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Background: Current clinical guidelines recommended primary human papillomavirus (HPV) screening for cervical cancer testing. Previous studies reported patient-level barriers (e.g., limited knowledge and attachment to Pap test) that may hinder wide adoption of primary HPV screening. We assessed these women-level factors following the implementation of primary HPV screening (July 2020) at Kaiser Permanente Southern California (KPSC). Methods: We administered a patient survey (mail and on-line) to female KPSC members aged 30-65 years who received primary HPV screening between October and December 2020. Those who preferred English vs. Spanish language were sampled separately. The survey included domains on knowledge about HPV and HPV screening, awareness of screening guidelines, and attitudes about HPV testing. Demographic data were collected using electronic health records. We used weighted multivariable logistic and modified Poisson regressions for associations between language preference and survey responses. Results: In total, 3,009 surveys were returned (38.0% response rate). Few women (7.0%) found HPV testing as an acceptable screening method. The majority of women (92.2%) remained unaware that HPV testing can replace Pap test for screening. The Pap test was the most preferred screening approach for 33.2% Spanish-speaking women vs. 19.9% English-speaking women. Only 20.6% knew that women aged 30-65 years can be screened every 5 years with cotest or primary HPV screening. Most women (96.4%) did not perceive stigma about taking the HPV test. Conclusion: Proactive patient education will help improve women's knowledge about primary HPV screening, which may facilitate its implementation in additional health care settings.

Objective: To describe patterns of cancer treatment and live birth outcomes that followed a cancer diagnosis during pregnancy. Study Design: The Adolescent and Young Adult (AYA) Horizon Study is an observational study evaluating outcomes in survivors of the five most common types of cancer in this age group (15-39 years old). Of the 23,629 individuals identified diagnosed with breast, lymphoma, thyroid, melanoma, or gynecological cancer in North Carolina (2000-2015) and California (2004-2016), we identified 555 live births to individuals who experienced cancer diagnosis during pregnancy. Births to individuals diagnosed with cancer during pregnancy were matched ∼1:5 on maternal age and year of delivery to live births to individuals without a cancer diagnosis ( N = 2,667). Multivariable Poisson regression was used to compare birth outcomes between pregnancies affected by a cancer diagnosis and unaffected matched pregnancies. Results: Cancer diagnosis during pregnancy was associated with an increased risk of preterm delivery (prevalence ratio [PR] 2.70; 95% confidence interval [CI] 2.24, 3.26); very preterm delivery (PR 1.74; 95% CI 1.12, 2.71); induction of labor (PR 1.48; 95% CI 1.27, 1.73); low birth weight (PR 1.97; 95% CI 1.55, 2.50); and cesarean delivery (PR 1.18; 95% CI 1.04, 1.34) but not associated with low Apgar score (PR 0.90; 95% CI 0.39, 2.06). In our sample, 41% of patients received chemotherapy, half of whom initiated chemotherapy during pregnancy, and 86% received surgery, 58% of whom had surgery during pregnancy. Of the 19% who received radiation, all received radiation treatment following pregnancy. Conclusion: We identified an increased risk of birth outcomes, including preterm and very preterm delivery, induction of labor, low birth weight, and cesarean delivery, to those experiencing a cancer diagnosis during pregnancy. This analysis contributes to the available evidence for those experiencing a cancer diagnosis during pregnancy.

Background: Adolescents and young adults frequently receive chemotherapy near death. We know less about the use of targeted agents and immunotherapy or trends over time., Methods: We conducted a retrospective cohort study of 1836 adolescents and young adults with cancer who died between 2009 and 2019 after receiving care at 1 of 3 sites (Dana-Farber Cancer Institute, Kaiser Permanente Northern California, and Kaiser Permanente Southern California). We reviewed electronic health data and medical records to examine use of cancer-directed therapy in the last 90 days of life, including chemotherapy, targeted therapy, immunotherapy, and investigational drugs., Results: Over the study period, 35% of adolescents and young adults received chemotherapy in the last 90 days of life; 24% received targeted therapy, 7% immunotherapy, and 5% investigational drugs. Additionally, 56% received at least 1 form of systemic cancer-directed therapy in the last 90 days of life. After adjustment for patient sex, race, ethnicity, age, site of care, diagnosis, and years from diagnosis to death, the proportion of adolescents and young adults receiving targeted therapy (odds ratio [OR] = 1.05 per year of death, 95% confidence interval [CI] = 1.02 to 1.10; P = .006), immunotherapy (OR = 1.27, 95% CI = 1.18 to 1.38; P < .0001), and any cancer-directed therapy (OR = 1.04, 95% CI = 1.01 to 1.08; P = .01) in the last 90 days of life increased over time., Conclusions: More than half of adolescents and young adults receive cancer therapy in the last 90 days of life, and use of novel agents such as targeted therapy and immunotherapy is increasing over time. Although some adolescents and young adults may wish to continue cancer therapy while living with advanced disease, efforts are needed to ensure that use of cancer-directed therapy meets preferences of adolescents and young adults approaching death., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.

