Clinician- and Patient-Directed Communication Strategies for Patients With Cancer at High Mortality Risk: A Cluster Randomized Trial.

Importance: Serious illness conversations (SICs) that elicit patients' values, goals, and care preferences reduce anxiety and depression and improve quality of life, but occur infrequently for patients with cancer. Behavioral economic implementation strategies (nudges) directed at clinicians and/or patients may increase SIC completion. Objective: To test the independent and combined effects of clinician and patient nudges on SIC completion. Design, Setting, and Participants: A 2 × 2 factorial, cluster randomized trial was conducted from September 7, 2021, to March 11, 2022, at oncology clinics across 4 hospitals and 6 community sites within a large academic health system in Pennsylvania and New Jersey among 163 medical and gynecologic oncology clinicians and 4450 patients with cancer at high risk of mortality (≥10% risk of 180-day mortality). Interventions: Clinician clusters and patients were independently randomized to receive usual care vs nudges, resulting in 4 arms: (1) active control, operating for 2 years prior to trial start, consisting of clinician text message reminders to complete SICs for patients at high mortality risk; (2) clinician nudge only, consisting of active control plus weekly peer comparisons of clinician-level SIC completion rates; (3) patient nudge only, consisting of active control plus a preclinic electronic communication designed to prime patients for SICs; and (4) combined clinician and patient nudges. Main Outcomes and Measures: The primary outcome was a documented SIC in the electronic health record within 6 months of a participant's first clinic visit after randomization. Analysis was performed on an intent-to-treat basis at the patient level. Results: The study accrued 4450 patients (median age, 67 years [IQR, 59-75 years]; 2352 women [52.9%]) seen by 163 clinicians, randomized to active control (n = 1004), clinician nudge (n = 1179), patient nudge (n = 997), or combined nudges (n = 1270). Overall patient-level rates of 6-month SIC completion were 11.2% for the active control arm (112 of 1004), 11.5% for the clinician nudge arm (136 of 1179), 11.5% for the patient nudge arm (115 of 997), and 14.1% for the combined nudge arm (179 of 1270). Compared with active control, the combined nudges were associated with an increase in SIC rates (ratio of hazard ratios [rHR], 1.55 [95% CI, 1.00-2.40]; P = .049), whereas the clinician nudge (HR, 0.95 [95% CI, 0.64-1.41; P = .79) and patient nudge (HR, 0.99 [95% CI, 0.73-1.33]; P = .93) were not. Conclusions and Relevance: In this cluster randomized trial, nudges combining clinician peer comparisons with patient priming questionnaires were associated with a marginal increase in documented SICs compared with an active control. Combining clinician- and patient-directed nudges may help to promote SICs in routine cancer care. Trial Registration: ClinicalTrials.gov Identifier: NCT04867850.

Switching from cigarettes to IQOS: the relative importance of IQOS-associated reward, reinforcement and abstinence relief.

INTRODUCTION: This study investigated whether IQOS, a heated tobacco product, can fully substitute for combustible cigarettes and the factors that promote substitution. METHODS: Adults who smoked cigarettes daily (N=90; 21-65 years) completed a baseline ad-lib smoking period (days 1-5), two laboratory visits (days 6-7) and a 2-week period where they were instructed to switch from smoking cigarettes to using IQOS 3.0 (days 8-21). Mixed-effect modelling estimated the changes in cigarettes per day (CPD) and the percentage of baseline CPD substituted by HeatSticks during the switch period. Predictors included IQOS-associated subjective reward, relative reinforcing value, craving relief and withdrawal relief. RESULTS: Participants reduced their CPD to about 30% of their baseline smoking rate by the end of the 14-day switch period (p<0001). A lower versus higher reinforcing value of smoking relative to IQOS (RRV; break point <5 vs ≥5) predicted greater reductions in CPD (ß=-1.31 (95% CI -2.35 to -0.27) p=0.013). Initially, IQOS use was 72% of the baseline smoking rate (ß=71.64 (95% CI 42.79 to 100.48) p<0.0001) and climbed by 0.8% per day (ß=0.82 (95% CI 0.01 to 1.64) p=0.05), for an average substitution rate of 83%. The subjective reward of IQOS was the only predictor of a higher substitution rate (ß=4.26 (95% CI 1.03 to 7.50) p=0.01). CONCLUSIONS: IQOS fully substituted for cigarettes in ~20% of people who were not immediately interested in quitting smoking while the remainder significantly reduced their smoking. Positive reinforcing effects of IQOS foster use and the transition away from combustible cigarettes. TRIAL REGISTRATION NUMBER: NCT05076708.

