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On February 2, 2022, President Biden and First Lady Dr. Biden reignited the Cancer Moonshot, setting a new goal to reduce age-standardized cancer mortality rates by at least 50% over the next 25 years in the United States. We estimated trends in U.S. cancer mortality during 2000 to 2019 for all cancers and the six leading types (lung, colorectum, pancreas, breast, prostate, liver). Cancer death rates overall declined by 1.4% per year from 2000 to 2015, accelerating to 2.3% per year during 2016 to 2019, driven by strong declines in lung cancer mortality (−4.7%/year, 2014 to 2019). Recent declines in colorectal (−2.0%/year, 2010–2019) and breast cancer death rates (−1.2%/year, 2013–2019) also contributed. However, trends for other cancer types were less promising. To achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. We reviewed opportunities to prevent, detect, and treat these common cancers that could further reduce population-level cancer death rates and also reduce disparities. Significance: We reviewed opportunities to prevent, detect, and treat common cancers, and show that to achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. See related commentary by Bertagnolli et al., p. 1049. This article is highlighted in the In This Issue feature, p. 1027

Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. Using the Women's Health Initiative study, we included 76,951 postmenopausal women followed for events for a median of 16.7 years to investigate the association between baseline self-reported stressful life events and incident breast cancer by ER status and whether the association was modified by social support. We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate HRs and 95% confidence intervals (95%CI). The mean age was 63 (SD, 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared with women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs. Quartile 1; HR = 1.30; 95%CI, 1.01–1.68; Ptrend = 0.050). Moreover, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR = 2.39; 95%CI, 1.29–4.44; Pinteraction Prevention Relevance: Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.

Purpose: Patients ≥18 months of age with International Neuroblastoma Staging System (INSS) stage 3 unfavorable histology (UH), MYCN-nonamplified (MYCN-NA) tumors have favorable survival rates compared with other high-risk neuroblastoma populations. The impact of select clinical and biological factors on overall survival (OS) and event-free survival (EFS) were evaluated. Experimental Design: Patients enrolled on Children's Oncology Group (COG) A3973 (n = 34), ANBL0532 (n = 27), and/or biology protocol ANBL00B1 (n = 72) were analyzed. Tumors with available DNA (n = 65) and RNA (n = 42) were subjected to whole-exome sequencing (WES) and RNA sequencing. WES analyses and gene expression profiling were evaluated for their impact on survival. Multivariate analyses of EFS/OS using significant factors from univariate analyses were performed. Results: 5-year EFS/OS for patients treated with high-risk therapy on A3973 and ANBL0532 were 73.0% ± 8.1%/87.9% ± 5.9% and 61.4% ± 10.2%/73.0% ± 9.2%, respectively (P = 0.1286 and P = 0.2180). In the A3973/ANBL0532 cohort, patients with less than partial response (PR; n = 5) at end-induction had poor outcomes (5-year EFS/OS: 0%/20.0% ± 17.9%. Univariate analyses of WES data revealed that subjects whose tumors had chromosome 1p or 11q loss/LOH and chromosome 5 or 9 segmental chromosomal aberrations had inferior EFS compared with those with tumors without these aberrations. Multivariate analysis revealed that 11q loss/LOH was an independent predictor of inferior OS [HR, 3.116 (95% confidence interval, 1.034–9.389), P = 0.0435]. Conclusions: Patients ≥18 months of age at diagnosis who had tumors with UH and MYCN-NA INSS stage 3 neuroblastoma assigned to high-risk therapy had an 81.6% ± 5.3% 5-year OS. Less than PR to induction therapy and chromosome 11q loss/LOH are independent predictors of inferior outcome and identify patients who should be eligible for future high-risk clinical trials.

We conducted integrative somatic–germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