Purpose: The purpose of this study is to evaluate the associations between neighborhood income, education, and neighborhood racial composition (measured as a low percentage of white residents) and risk of developing cardiovascular diseases (CVD), diabetes (DM), and severe depression among survivors of AYA cancer and matched non-cancer peers., Methods: Two-year survivors of AYA cancers diagnosed at age 15-39 yrs at Kaiser Permanente Southern California (diagnosed 2000-2012) and individually matched (1:13) non-cancer subjects were included. The development of CVD, DM, and severe depression was ascertained via electronic health records. Neighborhood characteristics were obtained from census-based geocoded data. Cox regression evaluated associations between neighborhood characteristics and the health outcomes of interest among both the cancer survivors and the non-cancer comparison cohort and effect modification by cancer survivor status on these relationships., Results: Among cancer survivors (n = 6774), living in mostly non-white neighborhoods, was associated with risk of CVD (hazard ratio (HR) = 1.54 (95% CI 1.00-2.36)), while lower education level (HR = 1.41 (95% CI 1.02-1.94)) was associated with risk of severe depression. None of the neighborhood characteristics were associated with risk of DM. Effect modification was found for neighborhood education and risk of DM and severe depression., Conclusion: When jointly considered, cancer survivors who resided in the most disadvantaged neighborhoods were at the highest risk of developing these health outcomes compared to other subgroups., Implications for Cancer Survivors: Our findings may inform screening strategy and addressing social determinants of health among AYA cancer survivors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Little evidence exists to guide continuation of screening beyond the recommended ages of national guidelines for breast, cervical, and colorectal cancers, although increasing age and comorbidity burden is likely to reduce the screening benefit of lower mortality., Objective: Characterize screening after recommended stopping ages, by age and comorbidities in a large, diverse sample., Design: Serial cross-sectional., Participants: All individuals in the PROSPR-I consortium cohorts from 75 to 89 years of age for breast cancer screening, 66-89 years of age for cervical cancer screening, and 76-89 years of age for colorectal cancer screening from 2011 to 2013. The lower age thresholds were based on the guidelines for each respective cancer type., Main Measures: Proportion of annual screening by cancer type in relation to age and Charlson comorbidity score and median years of screening past guideline age. We estimated the likelihood of screening past the guideline-based age as a function of age and comorbidity using logistic regression., Key Results: The study cohorts included individuals screening for breast (n = 33,475); cervical (n = 459,318); and colorectal (n = 556,356) cancers. In the year following aging out, approximately 30% of the population was screened for breast cancer, 2% of the population was screened for cervical, and almost 5% for colorectal cancer. The median number of years screened past the guideline-based recommendation was 5, 3, and 4 for breast, cervical, and colorectal cancer, respectively. Of those screening  > 10 years past the guideline-based age,15%, 46%, and 25% had  ≥ 3 comorbidities respectively. Colorectal cancer screening had the smallest decline in the likelihood of screening beyond the age-based recommendation., Conclusions: The odds of screening past guideline-based age decreased with comorbidity burden for breast and cervical cancer screening but not for colorectal. These findings suggest the need to evaluate shared decision tools to help patients understand whether screening is appropriate and to generate more evidence in older populations., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic posed critical challenges in providing care to ovarian cancer (OC) patients, including delays in OC diagnosis and treatment initiation. To accommodate for delays in OC surgery, the Society of Gynecologic Oncology (SGO) recommended preferential use of neoadjuvant chemotherapy during the pandemic. The purpose of this study was to assess the association of the COVID-19 pandemic with neoadjuvant chemotherapy use in patients diagnosed with OC., Methods: This retrospective cohort study included patients diagnosed with stage II-IV ovarian cancer of epithelial subtype between 01/01/2017-06/30/2021 at Kaiser Permanente Southern California (KPSC), a large integrated healthcare system in the United States. Ovarian cancer patients diagnosed between 2017-2020 were identified from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry. Patients diagnosed in 2021 were identified from the electronic medical records (EMR) using ICD-10 diagnosis codes, followed by medical chart review to validate diagnosis and extract information on histology and stage at diagnosis. March 4, 2020 was used as the cut-off to define pre-pandemic and pandemic periods. Patients diagnosed with COVID-19 between OC diagnosis and treatment completion were excluded. Data on neoadjuvant chemotherapy use were extracted from the cancer registry and EMR, supplemented by chart review. Modified Poisson regression was used to evaluate the association of the pandemic with neoadjuvant chemotherapy use., Results: Of 566 OC patients, 160 (28.3%) were diagnosed in the pandemic period. Patients diagnosed in the pandemic period were slightly younger (mean age 62.7 vs 64.9 years, p=0.07) and had a higher burden of Charlson comorbidities (p=0.05) than patients diagnosed in pre-pandemic period. No differences in time to treatment initiation were observed by pandemic periods. Neoadjuvant chemotherapy use was documented in 58.7% patients during the pandemic period compared to 47.3% in pre-pandemic period (p=0.01). After adjusting for covariates, patients diagnosed in the pandemic period were 29% more likely to receive neoadjuvant chemotherapy than patients diagnosed in pre-pandemic period [RR(95%CI): 1.29(1.12-1.49)]., Discussions: Ovarian cancer patients diagnosed in the COVID-19 pandemic were more likely to receive neoadjuvant chemotherapy than patients diagnosed before the pandemic. Future research on patient outcomes and trends in the post-pandemic period are warranted., Competing Interests: Author LX was employed by MedHealth Statistical Consulting Inc. Authors ES and MM are employees of Merck & Co, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The authors declare that this study received funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and AstraZeneca UK Ltd. The funder was involved in the study design and interpretation of data., (Copyright © 2024 Mukherjee, Shammas, Xu, Cannavale, Gilfillan, Szamreta, Monberg, Hodeib and Chao.)

Adolescents, young adults with cancer receive limited psychosocial and spiritual support near death.

Purpose: When a cancer diagnosis coincides with caring for children, it may influence the financial impacts of cancer and decisions to pursue advance care planning (ACP) or genetic testing. We examined associations between caring for children and financial hardship, ACP, and genetic testing among female adolescent and young adult (AYA) cancer survivors in North Carolina and California. Methods: Participants were diagnosed at ages 15-39 years with breast, melanoma, gynecologic, lymphoma, or thyroid cancer during 2004-2016. We estimated adjusted prevalence differences (aPDs) and ratios (aPRs) for each outcome by child caring status using marginal structural binomial regression models. Results: Among 1595 women ages 19-54 years at survey (median = 7 years since diagnosis), 819 (51.3%) reported that they were caring for children at diagnosis. Women caring for children had a higher prevalence of material financial hardship (e.g., medical debt; 30% vs. 21.9%; aPD = 9%, 95% confidence interval [CI]: 3 to 14; aPR = 1.39, 95% CI: 1.12 to 1.72) but similar levels of psychological financial hardship compared to noncaregivers. Women caring for children were more likely to complete ACPs (42.2% vs. 30.7%; aPD = 9%, 95% CI: 3 to 16; aPR = 1.30, 95% CI: 1.08 to 1.57). Among the 723 survivors of breast, endometrial, and ovarian cancer, the prevalence of genetic testing was higher among women caring for children (89%) than noncaregivers (81%); this difference was not statistically significant. Conclusion: Women caring for children at diagnosis may be at elevated risk for adverse financial outcomes and may benefit from additional financial navigation support. Childcare responsibilities may further complicate health decision-making for AYAs diagnosed with cancer.

Background: Many women diagnosed with cancer as adolescents and young adults (AYAs, age 15-39 years) want biological children after cancer but lack information on the potential impact of their cancer history on future reproductive outcomes. We investigated the risk of adverse birth outcomes among AYA cancer survivors., Methods: We identified insured women diagnosed with AYA breast cancer, thyroid cancer, gynecologic cancers, lymphoma, or melanoma from 2003 to 2016 in the state of North Carolina or the Kaiser Permanente health care systems in northern and southern California. Post-diagnosis births to cancer survivors were each matched with up to 5 births to women without cancer. Risk ratios for preterm birth (<37 completed weeks), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and small for gestational age (SGA, <10th percentile of weight for gestational age) were estimated using modified Poisson regression., Results: Analyses included 1648 births to 1268 AYA cancer survivors and 7879 births to 6066 women without cancer. Overall, risk of preterm birth, very preterm birth, low birth weight, and SGA did not significantly differ between births to women with and without cancer. However, births to women with gynecologic cancers had a significantly increased risk of low birth weight (risk ratio = 1.82; 95% confidence interval: 1.03 to 3.21) and suggested increased risk of preterm birth (risk ratio = 1.59; 95% confidence interval: 0.99 to 2.54). Chemotherapy exposure was not associated with increased risk of adverse birth outcomes., Conclusions: Women with gynecologic cancers, but not other cancers, had an increased risk of adverse birth outcomes compared to women without cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Adolescents and young adults (AYAs) with advanced cancer identify maintaining a good quality of life (QoL) as a central goal of end-of-life care. QoL is a dynamic and subjective overarching concept that refers to an individual's relative satisfaction with their own life. Despite its importance to AYAs with advanced cancer, a patient-centered definition of QoL is lacking in this population., Patients and Methods: This qualitative secondary analysis of semistructured interviews was conducted across 3 institutions and 1 online support community among AYA patients with advanced cancer, family caregivers, and health care providers who cared for living or recently deceased AYAs. Interviewees were asked about priorities in receipt of care. Interviews were transcribed using NVivo software for primary analysis, and previously coded excerpts were screened for references to QoL. Relevant excerpts were sorted into organizing domains., Results: Participants included 23 AYA patients, 28 family caregivers, and 29 health care providers (including physicians, nurses, nurse practitioners, social workers, and psychologists). Four domains of QoL were identified: psychosocial and physical well-being, dignity, normalcy, and personal and family relationships. Within each domain there was agreement across AYAs, caregivers, and health care providers, with nuanced perspectives provided by AYAs of different ages. Personal and family relationships was the most frequently referenced domain of QoL among all participants. A common feature of each domain was that adaptation to current circumstances impacted perspectives on QoL. Patients valued active participation in the development of a care plan that supported these domains., Conclusions: AYAs with advanced cancer, their caregivers, and health care providers agree on several broad domains of QoL in this population. To provide high-quality, patient-centered care, care plans should integrate these domains to enable AYAs to maximize their QoL throughout their advanced cancer care.