A Pilot Study to Evaluate the Use of Automated Nicotine Metabolite Ratio Reporting within Primary Care as an Implementation Strategy to Increase the Use of Tobacco Treatments.

INTRODUCTION: Concerns about safety and effectiveness of tobacco treatments reduce their use. We explored integrating the nicotine metabolite ratio (NMR), and messaging about its potential for improving safety and effectiveness, as a strategy to increase use of tobacco treatments within primary care. METHODS: Through a prospective cohort design, we explored the effects of integrating NMR testing within primary care on the provision of tobacco treatment; 65 patients completed assessments including NMR before a clinic visit. At the clinic visit, patients' clinicians received an electronic health record alert about the patient's NMR and personalized treatment recommendations to improve effectiveness and safety. Being asked about smoking and advised to quit, and a referral for tobacco treatment or medication prescription, were assessed within 30 days of the appointment and were compared to a usual care cohort (N=85). RESULTS: The NMR and usual care cohorts reported similar rates of being asked about smoking (92.3% vs. 92.9%, p=1.0), being advised to quit (72.3% vs. 74.1%, p=0.85), being referred for tobacco treatment (23.1% vs. 36.5%, p=0.11), and receiving tobacco use medications (20% vs. 27.1%, p=0.34). In the NMR cohort, fast vs. slow metabolizers were more likely to receive medication (26% vs. 0%, p=0.003) and all patients who received varenicline (n=8) were fast metabolizers. CONCLUSIONS: NMR results and treatment recommendations did not increase tobacco treatment rates in primary care, although it may increase treatment rates and use of varenicline for fast metabolizers. Future studies could test ways to use the NMR to increase tobacco treatment rates in clinical settings. IMPLICATIONS: This study generated a novel implementation strategy, namely an electronic health record alert about patients' NMR and personalized treatment recommendations, in an effort to increase tobacco treatment rates in primary care. While the strategy did not increase tobacco treatment rates, it may have boosted the rate of varenicline prescription for patients who metabolize nicotine faster, aligning with evidence-based practice.

Non-Isocentric Geometry for Next-Generation Tomosynthesis With Super-Resolution.

Our lab at the University of Pennsylvania (UPenn) is investigating novel designs for digital breast tomosynthesis. We built a next-generation tomosynthesis system with a non-isocentric geometry (superior-to-inferior detector motion). This paper examines four metrics of image quality affected by this design. First, aliasing was analyzed in reconstructions prepared with smaller pixelation than the detector. Aliasing was assessed with a theoretical model of r -factor, a metric calculating amplitudes of alias signal relative to input signal in the Fourier transform of the reconstruction of a sinusoidal object. Aliasing was also assessed experimentally with a bar pattern (illustrating spatial variations in aliasing) and 360°-star pattern (illustrating directional anisotropies in aliasing). Second, the point spread function (PSF) was modeled in the direction perpendicular to the detector to assess out-of-plane blurring. Third, power spectra were analyzed in an anthropomorphic phantom developed by UPenn and manufactured by Computerized Imaging Reference Systems (CIRS), Inc. (Norfolk, VA). Finally, calcifications were analyzed in the CIRS Model 020 BR3D Breast Imaging Phantom in terms of signal-to-noise ratio (SNR); i.e., mean calcification signal relative to background-tissue noise. Image quality was generally superior in the non-isocentric geometry: Aliasing artifacts were suppressed in both theoretical and experimental reconstructions prepared with smaller pixelation than the detector. PSF width was also reduced at most positions. Anatomic noise was reduced. Finally, SNR in calcification detection was improved. (A potential trade-off of smaller-pixel reconstructions was reduced SNR; however, SNR was still improved by the detector-motion acquisition.) In conclusion, the non-isocentric geometry improved image quality in several ways.

