusion of low-income and marginalized populations limits generalizability of the critical data guiding novel therapeutics and interventions used globally. Such lack of cancer clinical trial equity is troubling, considering that the populations frequently excluded from these trials are those with disproportionately higher cancer morbidity and mortality rates. There is an urgency to increase representation of marginalized populations to ensure that effective treatments are developed and equitably applied. Efforts to ameliorate these clinical trial inclusion disparities are met with a slew of multifactorial and multilevel challenges. We aim to review these challenges at the patient, clinician, system, and policy levels. We also highlight and propose solutions to inform future efforts to achieve cancer health equity.