Purpose: Adolescents and young adults (AYAs) with cancer receive high rates of medically intensive measures at the end of life. This study aimed to characterize the prevalence and timing of conversations about goals of care and advance care planning among AYAs at the end of life as one potential influence on care received., Methods: This was a review of electronic health data and medical records for 1,929 AYAs age 12-39 years who died after receiving care at one of three sites between 2003 and 2019, including documented conversations about goals of care and advance care planning, and care received., Results: A majority of AYAs were female (54%) and White (61%); 12% were Asian, 8% Black, and 27% Hispanic. Most patients had documented discussions about prognosis (86%), goals of care (83%), palliative care (79%), hospice (79%), and preferred location of death (64%). When last documented goals of care were evaluated, 69% of patients wanted care focused on palliation; however, 29% of those with palliative goals spent time in the intensive care unit (ICU) in the last month of life, and 32% had multiple emergency room (ER) visits. When goals-of-care discussions happened earlier, >30 days before death, AYAs were less likely to receive chemotherapy in the last 14 days of life ( P = .001), ICU care ( P < .001), ER visits ( P < .001), and hospitalizations in the last month ( P < .001)., Conclusion: High rates of medically intensive measures among AYAs near the end of life do not appear to be the result of a lack of discussions about goals of care and advance care planning. Although some interventions may be used to support palliative goals, earlier discussions have potential to reduce late-life intensive measures.

Background: We used a genome-wide discovery approach to identify methylation markers associated with metastasis in men with localized prostate cancer (PCa), as better identification of those at high risk of metastasis can inform treatment decision-making., Methods: We identified men with localized PCa at Kaiser Permanente California (January 1, 1997-December 31, 2006) who did not receive curative treatment and followed them for 10 years to determine metastasis status. Cases were chart review-confirmed metastasis, and controls were matched using density sampling. We extracted DNA from the cancerous areas in the archived diagnostic tissue blocks. We used Illumina's Infinium MethylationEPIC BeadChip for methylation interrogation. We used conditional logistic regression and Bonferroni's correction to identify methylation markers associated with metastasis. In a separate validation cohort (2007), we evaluated the added predictive utility of the methylation score beyond clinical risk score., Results: Among 215 cases and 404 controls, 31 CpG sites were significantly associated with metastasis status. Adding the methylation score to the clinical risk score did not meaningfully improve the c-statistic (0.80-0.81) in the validation cohort, though the score itself was statistically significant (p < 0.01). In the validation cohort, both clinical risk score alone and methylation marker score alone are well calibrated for predicted 10-year metastasis risks. Adding the methylation score to the clinical risk score only marginally improved predictive risk calibration., Conclusion: Our findings do not support the use of these markers to improve clinical risk prediction. The methylation markers identified may inform novel hypothesis in the roles of these genetic regions in metastasis development., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: The patient-clinician therapeutic alliance is an important aspect of high-quality cancer care. However, components of the therapeutic alliance in adolescents and young adults (AYAs, aged 12-39 years) with cancer have not been defined., Objective: To identify components of and barriers to the therapeutic alliance between AYAs, caregivers, and clinicians from the perspective of all key stakeholders., Design, Setting, and Participants: In this qualitative study, semistructured in-depth interviews with patients, caregivers, and clinicians were conducted from 2018 to 2021 with no additional follow-up, with content analysis of resulting transcripts. Participants were recruited from Dana-Farber Cancer Institute, Kaiser Permanente Northern California, Kaiser Permanente Southern California, and an online cancer support community (Cactus Cancer Society). Eligible participants were English- or Spanish-speaking. Eligible patients were aged 12 to 39 years with stage IV or recurrent cancer. Eligible caregivers cared for an AYA living with advanced cancer or one who had died within 5 years. Eligible clinicians routinely provided care for AYAs with cancer., Main Outcomes and Measures: Perspectives on therapeutic alliance., Results: Interviews were conducted with 80 participants: 23 were patients (48% were female; 78% were White), 28 were caregivers (82% were female; 50% were White), and 29 were clinicians (69% were female; 45% were White). The mean (SD) age of patients was 29 (7.3) years. Interviews identified 6 components of therapeutic alliance: (1) compassion; (2) sense of connection; (3) clinician presence; (4) information sharing; (5) shared goals; and (6) individualization of care. While some domains were represented in prior models of therapeutic alliance, a unique domain was identified related to the need for individualization of the approach to care for AYA patients and their caregivers. Interviews also identified potential barriers to building the therapeutic alliance specific to the AYA population, including managing discordant needs between patients and caregivers and communication challenges at the end of life., Conclusions and Relevance: This study identified core components and barriers to building therapeutic alliance in the AYA advanced cancer population from the perspective of all the key stakeholders in the relationship. A novel component highlighting the need for individualization was identified. This model enables a deeper understanding of how to build therapeutic alliance in the AYA advanced cancer population, which may guide clinician training and facilitate improved care for this vulnerable population.

Context: Quality measures have been devised for end-of-life care of older adults with cancer, but are lacking for adolescents and young adults (AYAs)., Objective: We previously conducted interviews with AYAs, family caregivers, and clinicians to identify priority domains for high quality care of AYAs with advanced cancer. The goal of this study was to use a modified Delphi process to form consensus around the highest priority quality indicators., Methods: A modified Delphi process was conducted with 10 AYAs with recurrent or metastatic cancer, 11 family caregivers, and 29 multidisciplinary clinicians, using small group web conferences. Participants were asked to rate the importance of each of 41 potential quality indicators, rank the 10 most important, and engage in discussion to reconcile differences., Results: Of 41 initial indicators, 34 were rated as highly important (rating seven, eight, or nine on a nine-point scale) by >70% of participants. The panel was unable to reach consensus around the 10 most important indicators. Instead, participants recommended retaining a larger set of indicators to reflect potential for different priorities across the population, resulting in a final set of 32 indicators. Recommended indicators broadly encompassed attention to physical symptoms; quality of life; psychosocial, and spiritual care; communication and decision-making; relationships with clinicians; care and treatment; and independence., Conclusion: A patient- and family-centered process for quality indicator development led to strong endorsement of multiple potential indicators by Delphi participants. Further validation and refinement will be performed using a survey of bereaved family members., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. All rights reserved.)