Predictors of improved clinician screening, assessment, and treatment for tobacco use for clients in community mental healthcare following training.

Introduction: People with mental illness (MI) are more likely to smoke cigarettes and less likely to receive treatment for tobacco use than the general population. Understanding factors associated with improved staff treatment of tobacco use in community mental health settings has received limited study. Methods: We used data from a completed cluster-randomized clinical trial that tested two interventions designed to increase treatment for tobacco use in mental health clinics. Among 222 clinic staff, we examined demographic and employment characteristics, changes in perceived skills, knowledge, and beliefs using the S-KAP (i.e., perceptions of staff responsibility to treat tobacco use; client quit motivation; client outcomes; and barriers) as predictors of change in clinician reported delivery of tobacco use treatment following training. Results: Clinician reported treatment of client tobacco use significantly increased from baseline to week 52 across both study arms (p<0.001). This increase in reported treatment for tobacco use was associated with increases from baseline to week 52 in clinician reported skills to treat tobacco use, perceptions of responsibility to treat client tobacco use, and perceptions about client motivation to quit smoking (p's<0.05). Conclusions: Training clinicians in community mental healthcare to address client tobacco use may improve outcomes by helping them to develop the needed skills, convincing them that treating tobacco use is part of their role as clinicians, and by helping clinicians to recognize that clients are motivated to quit smoking. These may be targets to improve how clinicians in community health settings address client tobacco use.

Protocol for a pragmatic stepped wedge cluster randomized clinical trial testing behavioral economic implementation strategies to increase supplemental breast MRI screening among patients with extremely dense breasts.

BACKGROUND: Increased breast density augments breast cancer risk and reduces mammography sensitivity. Supplemental breast MRI screening can significantly increase cancer detection among women with dense breasts. However, few women undergo this exam, and screening is consistently lower among racially minoritized populations. Implementation strategies informed by behavioral economics ("nudges") can promote evidence-based practices by improving clinician decision-making under conditions of uncertainty. Nudges directed toward clinicians and patients may facilitate the implementation of supplemental breast MRI. METHODS: Approximately 1600 patients identified as having extremely dense breasts after non-actionable mammograms, along with about 1100 clinicians involved with their care at 32 primary care or OB/GYN clinics across a racially diverse academically based health system, will be enrolled. A 2 × 2 randomized pragmatic trial will test nudges to patients, clinicians, both, or neither to promote supplemental breast MRI screening. Before implementation, rapid cycle approaches informed by clinician and patient experiences and behavioral economics and health equity frameworks guided nudge design. Clinicians will be clustered into clinic groups based on existing administrative departments and care patterns, and these clinic groups will be randomized to have the nudge activated at different times per a stepped wedge design. Clinicians will receive nudges integrated into the routine mammographic report or sent through electronic health record (EHR) in-basket messaging once their clinic group (i.e., wedge) is randomized to receive the intervention. Independently, patients will be randomized to receive text message nudges or not. The primary outcome will be defined as ordering or scheduling supplemental breast MRI. Secondary outcomes include MRI completion, cancer detection rates, and false-positive rates. Patient sociodemographic information and clinic-level variables will be examined as moderators of nudge effectiveness. Qualitative interviews conducted at the trial's conclusion will examine barriers and facilitators to implementation. DISCUSSION: This study will add to the growing literature on the effectiveness of behavioral economics-informed implementation strategies to promote evidence-based interventions. The design will facilitate testing the relative effects of nudges to patients and clinicians and the effects of moderators of nudge effectiveness, including key indicators of health disparities. The results may inform the introduction of low-cost, scalable implementation strategies to promote early breast cancer detection. TRIAL REGISTRATION: ClinicalTrials.gov NCT05787249. Registered on March 28, 2023.