Consultation is an important implementation strategy to improve treatment fidelity and clinical outcomes, yet research has not identified the aspects of consultation that differentially affects clinician skill development and client symptom change. Thus, the present study investigated the effect of the consultant, consultation activities, and consultants' (n = 6) perceptions of consultees (n = 60) on post-traumatic stress disorder (PTSD) treatment fidelity and client outcomes. In addition, we assessed the accuracy of consultants' evaluations of clinicians using the Perceived Enthusiasm, Skill, and Participation scale (P-ESP). Results indicated that there was a significant effect of consultant on adherence to, but not competence in, delivering Cognitive Processing Therapy (CPT). The effect of the consultant on PTSD symptom change was not significant. Consultants significantly differed in their discussion of CPT strategies and their application to individual cases, but did not differ on reviewing and providing feedback on fidelity. Consultant perceptions as assessed by the P-ESP were not associated with clinicians' current levels of adherence or competence, suggesting that consultants may not accurately assess clinician skill during consultation. Client PTSD symptom change neither predicted, nor was predicted by, consultants' perceptions of their consultees' skill. This article outlines potential reasons for consultant effects and possible biases at play that may reduce the accuracy of consultant perceptions and presents suggestions on alternative strategies to assess clinician skill during consultation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Lung cancer is a common cancer in people living with HIV, but the risk of cancer in this group has not been investigated for over a decade. We investigated trends in relative and absolute risk of lung cancer among people living with HIV of various age groups in the USA.In this population-based registry linkage study, we used 2001-16 data from the HIV/AIDS Cancer Match study, which links data from HIV and cancer registries from 13 regions in the USA. We included non-Hispanic White, non-Hispanic Black, and Hispanic individuals living with HIV aged 20-89 years in our study population. Average annual percentage changes in lung cancer rates were estimated with multivariable Poisson regression, and standardised incidence ratios (SIRs) and excess absolute risks were estimated comparing people living with HIV with the general US population. We used non-parametric cumulative incidence curves to estimate the 5-year cumulative incidence of lung cancer and two AIDS-defining cancers (non-Hodgkin lymphoma and Kaposi sarcoma).There were 3426 lung cancers in 4 310 304 person-years of follow-up in our study population. Age-standardised lung cancer incidence rates in people living with HIV declined by 6% per year (95% CI -7 to -5) during 2001-16, with greater declines in the 20-29 age group (-11%, -16 to 6) than in the older age groups (eg, -3% [-6 to 1] in those aged 70-89 years). During 2013-16, the SIR of lung cancer in people living with HIV was 2·01 (95% CI 1·52 to 2·61) in those aged 40-49 years, and 1·31 (1·12 to 1·52) in those aged 60-69 years, whereas the excess absolute risk among people living with HIV was 11·87 (3·95 to 21·89) per 100 000 person-years for those aged 40-49 years and 48·23 (6·88 to 95·47) per 100 000 person-years for those aged 60-69 years. Beginning in 2011, the 5-year cumulative incidence for lung cancer (1·36%, 95% CI 1·17 to 1·53) surpassed that of Kaposi sarcoma (0·12%, 0·06 to 0·17) and non-Hodgkin lymphoma (0·45%, 0·35 to 0·56) for people living with HIV aged 60-69 years.Between 2001 and 2016, the risk of lung cancer decreased for people living with HIV aged 20-69 years, but remained substantially elevated compared with the general population, probably due to a combination of smoking and immunosuppression. For people living with HIV aged 60 years and older, the risk of lung cancer exceeds that of two of the most common AIDS-defining cancers, highlighting the importance of lung cancer among the growing older population of people living with HIV.Intramural Research Program of the US National Cancer Institute.

We estimated years of life lost (YLLs) to all causes of death and YLL lost to cancer among persons with HIV (PWH) in the United States.Linked HIV and cancer registry data from the HIV/AIDS Cancer Match Study were used to identify incident cancers and deaths among PWH in 11 regions of the United States during 2006-2015.Mean YLL (MYLL) to all causes of death and MYLL to cancer during 2006-2015 were derived from the restricted mean survival estimated from Cox proportional hazards regression models. MYLLs were then upweighted to the national population of PWH to obtain all-cause total YLL (TYLL) and cancer-related TYLL in the United Staets during 2006-2015.Among 466 234 PWH in the study population, 25 772 (5.5%) developed cancer during 2006-2015. Nationally, an estimated 134 986 years of life were lost to cancer of all types during 2006-2015 among PWH, representing 9.6% of TYLL to all causes. Non-Hodgkin lymphoma (NHL), Kaposi sarcoma, anal cancer, and lung cancer were the four largest cancer contributors (45% of TYLL to cancer). The largest fraction of TYLL occurred among back PWH, MSM, and PWH aged 40-59 years old.PWH have higher mortality rates after developing cancer. NHL, Kaposi sarcoma and anal and lung cancers were large contributors to YLL to cancer in the United States population of PWH, highlighting opportunities to reduce cancer mortality through improved access to antiretroviral treatment, prevention, and screening.