Introduction: Abortion is a common gynecological procedure and plays a central role in women's health and autonomy. To maintain accessibility to abortion, it is important that sufficient obstetrics and gynecology (Ob/Gyn) residents intend to provide abortion care after residency. This study identifies factors that influence a resident's intention to provide abortions (IPA) post-training., Materials and Methods: A multiple-choice survey, addressing demographics, religious background, residency program metrics, training experience and intent to provide abortions (IPA), was answered by 409 Ob/Gyn residents. Chi-square test was performed on descriptive statistics and continuous variables were tested with ANOVA with p<0.05 considered significant., Results: Residents with IPA were predominantly female (p = 0.001), training in the Northeast and West (p<0.001), identifying either as non-religious, agnostic/atheist or Jewish (p<0.01), not actively practicing their religion (p<0.001) and leaning democrats (p<0.002). Those with IPA were more likely to train at hospitals without religious affiliation (p<0.008), to train at a Ryan Program (p<0.001), to place strong emphasis on choosing a program with family planning training (p<0.001), to join programs where a significant portion of the faculty performs abortions (p<0.001) and to have completed a higher number of first trimester medical and surgical abortion procedures during the last six months of training (p<0.001)., Conclusion: These results suggest that factors influencing a physician's intention to provide abortions are multifactorial, involving personal and program factors. A model predicting IPA is derived. To maximize IPA, residency programs can increase abortion volume, facilitate additional training and build a supportive faculty., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kramer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The use and misuse of opioids, as well as opioid use disorder (OUD) have increased remarkably among reproductive-aged and pregnant women. As many as 25% of pregnant women who report non-medical opioid use in the past month also report concurrent alcohol use. While teratogenic effects of alcohol are well established, there are limited studies evaluating fetal intracranial effects associated with medications for OUD (MOUD) and concurrent use of MOUD and alcohol during pregnancy. The objective of this study was to determine the effect of MOUD, with and without concomitant alcohol use, on fetal intracranial measurements. The type of maternal MOUD therapy (methadone vs. buprenorphine) was also examined., Methods: This study was a secondary analysis of a prospective cohort study among participants (n = 196) assigned into three groups (MOUD [n = 94], MOUD+Alcohol [n = 47], and unexposed controls [n = 55]). Co-exposure with either methamphetamines or cocaine were exclusionary criteria; other co-exposures were carefully characterized with prospective repeated self-report measures and biomarkers. Fetal ultrasound measurements at 18-22 weeks (2nd trimester) and 28-32 weeks (early 3rd trimester) were compared among study groups. In addition to standard morphometrics, we performed specialized intracranial measurements of caval-calvarial distance (CCD), frontal lobe width (FLW), frontal lobe length (FLL), and fronto-thalamic distance (FTD)., Results: Brain and cranial measurements between MOUD, with or without alcohol co-exposure, and unexposed controls were generally not significantly different in multivariable analyses. Subjects in the MOUD groups had earlier gestational age at delivery and lower birth weight and birth weight percentile compared to unexposed controls with differences driven primarily by the methadone subgroup. Significant differences in standard and specialized intracranial indices at both second and third trimester as well as differences in the change of HC percentile over time were observed in the methadone subgroup compared to controls, while no differences between buprenorphine subgroup and controls were observed for any measures., Conclusion: Patients receiving methadone therapy might require closer monitoring during pregnancy; however, detailed imaging of the fetal brain other than the standard measurements might not be warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ludmila Bakhireva reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Few studies have evaluated the effect of statin exposure on metastasis risk among prostate cancer patients not receiving curative treatment., Methods: We included men diagnosed with localized prostate cancer at an integrated health care system between 1997 and 2006 who did not receive curative treatment within 6 months of diagnosis. We followed these men until a metastatic event, disenrollment, death, or 12/31/2016. We collected all data from electronic health records supplemented by chart review. We used Cox regressions to examine the association between post-diagnostic statin exposure and metastasis, controlling for clinical characteristics and pre-diagnostic statin exposure., Results: There were 4245 men included. Mean age of diagnosis was 68.02 years. 46.6% of men used statins after prostate cancer diagnosis. During follow-up, 192 men developed metastasis (cumulative incidence rate: 14.5%). In the adjusted Cox model, statin use post-prostate cancer diagnosis was not significantly associated with a metastatic event (HR = 0.97, 95% CI = 0.69, 1.36). Pre-diagnostic statin use was also not associated with development of metastasis (HR = 0.76, 95% CI = 0.53, 1.10). We did not observe a dose-response for the proportion of person-time at-risk post-prostate cancer diagnosis on statins (HR = 0.98 per 10% increase in person-time exposed [95% CI = 0.93, 1.03])., Conclusions: We did not find an inverse association between post-diagnosis statin exposure and metastasis development in localized prostate cancer patients who did not receive active treatment. Our results did not offer support to the chemopreventive potential of post-diagnostic statin use among men on active surveillance., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies., Aims: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk., Methods and Results: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code., Conclusion: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Objective: To examine whether demographic and cancer-related characteristics and factors such as fertility discussion with a medical provider and fertility preservation use are associated with attempting pregnancy after adolescent and young adult cancer., Design: Cross-sectional online survey., Setting: Not applicable., Patient(s): Women with lymphoma, breast cancer, thyroid cancer, or gynecologic cancer diagnosed at 15-39 years from 2004 to 2016 were identified from the North Carolina Cancer Registry and the Kaiser Permanente Northern and Southern California health care systems and responded to an online survey addressing survivorship concerns, including fertility and reproductive outcomes., Exposures: Demographic characteristics, cancer characteristics, fertility discussion with a medical provider or fertility specialist between cancer diagnosis and starting cancer treatment, use of fertility preservation strategies (freezing embryos or oocytes) after cancer diagnosis., Main Outcome Measure(s): Pregnancy attempt after cancer diagnosis, defined by either a pregnancy or 12 months of trying to become pregnant without pregnancy., Result(s): Among 801 participants who had not reached their desired family size at diagnosis, 77% had a fertility discussion with any medical provider between cancer diagnosis and treatment initiation, and 8% used fertility preservation after cancer diagnosis. At survey (median =7 years after diagnosis; interquartile range, 4-10), 32% had attempted pregnancy. Neither fertility discussion with any medical provider nor fertility counseling with a fertility specialist was significantly associated with pregnancy attempts. However, the use of fertility preservation was significantly associated with attempting pregnancy (prevalence ratios = 1.74; 95% confidence interval: 1.31-2.32). Other characteristics positively associated with pregnancy attempts included younger age at diagnosis, longer time since diagnosis, having a partner (at diagnosis or at survey), and having a history of infertility before cancer diagnosis., Conclusion(s): Use of fertility preservation strategies was uncommon in our cohort but was associated with attempting pregnancy after cancer. Ensuring access to fertility preservation methods may help adolescent and young adult cancer survivors to plan and initiate future fertility., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Potential care gaps in the cervical cancer screening process among women diagnosed with cervical cancer in an era with increased human papillomavirus (HPV) testing have not been extensively evaluated., Methods: Women diagnosed with cervical cancer between ages 21 and 65 at four study sites between 2010 and 2014 were included. Screening histories were ascertained from 0.5 to 4 years prior to cervical cancer diagnosis. We identified potential care gaps in the screening history for each woman and classified them into one of three mutually exclusive types: lack of a screening test, screening test failure, and diagnostic/treatment care gap. Distributions of care gaps were tabulated by stage, histology, and study site. Multivariable nominal logistic regression was used to examine the associations between demographic and cancer characteristics and type of care gap., Results: Of 499 women evaluated, 46% lacked a screening test in the time window examined, 31% experienced a screening test failure, and 22% experienced a diagnostic/treatment care gap. More than half of the women with advanced cancer and squamous cell carcinoma lacked a screening test compared to 31% and 24% of women with localized cancer and adenocarcinoma, respectively. Women aged 21-29 at diagnosis were more likely to experience screening test failure and diagnostic/treatment care gap, while those aged 50-65 were more likely to lack a screening test, compared to women aged 30-39., Conclusions: Our findings demonstrate a continuing need to develop interventions targeting unscreened and under-screened women and improve detection and diagnosis of adenocarcinoma in women undergoing cervical cancer screening and diagnostic follow-up., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Adolescents and young adults (AYAs) with advanced cancer identify normalcy as an important component of quality end-of-life care. We sought to define domains of normalcy and identify ways in which clinicians facilitate or hinder normalcy during advanced cancer care., Procedure: This was a secondary analysis of a qualitative study that aimed to identify priority domains for end-of-life care. Content analysis of semi-structured interviews among AYAs aged 12-39 years with advanced cancer, caregivers, and clinicians was used to evaluate transcripts. Coded excerpts were reviewed to identify themes related to normalcy., Results: Participants included 23 AYAs with advanced cancer, 28 caregivers, and 29 clinicians. Participants identified five domains of normalcy including relationships, activities, career/school, milestones, and appearance. AYAs and caregivers identified that clinicians facilitate normalcy through exploration of these domains with AYAs, allowing flexibility in care plans, identification of short-term and long-term goals across normalcy domains, and recognizing losses of normalcy that occur during cancer care., Conclusions: AYAs with cancer experience multiple threats to normalcy during advanced cancer care. Clinicians can attend to normalcy and improve AYA quality of life by acknowledging these losses through ongoing discussions on how best to support domains of normalcy and by reinforcing AYA identities beyond a cancer diagnosis., (© 2022 Wiley Periodicals LLC.)