Seeing Through the Blind: Belief about Treatment Randomization and Smoking Cessation Outcome among People with Current or Past Major Depressive Disorder who Smoke in a Placebo-Controlled Trial of Varenicline.

INTRODUCTION: Blinding participants to randomization is a cornerstone of science. However, participant beliefs about their allocation can influence outcomes. We examined blind integrity, the association between trial arm belief and cessation, and potential mechanisms linking treatment arm and treatment arm belief among people with major depressive disorder (MDD) who smoke receiving varenicline in a placebo-controlled trial. METHODS: 175 participants were asked at the end of treatment (EOT) if they thought they received placebo, varenicline, or were not sure. We assessed the relationship between treatment arm belief and actual treatment allocation, examined the association between treatment arm belief and EOT cessation, and evaluated changes in craving, withdrawal, side effects, depression symptoms, and smoking reward as mediators through which treatment arm was believed. RESULTS: Treatment arm belief was significantly associated with actual arm assignment (χ2(2)=13.0, p=0.002). Participants in the varenicline arm were >3 times as likely to believe they were taking varenicline, vs. "not sure" (RR=3.05 [1.41-6.60], p=0.005). Participants in the placebo arm were just as likely to believe they were taking placebo vs. "not sure" (χ2[2]=0.75, p=0.69). Controlling for treatment arm, belief that one received varenicline was significantly associated with an increase in cessation rate (OR=5.91 [2.06-16.92], p=0.001). Change in the rewarding experience of smoking may mediate participant ability to discern getting varenicline B=0.077 [0.002-0.192], p <0.05). CONCLUSIONS: Participants receiving varenicline can discern that they received varenicline and this belief is associated with higher cessation rates. Research is needed to continue to examine how participants correctly identify their allocation to varenicline.

Analysis of BRCA1- and BRCA2-Related Pancreatic Cancer and Survival.

This cohort study compares the outcomes of patients with BRCA1 and BRCA-related pancreatic cancers using 2 large data sets.

Protocol to evaluate sequential electronic health record-based strategies to increase genetic testing for breast and ovarian cancer risk across diverse patient populations in gynecology practices.

BACKGROUND: Germline genetic testing is recommended by the National Comprehensive Cancer Network (NCCN) for individuals including, but not limited to, those with a personal history of ovarian cancer, young-onset (< 50 years) breast cancer, and a family history of ovarian cancer or male breast cancer. Genetic testing is underused overall, and rates are consistently lower among Black and Hispanic populations. Behavioral economics-informed implementation strategies, or nudges, directed towards patients and clinicians may increase the use of this evidence-based clinical practice. METHODS: Patients meeting eligibility for germline genetic testing for breast and ovarian cancer will be identified using electronic phenotyping algorithms. A pragmatic cohort study will test three sequential strategies to promote genetic testing, two directed at patients and one directed at clinicians, deployed in the electronic health record (EHR) for patients in OB-GYN clinics across a diverse academic medical center. We will use rapid cycle approaches informed by relevant clinician and patient experiences, health equity, and behavioral economics to optimize and de-risk our strategies and methods before trial initiation. Step 1 will send patients messages through the health system patient portal. For non-responders, step 2 will reach out to patients via text message. For non-responders, Step 3 will contact patients' clinicians using a novel "pend and send" tool in the EHR. The primary implementation outcome is engagement with germline genetic testing for breast and ovarian cancer predisposition, defined as a scheduled genetic counseling appointment. Patient data collected through the EHR (e.g., race/ethnicity, geocoded address) will be examined as moderators of the impact of the strategies. DISCUSSION: This study will be one of the first to sequentially examine the effects of patient- and clinician-directed strategies informed by behavioral economics on engagement with breast and ovarian cancer genetic testing. The pragmatic and sequential design will facilitate a large and diverse patient sample, allow for the assessment of incremental gains from different implementation strategies, and permit the assessment of moderators of strategy effectiveness. The findings may help determine the impact of low-cost, highly transportable implementation strategies that can be integrated into healthcare systems to improve the use of genomic medicine. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05721326. Registered February 10, 2023. https://www. CLINICALTRIALS: gov/study/NCT05721326.