Posttraumatic stress disorder (PTSD) is associated with significant individual and relationship impairment for people with PTSD and their romantic partners. Conjoint treatments, such as cognitive behavioral conjoint therapy for PTSD (CBCT), are designed to address individual and relationship factors, yet significant barriers impede accessing in-person therapy. Couple HOPES (i.e., Helping Overcome PTSD and Enhance Satisfaction) is a coach-guided, online couple intervention for PTSD based on CBCT that was designed to address these barriers. Previous investigations have found preliminary efficacy of Couple HOPES for improving PTSD symptoms, relationship functioning, and some individual functioning domains for the partner with probable PTSD. However, no study to date has tested individual outcomes for romantic partners, which is needed to fully evaluate the intervention's promise. The current study tested these partner outcomes in a combined, uncontrolled sample of 27 couples. Intent-to-intervene analyses found significant improvements at postintervention in four of eight tested outcomes, including ineffective arguing, g = 0.74; anger, g = 0.32; perceived health, g = 0.67; and quality of life, g = 0.56. Depressive symptoms, generalized anxiety, alcohol misuse, and work functioning did not significantly change, gs = 0.17-0.42. Among participants who completed a 1-month follow-up assessment, generalized anxiety, g = 0.43, and perceived health, g = 0.73, significantly improved over follow-up, whereas anger, g = -0.48, lost gains previously made. Results were largely consistent in the completer sample. These findings show the potential of Couple HOPES to have broad benefits not only for individuals with probable PTSD but also for their romantic partners.

The Sexual Delay Discounting Task (SDDT; Johnson & Bruner, 2012) is a behavioral economic task that assesses sexual risk-taking by measuring likelihood of immediate and delayed condom use. The SDDT is ecologically valid and has been used to test effects of various substances on sexual risk-taking. However, considerable variety in implementation, analysis, and reporting of the SDDT may limit rigor and reproducibility of findings. The current review synthesized studies that used the SDDT to evaluate these possible variabilities systematically. A two-step search (citation-tracking and keyword-based search) was conducted to identify studies that met inclusion criteria (i.e., used the SDDT). Eighteen peer-reviewed articles met inclusion criteria. The SDDT has been implemented primarily in three populations: individuals who use cocaine, men who have sex with men, and college students. Comparable results across diverse populations support the SDDT’s validity. A few studies administered substances before the SDDT. Evidence suggests that while cocaine and alcohol increased sexual risk-taking under some conditions, buspirone decreased preference for immediate condomless sex. There was also heterogeneity in the determination of data orderliness (i.e., outliers) and inconsistent reporting of task design and analysis. Considerable differences present in methodologic approaches could influence results. Reducing variation in the administration, analysis, and reporting of the SDDT will enhance rigor and reproducibility and maximize the task’s tremendous potential.

Supplemental Figure 1: Presents the flow chart of women that participated in the observational study that were included in the analytical sample.

PURPOSE Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation. METHODS In this phase II cohort of the KRYSTAL-1 study (NCT03785249; https://www.clinicaltrials.gov/ct2/show/NCT03785249 ; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary endpoint was objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. RESULTS As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% confidence interval [CI], 2.8 to 7.3) and median progression-free survival was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3 to 4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.

PURPOSE In 2006, Children's Oncology Group (COG) reclassified subgroups of toddlers diagnosed with neuroblastoma from high-risk to intermediate-risk, when the age cutoff for high-risk assignment was raised from 365 days (12 months) to 547 days (18 months). The primary aim of this retrospective study was to determine if excellent outcome was maintained after assigned reduction of therapy. PATIENTS AND METHODS Children RESULTS For 12-18mo/Stage4/FavBiology, 5-year EFS/OS (± SE) before (≤2006; n = 40) versus after (>2006; n = 55) assigned reduction in therapy was similar: 89% ± 5.1%/89% ± 5.1% versus 87% ± 4.6%/94% ± 3.2% ( P = .7; P = .4, respectively). For 12-18mo/Stage3/ MYCN-NA/Unfav, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/ MYCN-NA/Unfav classified as high-risk ≤2006 had an EFS/OS of 91% ± 4.4%/91% ± 4.5% versus 38% ± 1.3%/43% ± 1.3% for all other high-risk patients 2006 had an EFS/OS of 88% ± 4.3%/95% ± 2.9% versus 88% ± 0.9%/95% ± 0.6% for all other intermediate-risk patients CONCLUSION Excellent outcome was maintained among subsets of toddlers with neuroblastoma assigned to reduced treatment after reclassification of risk group from high to intermediate on the basis of new age cutoffs. Importantly, as documented in prior trials, intermediate-risk therapy is not associated with the degree of acute toxicity and late effects commonly observed with high-risk regimens.