Background: Limited guidance exists regarding implementation strategies that best facilitate cancer screening practice substitution and achieve optimal stakeholder-centered outcomes. Here we describe the protocol for a randomized pragmatic trial comparing two implementation strategies to facilitate substitution of primary HPV screening for Pap and HPV co-testing to perform routine cervical cancer screening of women aged 30-65 years at Kaiser Permanente Southern California (KPSC)., Methods: Twelve service areas within KPSC will be randomized to a "centrally-administered system-wide implementation + local-tailored implementation" strategy or a "centrally-administered system-wide implementation only" strategy. The centrally-administered strategy comprises clinician and staff educational activities. Sites in the local-tailored arm will then conduct a structured local needs assessment followed by site-specific selection and deployment of implementation interventions. Surveys and interviews will be conducted among women and providers from the primary care and ob/gyn departments prior to the system-wide transition, shortly after the transition, and after the completion of local-tailored interventions. A stakeholder advisory committee will assist with study design, defining stakeholder-centered outcomes, and developing data collection tools., Results: The primary outcome of interest is uptake of primary HPV screening. Secondary provider-centered outcomes include provider knowledge, delivery of patient education, satisfaction with the practice substitution process, and resistance to primary HPV screening. Secondary patient-centered outcomes include patient knowledge, stigma, and satisfaction with the screening process. Intervention fidelity will also be measured via surveys., Conclusions: Findings from this study will help inform future use of a local-tailored implementation strategy for adopting primary HPV screening at large health care systems. Findings may also be applicable to other types of practice substitution., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: We sought to evaluate the trends of HPV vaccination between 03/2019-09/2021 and whether the impact of the COVID pandemic on HPV vaccination varied by race/ethnicity and neighborhood deprivation index (NDI)., Methods: Electronic medical records at Kaiser Permanente Southern California were used to assess monthly volume of HPV vaccine doses administered among children aged 9-12.9yrs, and up-to-date coverage (% vaccinated) by age 13 between 03/2019-09/2021. Modified Poisson models were used to evaluate the interactions between race/ethnicity, NDI and the pandemic periods on HPV vaccine coverage., Results: HPV vaccine doses administered in 2020/2021 have returned to the 2019 level after the initial drop. The average up-to-date coverage in 05/2021-09/2021 (54.8%) remained lower than the pre-pandemic level (58.5%). The associations between race/ethnicity, NDI and HPV vaccine coverage did not vary due to the pandemic., Conclusion: HPV vaccine promotion efforts are needed to address COVID-19 pandemic's lasting impact on HPV vaccination coverage., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chao CR received research funding from Merck for an unrelated project., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Obesity is a risk factor for multiple myeloma (MM), yet results of prior studies have been mixed regarding the importance of early and/or later adult obesity; other measures of body composition have been less well studied., Methods: We evaluated associations of early adult (ages 18-21) and usual adult body mass index (BMI), waist circumference, and predicted fat mass with MM by pooling data from six U.S. prospective cohort studies comprising 544,016 individuals and 2756 incident diagnoses over 20-37 years of follow-up. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations, adjusted for age and other risk factors., Results: Each 5 kg/m 2 increase in usual adult BMI was associated with a 10% increased risk of MM (HR: 1.10; 95% CI: 1.05-1.15). Positive associations were also noted for early adult BMI (HR per 5 kg/m 2 : 1.14; 95% CI: 1.04-1.25), height (HR per 10 cm: 1.28; 95% CI: 1.20-1.37), waist circumference (HR per 15 cm: 1.09; 95% CI: 1.00-1.19), and predicted fat mass (HR per 5 kg: 1.06; 95% CI: 1.01-1.11)., Conclusions: These findings highlight the importance of avoidance of overweight/obesity and excess adiposity throughout adulthood as a potential MM risk-reduction strategy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Adolescents and young adults (AYAs) with cancer have high rates of hospital deaths. It is not clear if this reflects their preferences or barriers to dying at home., Methods: Between December 2018 and January 2021, we conducted in-depth interviews with AYAs (age 12-39 years) with stage IV or recurrent cancer, family caregivers including bereaved caregivers, and clinicians of AYAs with cancer. Patients were asked about their priorities for care including location of death, caregivers were asked what was most important in the care of their AYA family member, and clinicians were asked to reflect on priorities identified through caring for AYAs. Directed content analysis was applied to interview data, and themes regarding location of death were developed., Results: Eighty individuals (23 AYAs, 28 caregivers, and 29 clinicians) participated in interviews. Most AYAs and caregivers preferred a home death. However, some AYAs and caregivers opted for a hospital death to alleviate caregiver burden or protect siblings from the perceived trauma of witnessing a home death. Lack of adequate services to manage intractable symptoms at home and insufficient caregiver support led some AYAs/caregivers to opt for hospital death despite a preference for home death. Participants acknowledged the value of hospice while also pointing out its limitations in attaining a home death., Conclusion: Although most AYAs prefer to die at home, this preference is not always achieved. Robust home-based services for effective symptom management and caregiver support are needed to close the gap between preferred and actual location of death for AYAs.