Effects of cigarette package colors and warning labels on marlboro smokers' risk beliefs, product appraisals, and smoking behavior: a randomized trial.

OBJECTIVE: Plain packaging and graphic warning labels are two regulatory strategies that may impact cigarette risk beliefs and reduce consumption, but data are needed to better understand how smokers respond to such regulations. METHODS: Adult, daily, Marlboro non-menthol smokers (Red [n = 141] or Gold [n = 43]) completed a mixed factorial randomized trial. Participants smoked their usual cigarettes during baseline (5-days) and were randomized to receive cigarette packs with a warning label manipulation (graphic vs. text-only). Within each warning label condition, participants completed three within-subjects pack color manipulations (red, gold, plain), each lasting 15 days. Participants were blinded to the fact that all packs contained their usual cigarettes. Mixed-effects models examined between- and within-subject differences on risk beliefs, product perceptions, and smoking behavior. RESULTS: Warning type and package color did not impact cigarette consumption or subjective ratings. However, use increased in all conditions (2.59-3.59 cigarettes per day) relative to baseline. While smokers largely held correct risk beliefs at baseline (Mean = 6.02, SE = 0.17, Range:0-8), the cumulative number of incorrect or uncertain cigarette risk beliefs increased from baseline in all pack color manipulations in the text (IRR range = 1.70-2.16) and graphic (IRR range = 1.31-1.70) warning conditions. Across all pack color periods, those in the graphic (vs. text) warning condition had reduced odds of reporting their study cigarettes as 'safer' than regular cigarettes (OR range = 0.22-0.32). CONCLUSIONS: Pack color modification may increase uncertainty about several key cigarette risk beliefs, though graphic warnings may attenuate these effects. Regulatory agencies could consider supporting policy changes with information campaigns to maximize public knowledge. TRIAL REGISTRATION: November 25, 2014; Registration number: NCT02301351.

Cluster Randomized Pragmatic Clinical Trial Testing Behavioral Economic Implementation Strategies to Improve Tobacco Treatment for Patients With Cancer Who Smoke.

PURPOSE: Few cancer centers systematically engage patients with evidence-based tobacco treatment despite its positive effect on quality of life and survival. Implementation strategies directed at patients, clinicians, or both may increase tobacco use treatment (TUT) within oncology. METHODS: We conducted a four-arm cluster-randomized pragmatic trial across 11 clinical sites comparing the effect of strategies informed by behavioral economics on TUT engagement during oncology encounters with cancer patients. We delivered electronic health record (EHR)-based nudges promoting TUT across four nudge conditions: patient only, clinician only, patient and clinician, or usual care. Nudges were designed to counteract cognitive biases that reduce TUT engagement. The primary outcome was TUT penetration, defined as the proportion of patients with documented TUT referral or a medication prescription in the EHR. Generalized estimating equations were used to estimate the parameters of a linear model. RESULTS: From June 2021 to July 2022, we randomly assigned 246 clinicians in 95 clusters, and collected TUT penetration data from their encounters with 2,146 eligible patients who smoke receiving oncologic care. Intent-to-treat (ITT) analysis showed that the clinician nudge led to a significant increase in TUT penetration versus usual care (35.6% v 13.5%; OR = 3.64; 95% CI, 2.52 to 5.24; P < .0001). Completer-only analysis (N = 1,795) showed similar impact (37.7% clinician nudge v 13.5% usual care; OR = 3.77; 95% CI, 2.73 to 5.19; P < .0001). Clinician type affected TUT penetration, with physicians less likely to provide TUT than advanced practice providers (ITT OR = 0.67; 95% CI, 0.51 to 0.88; P = .004). CONCLUSION: EHR nudges, informed by behavioral economics and aimed at oncology clinicians, appear to substantially increase TUT penetration. Adding patient nudges to the implementation strategy did not affect TUT penetration rates.

Change in cardiovascular health among adults with current or past major depressive disorder enrolled in intensive smoking cessation treatment.

