B7-H3 is widely expressed in soft tissue sarcomas.

PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS. PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature. RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1. CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Behavioral Activation mHealth Application for Smoking Cessation: A Randomized Controlled Pilot Trial.

BACKGROUND: Behavioral activation (BA) is an effective intervention for both depression and substance use disorders. Combining BA with a standard smoking cessation intervention may improve quit rates by addressing depressive symptoms, a key barrier to quitting. This study preliminarily evaluated the acceptability and efficacy of the BA-based Actify! mobile health application (mHealth app) for smoking cessation. METHODS: We conducted a pilot randomized controlled trial (n=242) comparing Actify! with the National Cancer Institute's (NCI) app for smoking cessation (QuitGuide) on acceptability (user satisfaction, app openings), smoking abstinence, and mechanisms of change (behavioral activation and depressive symptoms) at 8 weeks and 6 months post-randomization. Participants were US adults recruited online who smoked daily. RESULTS: Treatment satisfaction was uniformly higher in the Actify! arm. Number of app openings was similar across arms (M=34.3 openings over 8 weeks in both arms). Self-reported 30-day point prevalence abstinence (PPA) at 8 weeks was 12.6% for Actify! vs. 7.3% for QuitGuide. Differences in 30-day PPA continued through 6 months (18.5% for Actify! vs. 12.2% for QuitGuide). Changes between baseline and 8 weeks in depressive symptoms and behavioral activation favored Actify!. Planned subgroup analyses suggested greater benefit of Actify! among participants with pre-treatment mild to moderate depression symptom severity compared to those with no depression symptoms. CONCLUSIONS: Actify! showed considerable promise as a novel mHealth treatment, as evidenced by high usage and higher user satisfaction and quit rates than QuitGuide at both short- and long-term follow-up. The next step is to evaluate Actify! in a fully-powered efficacy trial. IMPLICATIONS: Study findings demonstrate the promise of a behavioral activation (BA)-based mobile health app (Actify!) for smoking cessation as a population-level intervention that can effectively address depressive symptoms as a risk factor for worse smoking treatment outcomes. The Actify! app is the first standalone BA-based app to demonstrate potential for improved acceptability and efficacy relative to a standard care comparison app, with user satisfaction and smoking quit rates descriptively exceeding those of the National Cancer Institute's QuitGuide app.

Corticospinal inhibition investigated in relation to upper extremity motor function in cervical spinal cord injury.

OBJECTIVE: Corticospinal inhibitory mechanisms are relevant to functional recovery but remain poorly understood after spinal cord injury (SCI). Post-injury characteristics of contralateral silent period (CSP), a measure of corticospinal inhibition evaluated using transcranial magnetic stimulation (TMS), is inconsistent in literature. We envisioned that investigating CSP across muscles with varying degrees of weakness may be a reasonable approach to resolve inconsistencies and elucidate the relevance of corticospinal inhibition for upper extremity function following SCI. METHODS: We studied 27 adults with chronic C1-C8 SCI (age 48.8 ± 16.1 years, 3 females) and 16 able-bodied participants (age 33.2 ± 11.8 years, 9 females). CSP characteristics were assessed across biceps (muscle power = 3-5) and triceps (muscle power = 1-3) representing stronger and weaker muscles, respectively. We assessed functional abilities using the Capabilities of the Upper Extremity Test (CUE-T). RESULTS: Participants with chronic SCI had prolonged CSPs for biceps but delayed and diminished CSPs for triceps compared to able-bodied participants. Early-onset CSPs for biceps and longer, deeper CSPs for triceps correlated with better CUE-T scores. CONCLUSIONS: Corticospinal inhibition is pronounced for stronger biceps but diminished for weaker triceps muscle in SCI indicating innervation relative to the level of injury matters in the study of CSP. SIGNIFICANCE: Nevertheless, corticospinal inhibition or CSP holds relevance for upper extremity function following SCI.

Moving toward elucidating alternative motor pathway structures post-stroke: the value of spinal cord neuroimaging.

Stroke results in varying levels of motor and sensory disability that have been linked to the neurodegeneration and neuroinflammation that occur in the infarct and peri-infarct regions within the brain. Specifically, previous research has identified a key role of the corticospinal tract in motor dysfunction and motor recovery post-stroke. Of note, neuroimaging studies have utilized magnetic resonance imaging (MRI) of the brain to describe the timeline of neurodegeneration of the corticospinal tract in tandem with motor function following a stroke. However, research has suggested that alternate motor pathways may also underlie disease progression and the degree of functional recovery post-stroke. Here, we assert that expanding neuroimaging techniques beyond the brain could expand our knowledge of alternate motor pathway structure post-stroke. In the present work, we will highlight findings that suggest that alternate motor pathways contribute to post-stroke motor dysfunction and recovery, such as the reticulospinal and rubrospinal tract. Then we review imaging and electrophysiological techniques that evaluate alternate motor pathways in populations of stroke and other neurodegenerative disorders. We will then outline and describe spinal cord neuroimaging techniques being used in other neurodegenerative disorders that may provide insight into alternate motor pathways post-stroke.

Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson's Disease Pathology.

Parkinson's disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

Perioperative Chemotherapy and Chemoradiotherapy for Patients With Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.

Racial disparities in the screening mammography continuum within a heterogeneous health care system.