In 2022, more than 100 000 non-Hodgkin lymphoma (NHL) diagnoses are expected, yet few risk factors are confirmed. In this study, data from six US-based cohorts (568 717 individuals) were used to examine body size and risk of NHL. Over more than 20 years of follow-up, 11 263 NHLs were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) estimated associations with NHLs for adult body mass index (BMI), height, weight change, waist circumference and predicted fat mass. Adult height was broadly associated with NHL, but most strongly with B-cell NHLs among non-White participants (e.g. HR BLACK  = 2.06, 95% CI: 1.62-2.62). However, the strongest association among the anthropometric traits examined was for young adult BMI and risk of diffuse large B-cell lymphoma (DLBCL), particularly those who maintained a higher BMI into later adulthood. Individuals with BMI over 30 kg/m 2 throughout adulthood had more than double the DLBCL risk (HR = 2.67, 95% CI: 1.71-4.17) compared to BMI 18.5-22.9 kg/m 2 . Other anthropometric traits were not associated with NHL after controlling for BMI. These results suggest that sustained high BMI is a major driver of DLBCL risk. If confirmed, we estimate that up to 23.5% of all DLBCLs (and 11.1% of all NHLs) may be prevented with avoidance of young adult obesity., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Financial hardship among adolescents and young adults (AYA) with cancer who receive gonadotoxic treatments may be exacerbated by the use of fertility services. This study examined whether AYA women with cancer who used fertility preservation had increased financial hardship., Methods: AYA women with cancer in North Carolina and California completed a survey in 2018-2019. Cancer-related financial hardship was compared between women who cryopreserved oocytes or embryos for fertility preservation after cancer diagnosis (n = 65) and women who received gonadotoxic treatment and reported discussing fertility with their provider, but did not use fertility preservation (n = 491). Multivariable log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CI)., Results: Women were a median age of 33 years at diagnosis and 7 years from diagnosis at the time of survey. Women who used fertility preservation were primarily ages 25 to 34 years at diagnosis (65%), non-Hispanic White (72%), and had at least a Bachelor's degree (85%). In adjusted analysis, use of fertility preservation was associated with 1.50 times the prevalence of material financial hardship (95% CI: 1.08-2.09). The magnitude of hardship was also substantially higher among women who used fertility preservation: 12% reported debt of ≥$25,000 versus 5% in the referent group., Conclusions: This study provides new evidence that cryopreserving oocytes or embryos after cancer diagnosis for future family building is associated with increased financial vulnerability., Impact: More legislation that mandates insurance coverage to mitigate hardships stemming from iatrogenic infertility could improve access to fertility preservation for young women with cancer., (©2022 American Association for Cancer Research.)

There is little data about treatment practices for relapsed/refractory Hodgkin Lymphoma (HL) in nonacademic settings. We describe sequential treatments and outcomes among HL patients who experienced treatment failure in an integrated community-oncology setting. We performed a retrospective cohort study among patients ≥12 years diagnosed with Stage II-IV HL from 2007 to 2012 at Kaiser Permanente Southern California (KPSC). Of 463 HL patients, 75 (16.1%) experienced treatment failure. Patients with failure received between 1 and 8 salvage therapies; 28% received ≥4 lines of therapy. Fifty-nine of 75 (79%) were initially salvaged with ifosfamide-based therapy, 44 of whom underwent hematopoietic cell transplant. Ultimately, 47% of patients died, with most deaths due to HL. Survival was shorter with increasing age at diagnosis ( p  = 0.02) and with greater number of lines of therapy ( p  = 0.02). In a community oncology setting, HL patients received multiple lines of salvage. Despite extensive treatment, nearly half of patients died of HL following relapsed/refractory disease.

Adhesions frequently occur postoperatively, causing morbidity. In this noninterventional observational cohort study, we enrolled patients who presented for repeat abdominal surgery, after a history of previous abdominal myomectomy, from March 1998 to June 20210 at St. Vincent's Catholic Medical Centers. The primary outcome of this pilot study was to compare adhesion rates, extent, and severity in patients who were treated with intraperitoneal triamcinolone acetonide during the initial abdominal myomectomy ( n = 31) with those who did not receive any antiadhesion interventions ( n = 21), as documented on retrospective chart review. Adhesions were blindly scored using a standard scoring system. About 32% of patients were found to have adhesions in the triamcinolone group compared to 71% in the untreated group ( p < 0.01). Compared to controls, adhesions were significantly less in number (0.71 vs. 2.09, p < 0.005), severity (0.54 vs. 1.38, p < 0.004), and extent (0.45 vs. 1.28, p < 0.003). To understand the molecular mechanisms, human fibroblasts were incubated in hypoxic conditions and treated with triamcinolone or vehicle. In vitro studies showed that triamcinolone directly prevents the surge of reactive oxygen species triggered by 2% hypoxia and prevents the increase in TGF-β1 that leads to the irreversible conversion of fibroblasts to an adhesion phenotype. Triamcinolone prevents the increase in reactive oxygen species through alterations in mitochondrial function that are HIF-1α-independent. Controlling mitochondrial function may thus allow for adhesion-free surgery and reduced postoperative complications.

Background: Glioma stem-like cells (GSCs) are greatly responsible for the progression of glioma. Long noncoding RNAs (lncRNAs) play an important role in glioma tumor progression. This study aims to explore the role and underlying mechanism of lncRNA SNHG9 in regulating GSC cell growth., Methods: GSCs were obtained from glioma cells (U87 and U251) and referred to as GSC-87 and GSC-251, respectively. The interactions between miR-326 and SNHG9 or SOX9 were analyzed using luciferase reporter assay. Cell growth of GSCs was evaluated by EdU assay and sphere formation assay., Results: SNHG9 expression was significantly higher in GSC-87 and GSC-251 cells than in U87 and U251 cells. SNHG9 overexpression promoted GSC cell growth, whereas SNHG9 knockdown inhibited GSC cell growth. Mechanistically, SNHG9 acted as a competitive endogenous RNA of miR-326 to elevate the expression of SOX9, a direct target of miR-326. Moreover, transfection with miR-326 inhibitor counteracted SNHG9 knockdown-mediated inhibition of GSC cell growth., Conclusions: SNHG9 facilitates growth of GSCs via the miR-326/SOX9 axis. This study provides a promising therapeutic target for glioma treatment., (© 2021 John Wiley & Sons, Ltd.)