BACKGROUND: Elevated depressive symptoms and cigarette smoking are independently associated with poorer cardiovascular health (CVH), but it is unknown whether their treatment can synergistically improve CVH. We sought to characterize CVH of adults with comorbid depression and smoking and examine changes in CVH associated with changes in smoking and depression. METHODS: Participants (N = 300, 55 % women) were adult smokers (≥ 1 cigarette/day) with lifetime major depressive disorder enrolled in a 12-week intervention trial targeting depression and smoking. Multiple linear regression examined prospective associations between changes in depression (Beck Depression Inventory-II), smoking (past 24-hour cigarettes or smoking abstinence), and modified CVH score (per American Heart Association, excluding smoking: diet, physical activity, body mass index, blood glucose, cholesterol, blood pressure). RESULTS: Baseline mean CVH score was 5.87/12 points (SD = 2.13). No participants met "ideal" on all CVH components (blood glucose: 48 %, cholesterol: 46 %, physical activity: 38 %, body mass index: 24 %, blood pressure: 22 %, diet: 3 %). CVH scores did not change from baseline to end-of-treatment (M = 0.18 points, SD = 1.36, p = .177), nor did change in depression × smoking predict change in CVH (p = .978). However, greater reductions in depression were significantly associated with greater improvements in CVH (ß = -0.04, SE = 0.01, p = .015). LIMITATIONS: This study was limited by a short follow-up period, missing blood glucose and cholesterol data, and treatment-seeking smokers. CONCLUSIONS: Adults with comorbid depression and smoking had poor CVH. Although integrated treatment for depression and smoking improved both conditions, only reductions in depression were associated with improvements in CVH. These findings have implications for integrating psychosocial treatment into CVH promotion efforts. REGISTRATION: NCT02378714 (clinicaltrials.gov).

Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: A 2 × 2 factorial, randomized, placebo-controlled trial.

BACKGROUND AND AIMS: Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination. DESIGN, SETTING, PARTICIPANTS: This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD. INTERVENTIONS: BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14. MEASUREMENTS: Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs). FINDINGS: No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ2 (1) = 0.19, P = 0.67). BASC and ST did not differ (χ2 (1) = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ2 (1) = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline. CONCLUSION: A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy.

Behavioral activation for smoking cessation and the prevention of smoking cessation-related weight gain: A randomized trial.

BACKGROUND: Post-cessation weight gain (PCWG) is an obstacle to smoking cessation. This trial evaluated a behavioral intervention targeting alternative rewards to smoking and high calorie snacking to promote smoking cessation while mitigating PCWG. METHODS: Adult smokers (n = 288; 119 females, 169 males) received eight weeks of transdermal nicotine and were randomized to eight sessions of behavioral activation for smoking cessation and the mitigation of PCWG (BAS+) or standard smoking cessation counseling (SC). Primary outcomes were 7-day point prevalence abstinence and PCWG 26 weeks after the target quit date. Change in caloric intake from pre-treatment through the 26-week follow-up was a secondary outcome. Data were collected from September 2016 to February 2021, and analyses were completed in July 2022. RESULTS: BAS+ and SC did not differ in smoking abstinence rates at the 26-week follow-up (OR=0.80, 95%CI 0.50-1.27, p = 0.34; 18% versus 23%). There were no significant differences in PCWG between BAS+ and SC who were 7-day point prevalence abstinent (ß = -0.29, 95%CI -2.13 to 1.65, p = 0.77; 2.60 versus 2.20 pounds, respectively) or among those continuously abstinent (5.78 versus 5.34 pounds, respectively). There were no significant differences in caloric intake between BAS+ and SC from baseline to the 26-week follow-up (ß = 110.65, 95%CI -96.72 to 318.02, p = 0.30; -19.1 versus -116.9 kcals/day, respectively). CONCLUSIONS: The results do not support the efficacy of BAS+ for smoking cessation and the prevention of PCWG. These findings join a growing body of research highlighting the challenge of minimizing PCWG and promoting smoking abstinence.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study.

PURPOSE: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. METHODS: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. RESULTS: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years). CONCLUSION: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

Enhancing access to and diversity in cancer clinical trials through a financial reimbursement program: Protocol to evaluate a novel program.