Supplemental Table 1. 15 leading causes of cancer death in the U.S. in 2019. Supplemental table 2. Trends in total cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 3. Trends in lung cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 4. Trends in colorectal cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 5. Trends in pancreatic cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 6. Trends in female breast cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 7. Trends in prostate cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 8. Trends in liver/IHBD cancer mortality rates, incidence rates and relative survival in the U.S. Supplemental table 9. Trends in cancer mortality rates in the U.S., 2000-2019 for selected sites. Supplemental Table 10. US breast cancer incidence-based mortality*. Supplemental Table 11. U.S. breast cancer incidence-based mortality by age at death. Supplemental Figure 1. Liver cancer incidence (1992-2019), survival (2000-2019) and mortality (2000-2019 projected through 2047). This figure excludes cases of intrahepatic bile duct cancer.

Background Starting in 2018, national death certificates included a new racial classification system that accounts for multiple-race decedents and separates Native Hawaiian and Pacific Islander (NHPI) individuals from Asian individuals. We estimated cancer death rates across updated racial and ethnic categories, sex, and age. Methods Age-standardized US cancer mortality rates and rate ratios from 2018 to 2020 among individuals aged 20 years and older were estimated with national death certificate data by race and ethnicity, sex, age, and cancer site. Results In 2018, there were approximately 597 000 cancer deaths, 598 000 in 2019, and 601 000 in 2020. Among men, cancer death rates were highest in Black men (298.2 per 100 000; n = 105 632), followed by White (250.8; n = 736 319), American Indian/Alaska Native (AI/AN; 249.2; n = 3376), NHPI (205.6; n = 1080), Latino (177.2; n = 66 167), and Asian (147.9; n = 26 591) men. Among women, Black women had the highest cancer death rates (206.5 per 100 000; n = 104 437), followed by NHPI (192.1; n = 1141), AI/AN (189.9; n = 3239), White (183.0; n = 646 865), Latina (128.4; n = 61 579), and Asian (111.4; n = 26 396) women. The highest death rates by age group occurred among NHPI individuals aged 20-49 years and Black individuals aged 50-69 and 70 years and older. Asian individuals had the lowest cancer death rates across age groups. Compared with Asian individuals, total cancer death rates were 39% higher in NHPI men and 73% higher in NHPI women. Conclusions There were striking racial and ethnic disparities in cancer death rates during 2018-2020. Separating NHPI and Asian individuals revealed large differences in cancer mortality between 2 groups that were previously combined in vital statistics data.

Supplemental Table 2: Presents the hazard ratios for the association between Stressful Life Events and incident breast cancer by participant characteristics and estrogen receptor status.

Supplemental Table 1: Describes the Stressful Life Events and Social Support scales used in the study.

Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. Using the Women's Health Initiative study, we included 76,951 postmenopausal women followed for events for a median of 16.7 years to investigate the association between baseline self-reported stressful life events and incident breast cancer by ER status and whether the association was modified by social support. We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate HRs and 95% confidence intervals (95%CI). The mean age was 63 (SD, 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared with women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs. Quartile 1; HR = 1.30; 95%CI, 1.01–1.68; Ptrend = 0.050). Moreover, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR = 2.39; 95%CI, 1.29–4.44; PinteractionPrevention Relevance:Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.

Supplemental Figure S2 Outcome by Chromosome 9 Status. (A) EFS and (B) OS by Chromosome 9 status

Supplementary Figure from Vitamin D Receptor Activation Attenuates Hippo Pathway Effectors and Cell Survival in Metastatic Neuroblastoma

Supplementary Data from Vitamin D Receptor Activation Attenuates Hippo Pathway Effectors and Cell Survival in Metastatic Neuroblastoma

Supplemental Figure S3 Non-negative Matrix Factorization (NMF) Clustering of Tumor Specimens. (A) Clustering similarity matrix and (B) Silhouette plot of samples by cluster id. (C) Enrichment score for adrenergic (ADRN), mesenchymal (MES), and Schwann cell profile (SCP) gene signatures.