Aim: The study aims to determine resident applicant metrics most predictive of academic and clinical performance as measured by the Council of Resident Education in Obstetrics and Gynecology (CREOG) examination scores and Accreditation Council for Graduate Medical Education (ACGME) clinical performance (Milestones) in the aftermath of United States Medical Licensing Examination Scores (USMLE) Step 1 becoming a pass/fail examination., Methods: In this retrospective study, electronic and paper documents for Wayne State University Obstetrics and Gynecology residents matriculated over a 5-year period ending July 2018 were collected. USMLE scores, clerkship grade, and wording on the letters of recommendation as well as Medical Student Performance Evaluation (MSPE) were extracted from the Electronic Residency Application Service (ERAS) and scored numerically. Semiannual Milestone evaluations and yearly CREOG scores were used as a marker of resident performance. Statistical analysis on residents (n = 75) was performed using R and SPSS and significance was set at P  < .05., Results: Mean USMLE score correlated with CREOG performance and, of all 3 Steps, Step 1 had the tightest association. MSPE and class percentile also correlated with CREOGs. Clerkship grade and recommendation letters had no correlation with resident performance. Of all metrics provided by ERAS, none taken alone, were as useful as Step 1 scores at predicting performance in residency. Regression modeling demonstrated that the combination of Step 2 scores with MSPE wording restored the predictive ability lost by Step 1., Conclusions: The change of USMLE Step 1 to pass/fail may alter resident selection strategies. Other objective markers are needed in order to evaluate an applicant's future performance in residency., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: The incidence of early-onset colorectal cancer (eoCRC) diagnosed among individuals under age 50 has been rising. However, risk factors for eoCRC are unclear. We investigated whether metabolic abnormalities are risk factors for eoCRC adenocarcinoma., Methods: Invasive colorectal adenocarcinoma cases diagnosed between ages 15 and 49 from 2008 to 2018 at Kaiser Permanente Southern California (KPSC) were identified. Those with a history of inflammatory bowel disease were excluded. Noncancer controls were selected 5:1 for each case matched by age, sex, and length of membership prior to index date. Data were collected from KSPC's electronic medical records. The exposures of interest included obesity, type II diabetes, hypertension, and dyslipidemia, assessed from ≥1 year prior to eoCRC diagnosis/index date. Conditional logistic regressions were used to evaluate the associations between these metabolic risk factors and risk of eoCRC adenocarcinoma, adjusting for race/ethnicity, smoking, family history, neighborhood socioeconomic status, and health care utilization., Results: A total of 1,032 cases and 5,128 controls were included. Risk of colorectal adenocarcinoma was significantly associated with obesity [odds ratio (OR) = 1.41; 95% confidence interval (CI), 1.15-1.74], but not diabetes, hypertension or dyslipidemia. In analysis stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma OR = 1.56 (1.17-2.07), but its association with rectal adenocarcinoma was less clear OR = 1.19 (0.85-1.68). No significant interaction was detected between obesity and age (≥40 vs. <40), and obesity and sex., Conclusions: Obesity was associated with risk for eoCRC adenocarcinoma., Impact: This finding could help inform early-onset colorectal adenocarcinoma screening and prevention recommendations. See related commentary by Hayes, p. 1775 ., (©2021 American Association for Cancer Research.)

Background: New cervical cancer screening guidelines recommend primary human papillomavirus (HPV) testing for women age 30-65 years. Healthcare organizations are preparing to de-implement the previous recommended strategies of Pap testing or co-testing (Pap plus HPV test) and substitute primary HPV testing. However, there may be significant challenges to the replacement of this entrenched clinical practice, even with an evidence-based substitution. We sought to identify stakeholder-perceived barriers and facilitators to this substitution within a large healthcare system, Kaiser Permanente Southern California., Methods: We conducted semi-structured qualitative interviews with clinician, administrative, and patient stakeholders regarding (a) acceptability and feasibility of the planned substitution; (b) perceptions of barriers and facilitators, with an emphasis on those related to the de-implementation/implementation cycle of substitution; and (c) perceived readiness to change. Our interview guide was informed by the Consolidated Framework for Implementation Research (CFIR). Using a team coding approach, we developed an initial coding structure refined during iterative analysis; the data were subsequently organized thematically into domains, key themes, and sub-themes using thematic analysis, followed by framework analysis informed by CFIR., Results: We conducted 23 interviews: 5 patient and 18 clinical/administrative. Clinicians perceived that patients feel more tests equals better care, and clinicians and patients expressed fear of missed cancers ("…it'll be more challenging convincing the patient that only one test is…good enough to detect cancer."). Patients perceived practice changes resulting in "less care" are driven by the desire to cut costs. In contrast, clinicians/administrators viewed changing from two tests to one as acceptable and a workflow efficiency ("…It's very easy and half the work."). Stakeholder-recommended strategies included focusing on the increased efficacy of primary HPV testing and developing clinician talking points incorporating national guidelines to assuage "cost-cutting" fears., Conclusions: Substitution to replace an entrenched clinical practice is complex. Leveraging available facilitators is key to ease the process for clinical and administrative stakeholders-e.g., emphasizing the efficiency of going from two tests to one. Identifying and addressing clinician and patient fears regarding cost-cutting and perceived poorer quality of care is critical for substitution. Multicomponent and multilevel strategies for engagement and education will be required., Trial Registration: ClinicalTrials.gov, # NCT04371887., (© 2021. The Author(s).)

Importance: End-of-life care quality indicators specific to adolescents and young adults (AYAs) aged 12 to 39 years with cancer have not been developed., Objective: To identify priority domains for end-of-life care from the perspectives of AYAs, family caregivers, and clinicians, and to propose candidate quality indicators reflecting priorities., Design, Setting, and Participants: This qualitative study was conducted from December 6, 2018, to January 5, 2021, with no additional follow-up. In-depth interviews were conducted with patients, family caregivers, and clinicians and included a content analysis of resulting transcripts. A multidisciplinary advisory group translated priorities into proposed quality indicators. Interviews were conducted at the Dana-Farber Cancer Institute, Kaiser Permanente Northern California, Kaiser Permanente Southern California, and an AYA cancer support community (lacunaloft.org). Participants included 23 AYAs, 28 caregivers, and 29 clinicians., Exposure: Stage IV or recurrent cancer., Main Outcomes and Measures: Care priorities., Results: Interviews were conducted with 23 patients (mean [SD] age, 29.3 [7.3] years; 12 men [52%]; 18 White participants [78%]), 28 family caregivers (23 women [82%]; 14 White participants [50%]), and 29 clinicians (20 women [69%]; 13 White participants [45%]). Caregivers included 22 parents (79%), 5 spouses or partners (18%), and 1 other family member (4%); the 29 clinicians included 15 physicians (52%), 6 nurses or nurse practitioners (21%), and 8 social workers or psychologists (28%). Interviews identified 7 end-of-life priority domains: attention to physical symptoms, attention to quality of life, psychosocial and spiritual care, communication and decision-making, relationships with clinicians, care and treatment, and independence. Themes were consistent across the AYA age range and participant type. Although some domains were represented in quality indicators developed for adults, unique domains were identified, as well as AYA-specific manifestations of existing domains. For example, quality of life included global quality of life; attainment of life goals, legacy, and meaning; support of personal relationships; and normalcy. Within communication and decision-making, domains included communication early in the disease course, addressing prognosis and what to expect at the end of life, and opportunity for AYAs to hold desired roles in decision-making. Care and treatment domains relevant to cancer therapy, use of life-prolonging measures, and location of death emphasized the need for preference sensitivity rather than a standard path. This finding differs from existing adult indicators that propose that late-life chemotherapy, intensive measures, and hospital death should be rare., Conclusions and Relevance: The findings of this qualitative study suggest that AYAs with cancer have priorities for care at the end of life that are not fully encompassed in existing indicators for adults. Use of new indicators for this young population may better reflect patient- and family-centered experiences of quality care.

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States., Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data., Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall ( N = 1,679), and notably lower among minority groups compared with non-Hispanic white women., Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements., Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care., (©2021 American Association for Cancer Research.)

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene ( HOXB13 ), as well as a novel candidate gene ( ILDR1 ), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10 -191 ). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637 ., (©2020 American Association for Cancer Research.)