As clinical trials have become more complex, with increasing numbers of required procedures and clinic visits, gaining access to promising new treatments has become even more challenging for many individuals. To address these barriers, we implemented a financial reimbursement and outreach program designed to increase the number and diversity of participants in cancer clinical trials at centers in Dallas, Houston, and Philadelphia. As endorsed by U.S. Food and Drug Administration (FDA) and the Texas and Pennsylvania State Legislatures, the program provides financial reimbursement for non-clinical costs (e.g., travel, lodging) to patients on cancer clinical trials with household income up to 700% the Federal poverty rate. The research study described here, centered at the Dallas site, evaluates program impact by assessing (1) numbers and diversity of patients enrolled to cancer clinical trials before and after program implementation; (2) characteristics of patients offered participation in the program who do versus do not enroll; (3) characteristics of patients enrolled in the program who do versus do not complete the reimbursement process. To evaluate perceived barriers and facilitators of program participation, we will conduct semi-structured interviews and administer the Comprehensive Score for Financial Toxicity Patient Reported Outcome Measure (COST PROM) and the Short Assessment of Health Literacy (SAHL). This program will examine how reimbursement of non-clinical costs can improve access to cancer clinical trials, with the eventual goal of increasing trial enrollment, diversity, representativeness, and generalizability.

Combining natural and artificial intelligence for robust automatic anatomy segmentation: Application in neck and thorax auto-contouring.

BACKGROUND: Automatic segmentation of 3D objects in computed tomography (CT) is challenging. Current methods, based mainly on artificial intelligence (AI) and end-to-end deep learning (DL) networks, are weak in garnering high-level anatomic information, which leads to compromised efficiency and robustness. This can be overcome by incorporating natural intelligence (NI) into AI methods via computational models of human anatomic knowledge. PURPOSE: We formulate a hybrid intelligence (HI) approach that integrates the complementary strengths of NI and AI for organ segmentation in CT images and illustrate performance in the application of radiation therapy (RT) planning via multisite clinical evaluation. METHODS: The system employs five modules: (i) body region recognition, which automatically trims a given image to a precisely defined target body region; (ii) NI-based automatic anatomy recognition object recognition (AAR-R), which performs object recognition in the trimmed image without DL and outputs a localized fuzzy model for each object; (iii) DL-based recognition (DL-R), which refines the coarse recognition results of AAR-R and outputs a stack of 2D bounding boxes (BBs) for each object; (iv) model morphing (MM), which deforms the AAR-R fuzzy model of each object guided by the BBs output by DL-R; and (v) DL-based delineation (DL-D), which employs the object containment information provided by MM to delineate each object. NI from (ii), AI from (i), (iii), and (v), and their combination from (iv) facilitate the HI system. RESULTS: The HI system was tested on 26 organs in neck and thorax body regions on CT images obtained prospectively from 464 patients in a study involving four RT centers. Data sets from one separate independent institution involving 125 patients were employed in training/model building for each of the two body regions, whereas 104 and 110 data sets from the 4 RT centers were utilized for testing on neck and thorax, respectively. In the testing data sets, 83% of the images had limitations such as streak artifacts, poor contrast, shape distortion, pathology, or implants. The contours output by the HI system were compared to contours drawn in clinical practice at the four RT centers by utilizing an independently established ground-truth set of contours as reference. Three sets of measures were employed: accuracy via Dice coefficient (DC) and Hausdorff boundary distance (HD), subjective clinical acceptability via a blinded reader study, and efficiency by measuring human time saved in contouring by the HI system. Overall, the HI system achieved a mean DC of 0.78 and 0.87 and a mean HD of 2.22 and 4.53 mm for neck and thorax, respectively. It significantly outperformed clinical contouring in accuracy and saved overall 70% of human time over clinical contouring time, whereas acceptability scores varied significantly from site to site for both auto-contours and clinically drawn contours. CONCLUSIONS: The HI system is observed to behave like an expert human in robustness in the contouring task but vastly more efficiently. It seems to use NI help where image information alone will not suffice to decide, first for the correct localization of the object and then for the precise delineation of the boundary.