Purpose:Patients ≥18 months of age with International Neuroblastoma Staging System (INSS) stage 3 unfavorable histology (UH), MYCN-nonamplified (MYCN-NA) tumors have favorable survival rates compared with other high-risk neuroblastoma populations. The impact of select clinical and biological factors on overall survival (OS) and event-free survival (EFS) were evaluated.Experimental Design:Patients enrolled on Children's Oncology Group (COG) A3973 (n = 34), ANBL0532 (n = 27), and/or biology protocol ANBL00B1 (n = 72) were analyzed. Tumors with available DNA (n = 65) and RNA (n = 42) were subjected to whole-exome sequencing (WES) and RNA sequencing. WES analyses and gene expression profiling were evaluated for their impact on survival. Multivariate analyses of EFS/OS using significant factors from univariate analyses were performed.Results:5-year EFS/OS for patients treated with high-risk therapy on A3973 and ANBL0532 were 73.0% ± 8.1%/87.9% ± 5.9% and 61.4% ± 10.2%/73.0% ± 9.2%, respectively (P = 0.1286 and P = 0.2180). In the A3973/ANBL0532 cohort, patients with less than partial response (PR; n = 5) at end-induction had poor outcomes (5-year EFS/OS: 0%/20.0% ± 17.9%. Univariate analyses of WES data revealed that subjects whose tumors had chromosome 1p or 11q loss/LOH and chromosome 5 or 9 segmental chromosomal aberrations had inferior EFS compared with those with tumors without these aberrations. Multivariate analysis revealed that 11q loss/LOH was an independent predictor of inferior OS [HR, 3.116 (95% confidence interval, 1.034–9.389), P = 0.0435].Conclusions:Patients ≥18 months of age at diagnosis who had tumors with UH and MYCN-NA INSS stage 3 neuroblastoma assigned to high-risk therapy had an 81.6% ± 5.3% 5-year OS. Less than PR to induction therapy and chromosome 11q loss/LOH are independent predictors of inferior outcome and identify patients who should be eligible for future high-risk clinical trials.

Background Incidence of anal squamous cell carcinoma (SCC) has increased in the United States. People living with HIV (PLWH) have an elevated risk of anal SCC, and changes in the number of anal SCCs among PLWH may have influenced general population trends. Methods Data were obtained from a linkage of HIV and cancer registries in 12 US regions. The proportion of anal SCCs occurring among PLWH was estimated by sex, age group, and race and ethnicity. To assess the impact of anal SCCs among PLWH on general population trends, annual percent changes (APCs) in incidence rates including and excluding anal SCCs among PLWH were estimated. Results Between 2001 and 2015, 14.5% of 16 110 anal SCC diagnoses occurred in PLWH. In 2013-2015, 35% of anal SCCs among men occurred in PLWH, but only 2% among women. The proportion of anal SCCs among PLWH was highest among 20- to 49-year-olds and Black and Hispanic individuals. General population anal SCC trends among men were strongly influenced by anal SCCs among PLWH: rates increased 4.6%/y (95% confidence interval [CI] = 1.4% to 8.0%) from 2001 to 2009 followed by a statistically non-significant decline (APC = −2.7%/y, 95% CI = −7.1% to 2.0%) from 2009 to 2015, but without anal SCCs among PLWH, rates were stable (APC = 0.7%/y, 95% CI = −0.8% to 2.3%). Anal SCC rates among women increased 3.8%/y (95% CI = 3.2% to 4.4%) during 2001-2012 and then declined statistically non-significantly (APC = −3.8%/y, 95% CI = −6.9% to −0.6%), and anal SCCs among PLWH had little impact on these trends. Conclusions During 2001-2015, anal SCCs among PLWH contributed strongly to changes in incidence trends in the general US population among men, but not women.

Correlational evidence has linked methamphetamine use and HIV sexual risk behavior, but the direct effects of methamphetamine on sexual desire and sexual decision making in humans have not been tested. This study was designed to test the effect of methamphetamine administration on sexual desire and hypothetical condom-use decisions as measured by the Sexual Delay Discounting Task. Recreational stimulant users (n = 19) participated in this within-subject, placebo-controlled study comparing the effects of 0 mg, 20 mg, and 40 mg of oral methamphetamine. Compared to placebo, methamphetamine caused dose-related and time-related increases in a single-item sexual desire rating and some standard stimulant abuse liability ratings, as well as dose-related increases in the Sexual Arousal and Desire Inventory (SADI; a multidimensional scale capturing positive and negative aspects of desire/arousal). However, methamphetamine caused no significant mean differences in likelihood of condom use within the Sexual Delay Discounting Task or the Monetary Discounting Task. SADI scores were negatively correlated with change from placebo in condom use likelihood in the Sexual Delay Discounting Task for some partner conditions (i.e., decreased reported likelihood of condom use in participants who experienced increased desire/arousal and vice versa). These mixed results may be consistent with methamphetamine's role as both a treatment for attention-deficit/hyperactivity disorder and as a drug of abuse associated with increased delay discounting, and they suggest that methamphetamine's effects on discounting may be modulated by the reinforcing properties of what is being discounted. Delay discounting may be an understudied element of risky sexual decision making, particularly among individuals who use methamphetamine. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Survival for high-risk neuroblastoma remains poor. Most patients who recur, present with metastatic disease, and few targetable pathways that govern spread to distant sites are currently known. We previously developed a metastatic mouse model to select cells with enhanced ability to spread to the bone and brain and identified a signature based on differentially expressed genes, which also predicted patient survival. To discover new neuroblastoma therapies, we utilized the Connectivity Map to identify compounds that can reverse this metastatic transcriptional signature and found calcipotriol, a vitamin D3 analog, to be a compound that selectively targets cell lines with enhanced metastatic potential. Calcipotriol treatment of enhanced metastatic, but not parental, cells reduces proliferation and survival via vitamin D receptor (VDR) signaling, increases the expression of RASSF2, a negative regulator of the Hippo signaling pathway, and reduces the levels of the Hippo pathway effectors YAP and TAZ. RASSF2 is required for the effects of calcipotriol and for the reduction of levels and nuclear localization of YAP/TAZ. Migration of the enhanced metastatic cells and YAP/TAZ levels are reduced after calcipotriol treatment and YAP overexpression reduces calcipotriol sensitivity. Furthermore, metastatic cells that overexpress VDR also showed lower tumor burden in vivo. Implications: This newly identified link between VDR signaling and the Hippo pathway could inform treatment strategies for metastatic neuroblastoma.