On March 19, 2020, the governor of California issued a statewide stay-at-home order to contain the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19).* The order reduced accessibility to and patient attendance at outpatient medical visits, † including preventive services such as cervical cancer screening. In-person clinic visits increased when California reopened essential businesses on June 12, 2020. § Electronic medical records of approximately 1.5 million women served by Kaiser Permanente Southern California (KPSC), a large integrated health care system, were examined to assess cervical cancer screening rates before, during, and after the stay-at-home order. KPSC policy is to screen women aged 21-29 years every 3 years with cervical cytology alone (Papanicolaou [Pap] test); those aged 30-65 years were screened every 5 years with human papillomavirus (HPV) testing and cytology (cotesting) through July 15, 2020, and after July 15, 2020, with HPV testing alone, consistent with the latest recommendations from U.S. Preventive Services Task Force. ¶ Compared with the 2019 baseline, cervical cancer screening rates decreased substantially during the stay-at-home order. Among women aged 21-29 years, cervical cytology screening rates per 100 person-months declined 78%. Among women aged 30-65 years, HPV test screening rates per 100 person-months decreased 82%. After the stay-at-home order was lifted, screening rates returned to near baseline, which might have been aided by aspects of KPSC's integrated, organized screening program (e.g., reminder systems and tracking persons lost to follow-up). As the pandemic continues, groups at higher risk for developing cervical cancers and precancers should be evaluated first. Ensuring that women receive preventive services, including cancer screening and appropriate follow-up in a safe and timely manner, remains important., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: The importance of addressing adverse financial effects of cancer among adolescents and young adults (AYAs) is paramount as survival improves. In the current study, the authors examined whether cancer-related employment disruption was associated with financial hardship among female AYA cancer survivors in North Carolina and California., Methods: AYA cancer survivors identified through the North Carolina Central Cancer Registry and the Kaiser Permanente Northern/Southern California tumor registries responded to an online survey. Disrupted employment was defined as reducing hours, taking temporary leave, or stopping work completely because of cancer. Financial hardship was defined as material conditions or psychological distress related to cancer. Descriptive statistics and chi-square tests were used to characterize the invited sample and survey respondents. Marginal structural binomial regression models were used to estimate prevalence differences (PDs) and 95% confidence intervals (95% CIs)., Results: Among 1328 women employed at the time of their diagnosis, women were a median age of 34 years at the time of diagnosis and 7 years from diagnosis at the time of the survey and approximately 32% experienced employment disruption. A substantial percentage reported financial hardship related to material conditions (27%) or psychological distress (50%). In adjusted analyses, women with disrupted employment had a 17% higher burden of material conditions (95% CI, 10%-23%) and an 8% higher burden of psychological distress (95% CI, 1%-16%) compared with those without disruption., Conclusions: Financial hardship related to employment disruption among female AYA cancer survivors can be substantial. Interventions to promote job maintenance and transition back to the workforce after treatment, as well as improved workplace accommodations and benefits, present an opportunity to improve cancer survivorship., (© 2020 American Cancer Society.)

Background: There is limited research on the racial/ethnic differences in long-term outcomes for men with untreated, localized prostate cancer., Methods: Men diagnosed with localized, Gleason ≤7 prostate cancer who were not treated within 1 year of diagnosis from 1997-2007 were identified. Cumulative incidence rates of the following events were calculated; treatment initiation, metastasis, death due to prostate cancer and all-cause mortality, accounting for competing risks. The Cox model of all-cause mortality and Fine-Gray sub distribution model to account for competing risks were used to test for racial/ethnic differences in outcomes adjusted for clinical factors., Results: There were 3925 men in the study, 749 Hispanic, 2415 non-Hispanic white, 559 non-Hispanic African American, and 202 non-Hispanic Asian/Pacific Islander (API). Median follow-up was 9.3 years. At 19 years, overall cumulative incidence of treatment, metastasis, death due to prostate cancer, and all-cause mortality was 25.0%, 14.7%, 11.7%, and 67.8%, respectively. In adjusted models compared to non-Hispanic whites, African Americans had higher rates of treatment (HR = 1.39, 95% CI = 1.15-1.68); they had an increased risk of metastasis beyond 10 years after diagnosis (HR = 4.70, 95% CI = 2.30-9.61); API and Hispanic had lower rates of all-cause mortality (HR = 0.66, 95% CI = 0.52-0.84, and HR = 0.72, 95% CI = 0.62-0.85, respectively), and API had lower rates of prostate cancer mortality in the first 10 years after diagnosis (HR = 0.29, 95% CI = 0.09-0.90) and elevated risks beyond 10 years (HR = 5.41, 95% CI = 1.39-21.11)., Conclusions: Significant risks of metastasis and prostate cancer mortality exist in untreated men beyond 10 years after diagnosis, but are not equally distributed among racial/ethnic groups., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Given the immunosuppressive nature of pancreatic cancer, we investigated the relationship between epigenetic modification of immune-regulatory cytokine genes and pancreatic cancer outcomes. Materials & methods: We evaluated DNA methylation of 184 pancreatic tumor samples from The Cancer Genome Atlas for 111 CpG loci in seven cytokine genes: IL10 , IL6 , IL8 , TGFβ1 , TGFβ2 , TGFβ3 and TNF . We used Cox regression to evaluate the associations between methylation and overall survival, disease-specific survival and disease progression (α = 0.05). Results: Poorer survival was associated with increased methylation in fifteen CpG probes in TGFβ1 , TGFβ2 , TGFβ3 and TNF . We also detected improved outcomes for three loci in IL10 , IL8 and IL6 . Conclusion: Epigenetic regulation of cytokine-related gene expression may be associated with pancreatic cancer outcomes.

Background & Aims: Observational studies of predominantly white populations have found new-onset diabetes to be associated with increased risk of pancreatic cancer. We sought to determine whether this relationship applies to other races or ethnicities and to identify metabolic profiles associated with increased risk of pancreatic cancer., Methods: We conducted a population-based cohort study of Asian, black, Hispanic and white patients from Kaiser Permanente Southern California from 2006 through 2016 (n = 1,499,627). Patients with diabetes were identified based on glucose and hemoglobin A1c (HbA1c) measurements. We used Cox regression to assess the relationship between diabetes status and duration and pancreatic cancer. For patients with recent diagnoses of diabetes (1 year or less) we compared longitudinal changes in glucose, HbA1c, and weight, from time of diabetes diagnosis through 3 years prior to the diagnosis, in patients with vs without pancreatic cancer., Results: We identified 2,002 incident cases of pancreatic cancer from nearly 7.5 million person-years of follow-up. Compared to patients without diabetes, individuals who received a recent diagnosis of diabetes had an almost 7-fold increase in risk of pancreatic cancer (relative risk, 6.91; 95% CI, 5.76-8.30). Among patients with a recent diagnosis of diabetes, those who developed pancreatic cancer had more rapid increases in levels of glucose (Δslope: cases, 37.47 mg/dL vs non-cases, 27.68 mg/dL) and HbA1c (Δslope: cases, 1.39% vs non-cases, 0.86%) in the month preceding the diagnosis of diabetes, and subtle weight loss in the prior years (slope: cases -0.18 kg/interval vs non-cases 0.33 kg/interval). These longitudinal changes in markers of metabolism were stronger for specific race and ethnic groups., Conclusions: In a study of a large ethnically diverse population, we found risk of pancreatic cancer to be increased among patients with a diagnosis of diabetes in the past year among different races and ethnicities. Weight loss and rapid development of poor glycemic control were associated with increased risk of pancreatic cancer in multiple races., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)