Uptake and Survival Outcomes Following Immune Checkpoint Inhibitor Therapy Among Trial-Ineligible Patients With Advanced Solid Cancers.

IMPORTANCE: Immune checkpoint inhibitors (ICIs) are part of standard of care for patients with many advanced solid tumors. Patients with poor performance status or organ dysfunction are traditionally ineligible to partake in pivotal randomized clinical trials of ICIs. OBJECTIVE: To assess ICI use and survival outcomes among patients with advanced cancers who are traditionally trial ineligible based on poor performance status or organ dysfunction. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted in 280 predominantly community oncology practices in the US and included 34 131 patients (9318 [27.3%] trial ineligible) who initiated first-line systemic therapy from January 2014 through December 2019 for newly diagnosed metastatic or recurrent nontargetable non-small cell lung, urothelial cell, renal cell, or hepatocellular carcinoma. Data analysis was performed from December 1, 2019, to June 1, 2021. EXPOSURES: Trial ineligibility (Eastern Cooperative Oncology Group performance status ≥2 or the presence of kidney or liver dysfunction); first-line systemic therapy. MAIN OUTCOMES AND MEASURES: The association between trial ineligibility and ICI monotherapy uptake was assessed using inverse probability-weighted (IPW) logistic regressions. The comparative survival outcomes following ICI and non-ICI therapy among trial-ineligible patients were assessed using treatment IPW survival analyses. Because we observed nonproportional hazards, we reported 12-month and 36-month restricted mean survival times (RMSTs) and time-varying hazard ratios (HRs) of less than 6 months and 6 months or greater. RESULTS: Among the overall cohort (n = 34 131), the median (IQR) age was 70 (62-77) years; 23 586 (69%) were White individuals, and 14 478 (42%) were women. Over the study period, the proportion of patients receiving ICI monotherapy increased from 0% to 30.2% among trial-ineligible patients and 0.1% to 19.4% among trial-eligible patients. Trial ineligibility was associated with increased ICI monotherapy use (IPW-adjusted odds ratio compared with non-ICI therapy, 1.8; 95% CI, 1.7-1.9). Among trial-ineligible patients, there were no overall survival differences between ICI monotherapy, ICI combination therapy, and non-ICI therapy at 12 months (RMST, 7.8 vs 7.7 vs 8.1 months) or 36 months (RMST, 15.0 vs 13.9 vs 14.4 months). Compared with non-ICI therapy, ICI monotherapy showed evidence of early harm (IPW-adjusted HR within 6 months, 1.2; 95% CI, 1.1-1.2) but late benefit (adjusted HR among patients who survived 6 months, 0.8; 95% CI, 0.7-0.8). CONCLUSIONS AND RELEVANCE: In this cohort study, compared with trial-eligible patients, trial-ineligible patients with advanced cancers preferentially received first-line ICI therapy. A survival difference was not detected between ICI and non-ICI therapies among trial-ineligible patients. Positive results for ICI in phase 3 trials may not translate to this vulnerable population.

Impact of the COVID-19 pandemic on treatment patterns for US patients with metastatic solid cancer.

BACKGROUND: The COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is unknown. We assessed the COVID-19 pandemic's impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer. METHODS: We used an electronic health record-derived longitudinal database curated via technology-enabled abstraction to identify 14,136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at ∼280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy. RESULTS: The adjusted probability of treatment within 30 days of diagnosis [95% confidence interval] was similar across periods: January-March 2019 41.7% [32.2%, 51.1%]; April-July 2019 42.6% [32.4%, 52.7%]; January-March 2020 44.5% [30.4%, 58.6%]; April-July 2020 46.8% [34.6%, 59.0%]; adjusted percentage-point difference-in-differences 1.4% [-2.7%, 5.5%]. Among 5,962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences 1.6% [-2.6%, 5.8%]). There was no meaningful effect modification by cancer type, race, or age. CONCLUSIONS: Despite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not impact time to treatment initiation or treatment selection for patients with metastatic solid cancers.