Background: Triple Negative Breast Cancer (TNBC) is an aggressive and heterogeneous subtype characterized by ER/PR/HER2 negative status. Much of the disease potential and aggressive nature of this subtype derives from inter- and intra-tumoral heterogeneity, which makes developing targeted therapies challenging. A key contributor to both heterogeneity in TNBC and later stage chemo-resistance and metastasis is the Epithelial-to-Mesenchymal transition (EMT). This developmental program is frequently exploited in the context of cancer to increase migratory abilities, invasiveness, metastatic potential, and resistance to chemotherapy. Indeed, EMT has been demonstrated and linked to poor prognosis and decreased survival in many solid cancer types. Cells have been found to reside in multiple stable intermediate states along the EMT spectrum, which confer increased aggressive, metastatic, and chemoresistance attributes to a heterogeneous tumor through increased stem-like characteristics. Identifying and targeting this disease-potentiating population in patient tumors is a major hurdle in overcoming metastatic disease. Knowledge gap: Despite major advances in our understanding, the contributions of EMT research to improvements in diagnostic pathology or cancer therapy have been minimal. One reason for this gap stems from our inability to accurately detect and quantify epithelial-mesenchymal heterogeneity in primary tumor specimens. Secondly, the significance of recently identified intermediate or partial EMT states to predicting tumor prognosis and therapy response are unclear. Approach & Results: To study the role of various states within the EMT spectrum and their regulatory networks, the heterogeneous breast cancer cell line, SUM149PT, was used to derive six single cell clones encompassing the spectrum of EMT states, from epithelial to mesenchymal. Interrogation of this model system in vivo has revealed increased tumor growth and metastatic potential in the intermediate EMT states when compared to the extreme epithelial and mesenchymal states. To further elucidate EMT states in vivo, we employ a 6-marker multi-round immunofluorescence-based staining approach to identify cells that reside in various states along the EMT spectrum. We subsequently used an entropy-based approach and nearest-neighbor analysis on these tumors with the purpose of scoring heterogeneity and overall EMT state. Notably, this analysis segregated stromal infiltrates and their contributions to aggregate EMT scoring, which has been a major hurdle in using EMT as a scoring metric in patient samples. Overall, SUM149 clone-derived tumors held true to the relative EMT states of the starting cell populations; intermediate-derived tumors displayed high heterogeneity while epithelial and mesenchymal clone-derived tumors had lower levels of heterogeneity, despite retaining different EMT scores. Decoupling of heterogeneity and EMT state in this way provides two metrics to assess potential metastatic ability of a tumor. This staining method and analysis has been successfully applied in a preliminary set of patient tumors, showing promise for these two factors, E-M Heterogeneity and EMT score, as a tumor prognostic indicator to inform therapeutic decision-making. Conclusions: EMT tumor states and EMT-derived intra-tumoral heterogeneity play an important role in tumor metastasis and disease progression. Here, we have validated a multiplexed staining approach to quantify these metrics within a tumor, while segregating out stromal infiltrating cells. In the future, this staining and quantification shows promise as a means of predicting patient prognosis and informing potential treatment options based on targeting EMT states Citation Format: Meredith S Brown, Behnaz Abdollahi, Nevena Ognjenovic, Kristen E Muller, Saeed Hassanpour, Diwakar R Pattabiraman. Quantifying epithelial-mesenchymal tumor heterogeneity for prediction of patient prognosis based on EMT state [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-19.

We sought to derive and validate a model to predict inpatient mortality after veno-arterial extracorporeal life support (VA-ECLS) based on readily available, precannulation clinical data.Refractory cardiogenic shock supported by VA-ECLS is associated with high morbidity and mortality.VA-ECLS cases at our institution from January 2014 through July 2019 were retrospectively reviewed. Exclusion criteria were cannulation: (1) at another institution; (2) for primary surgical indication; or (3) for extracorporeal cardiopulmonary resuscitation. Multivariable logistic regression compared those with and without inpatient mortality. Multiple imputation was performed and optimism-adjusted area under the curve (oAUC) values were computed.VA-ECLS cases from August 2019 through November 2020 were identified as a validation cohort. In the derivation cohort (n = 135), the final model included Lactate (mmol/L), hemoglobin (g/dl; Anemia), Coma (Glasgow Coma Scale [GCS] 8) and resusciTATEd cardiac arrest (LACTATE score; oAUC = 0.760). In the validation cohort (n = 30, LACTATE showed similar predictability [AUC = 0.710]). A simplified (LACT-8) score was derived by dichotomizing lactate (8) and hemoglobin (8) and summing together the number of components for each patient. LACT-8 performed similarly (derivation, oAUC = 0.724; validation, AUC = 0.725). In the derivation cohort, both scores outperformed SAVE (oAUC = 0.568) and SOFA (oAUC = 0.699) scores. A LACT-8 ≥ 3 had a specificity for mortality of 97.9% and 92.9%, in the derivation and validation cohorts, respectively.The LACT-8 score can predict inpatient mortality prior to before cannulation for VA-ECLS. LACT-8 can be implemented utilizing clinical data without the need for an online calculator.

Point-of-care (POC) tests to detect SARS-CoV-2 antibodies offer quick assessment of serostatus after natural infection or vaccination. We compared the field performance of the BioMedomics COVID-19 IgM/IgG Rapid Antibody Test against an ELISA in 303 participants enrolled in a SARS-CoV-2 household cohort study. The rapid antibody test was easily implemented with consistent interpretation across 14 users in a variety of field settings. Compared with ELISA, detection of seroconversion lagged by 5 to 10 days. However, it retained a sensitivity of 90% (160/177, 95% confidence interval [CI] 85–94%) and specificity of 100% (43/43, 95% CI 92–100%) for those tested 3 to 5 weeks after symptom onset. Sensitivity was diminished among those with asymptomatic infection (74% [14/19], 95% CI 49–91%) and early in infection (45% [29/64], 95% CI 33–58%). When used appropriately, rapid antibody tests offer a convenient way to detect symptomatic infections during convalescence.

Supplementary Table S2

Here we compare estimates of NHL-specific survival (using varying definitions of a cancer-specific (gold standard survival measure from registry data).

Supplementary Tables 1-3. Supplementary Table 1 - a) Correlations between selectb serum inflammation markers among lung cancer controls. b) Correlations between select and serum inflammation markers among NHL controls. c) Correlations between selectb serum inflammation markers among ovarian cancer controls. Supplementary Table 2. Odds ratios (ORs)a and 95% confidence intervals (CIs) for selectb circulating inflammation markers and body mass index. Supplementary Table 3. Odds ratios (ORs)a and 95% confidence intervals (CIs) for select circulating inflammation markers and body mass index (per 5-kg/m2) by case-control study

Figure S1 - Sensitivity of NB cell lines to allosteric SHP2 inhibitors. Figure S2 - Sensitivity of NB cell lines to catalytic SHP2 inhibitors. Figure S3 - Sensitivity to SHP2 inhibitors in isogenic NB cells with exogenous PTPN11 mutations. Figure S4 - NRAS status determines sensitivity to SHP2 and MAPK inhibition. Figure S5 - MAPK inhibitors sensitize NB cells to SHP099 and II-B08. Figure S6 - SHP2 inhibitors are synergistic with trametinib and other MAPK inhibitors. Figure S7 - MAPK inhibitors synergize with SHP2 inhibitors in ALK-mutant NB cells. Figure S8 - Assessment of drug tolerability for SHP099 and trametinib in vivo. Figure S9 - Pre-clinical assessment of SHP099 plus trametinib in NRAS-mutant NB xenografts. Figure S10 - Pre-clinical assessment of SHP099 plus ulixertinib in NRAS-mutant NB xenografts.

Supplementary Table S1. Annual percent change in age-adjusted anal cancer incidence rates by sex, race/ethnicity, histology and behavior, SEER 13, 1992-2011. Supplementary Figure S1. Age-adjusted anal cancer SCC incidence rates across calendar years for non-HispaniSupplementary Figure S2. Age-adjusted anal cancer SCC, ADC and squamous CIS incidence rates across calendar years using data from SEER 9 and SEER 13, 1992-2011.c whites by sex and age group using data from SEER 13, 1992-2011.

Includes supplementary methodology for cell culture, chemicals, plasmids and transfections, GTP pulldown and immunoblotting analyses, and antibodies used for study.

Survival for high-risk neuroblastoma remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of neuroblastoma tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (ALK) gene. However, at neuroblastoma recurrence, more frequent mutations in genes in the RAS–MAPK pathway have been detected. The PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and we and others have shown that pharmacologic inhibition of SHP2 suppresses the growth of various tumor types harboring KRAS mutations such as pancreatic and lung cancers. Here we report inhibition of growth and downstream RAS–MAPK signaling in neuroblastoma cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, and RMC-4550. However, neuroblastoma cell lines harboring endogenous NRASQ61K mutation (which is commonly detected at relapse) or isogenic neuroblastoma cells engineered to overexpress NRASQ61K were distinctly resistant to SHP2 inhibitors. Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in neuroblastoma in vitro and in vivo. These results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS–MAPK pathway may be effective against conventional therapy-resistant relapsed neuroblastoma, including those that have acquired NRAS mutations.Significance:These findings suggest that conventional therapy–resistant, relapsed neuroblastoma may be effectively treated via combined inhibition of SHP2 and MEK or ERK of the RAS–MAPK pathway.

Background: Coffee drinking has been inversely associated with mortality as well as cancers of the endometrium, colon, skin, prostate, and liver. Improved insulin sensitivity and reduced inflammation are among the hypothesized mechanisms by which coffee drinking may affect cancer risk; however, associations between coffee drinking and systemic levels of immune and inflammatory markers have not been well characterized.Methods: We used Luminex bead-based assays to measure serum levels of 77 immune and inflammatory markers in 1,728 older non-Hispanic Whites. Usual coffee intake was self-reported using a food frequency questionnaire. We used weighted multivariable logistic regression models to examine associations between coffee and dichotomized marker levels. We conducted statistical trend tests by modeling the median value of each coffee category and applied a 20% false discovery rate criterion to P values.Results: Ten of the 77 markers were nominally associated (P trend < 0.05) with coffee drinking. Five markers withstood correction for multiple comparisons and included aspects of the host response namely chemotaxis of monocytes/macrophages (IFNγ, CX3CL1/fractalkine, CCL4/MIP-1β), proinflammatory cytokines (sTNFRII), and regulators of cell growth (FGF-2). Heavy coffee drinkers had lower circulating levels of IFNγ [odds ratios (OR), 0.35; 95% confidence intervals (CI), 0.16–0.75], CX3CL1/fractalkine (OR, 0.25; 95% CI, 0.10–0.64), CCL4/MIP-1β (OR, 0.48; 95% CI, 0.24–0.99), FGF-2 (OR, 0.62; 95% CI, 0.28–1.38), and sTNFRII (OR, 0.34; 95% CI, 0.15–0.79) than non-coffee drinkers.Conclusions: Lower circulating levels of inflammatory markers among coffee drinkers may partially mediate previously observed associations of coffee with cancer and other chronic diseases.Impact: Validation studies, ideally controlled feeding trials, are needed to confirm these associations. Cancer Epidemiol Biomarkers Prev; 24(7); 1052–60. ©2015 AACR.

Supplementary Figure 1 from Circulating Markers of Interstitial Lung Disease and Subsequent Risk of Lung Cancer

SupplementaryTable S5. Odds ratios (OR) for high versus low levels e for eight circulating inflammatory markers (P-trend

Supplementary Materials and Methods: Details on development of sampling weights and their use in analysis.

Supplementary Table S4. Categorization of markers by weighted percent of values below the lower limit of detection (LOD)

Background: For decades, non–Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends in NHL incidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates.Methods: NHL incidence data during 1992–2009 were derived from 10 U.S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses.Results: Of 115,643 NHL cases diagnosed during 1992–2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (≤1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992–2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992–2003, before becoming stable through 2009. Similar trends were observed for DLBCLs and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing.Conclusions: NHL incidence rates in the United States have plateaued over the last 5–10 years, independent of HIV infection.Impact: Although the causes of the long-term increase in NHL incidence rates in the United States remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV. Cancer Epidemiol Biomarkers Prev; 22(6); 1069–78. ©2013 AACR.

Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention.Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.