BACKGROUND: Decreased mammography drives breast cancer disparities. Black women have lower rates of mammography completion than White women, and this contributes to disparities in outcomes. Points of disparity along the continuum for screening mammography remain underresearched. METHODS: The authors compared mammography referrals for Black and White women aged 40-74 years at a heterogeneous academic medical center. Completion of steps of the screening mammography continuum was compared between Black and White women within two age cohorts: 40-49 and 50-74 years. Multivariable logistic regression was used to evaluate the association between race and mammogram completion. RESULTS: Among 26,476 women, 3090 (12%) were Black, and 23,386 (88%) were White. Among Black women aged 50-74 years who were due for mammography, 40% had referrals, 39% were scheduled, and 21% completed mammography; the corresponding values for White women were 42%, 41%, and 27%, respectively. Similar differences in referral outcomes were noted for women aged 40-49 years, although Black women had lower rates of provider-initiated referrals (9% vs. 13%). Adjusted analyses for those aged 40-49 and 50-74 years demonstrated an association between Black race and lower rates of mammography completion (odds ratio [OR] for 40-49 years, 0.74; 95% CI, 0.57-0.95; p = .02; OR for 50-74 years, 0.85; 95% CI, 0.74-0.98; p = .02). In multivariable analyses, noncommercial insurance and higher comorbidity were associated with lower rates of mammography. Provider-initiated referral was positively correlated to mammogram completion. CONCLUSIONS: Black race was associated with 15%-26% lower mammography completion (adjusted). Both groups experienced the highest attrition after scheduling mammograms, although attrition was more precipitous for Black women. These findings have implications for future interventions, including increasing provider-initiated referrals and decreasing barriers to attending scheduled mammograms.

Racial and sex differences in tumor genomics in urothelial carcinoma.

PURPOSE: Differences in bladder cancer outcomes have been demonstrated by sex and race/ethnicity, with studies showing a higher burden of adverse outcomes among women and racially minoritized populations. Despite these epidemiologic differences, populations with disproportionally adverse outcomes are often underrepresented in genomic cohorts. This exclusion impacts the accuracy and generalizability of genomic studies in bladder cancer and has the potential to widen disparities by sex and/or race/ethnicity. BASIC PROCEDURES: We analyzed pooled somatic mutational data from publicly available cohorts in the cBioPortal open access platform. FINDINGS: A total of 796 unique patients were identified. Average age for the cohort was 67 years (range: 25-98 years), 188 (24%) were female, and the majority were White (n = 423, 85% among those who report race). Median total mutation count was 91 (IQR: 20, 202) per patient. We used multivariable logistic regression to independently evaluate the association between race/sex and mutation status in each of 122 genes of interest, identified from TCGA, adjusting for age and bladder cancer invasive status. In adjusted analyses, male sex was associated with increased risk of mutation in ARID1A, CHD6, and NCOR1 compared with female sex. White race was associated with increased risk of mutation in ARID1A, EP300, PIK3CA, and TP53 and decreased risk of mutation in HRAS compared with non-White race. CONCLUSIONS: These differences highlight the importance of enriching cohorts for female and non-White patients in genomic studies and clinical trials, especially as we test the use of molecular biomarkers to personalize care for patients with bladder cancer.

Acute kidney injury and chronic kidney disease in umbilical cord blood transplant recipients.

Introduction: Acute kidney injury (AKI) is a frequent early complication post hematopoietic stem cell transplant (HSCT), associated with high morbidity and mortality. Cord blood transplant (CBT) recipients are potentially exposed to more nephrotoxic insults, compared to patients undergoing HSCT from other donor sources. We aimed to identify risk factors for AKI in patients undergoing CBT. We also aimed to identify the impact of AKI on chronic kidney disease (CKD) and survival outcomes by one-year post-CBT. Methods: Adults and children who underwent a first CBT at our Institution were retrospectively evaluated. AKI was staged according to Kidney Disease Improving Global Outcomes (KDIGO) definitions. Cox regression models were used to estimate the association of demographic factors and post-CBT parameters with the cause-specific hazard of AKI. Results: We identified 276 patients. Median age was 32 years, 28% (77/276) were children (<18 years) and 129 (47%) were white. A myeloablative conditioning regimen was administered to 243 patients (88%) and 248 (90%) received cyclosporine for GVHD prophylaxis. One-hundred and eighty-six patients (67%) developed AKI by day 60 post-transplant, with 72 (26%) developing severe AKI (stage 2 and 3). In a multivariable analysis, each increase in bilirubin level of 1 mg/dL was associated with a 23% increase in the risk of severe AKI (adjusted HR 1.23, 95% CI 1.13 - 1.34, p<.0001). Conversely, systemic steroid administration appeared to be protective of severe AKI (unadjusted HR 0.36, 95% CI 0.18 - 0.72, p=.004) in a univariate model . Two-hundred-forty-seven patients were evaluable at the one-year time point. Among those, 100 patients (40%) developed CKD one-year post-CBT. Severe AKI was associated with a higher hazard of non-relapse mortality (adjusted HR=3.26, 95% CI 1.65-6.45, p=.001) and overall mortality (adjusted HR=2.28, 95% CI 1.22-4.27, p=.01). Discussion: AKI is a frequent complication after CBT and is associated with worse outcomes. Questions remain as to the mechanism of the protective role of steroids on kidney function in the setting of CBT.

Elevated EVL Methylation Level in the Normal Colon Mucosa Is a Potential Risk Biomarker for Developing Recurrent Adenomas.

BACKGROUND: Individuals with adenomatous colorectal polyps undergo repeated colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas. METHODS: Patients with ≥1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with colorectal cancer at baseline (model 3). RESULTS: Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of colorectal cancer. Older age, never smoking, and baseline colorectal cancer were associated with higher levels of mEVL (P ≤ 0.05). Each log base 10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1 [OR, 2.64; 95% confidence interval (CI), 1.09-6.36], and adenoma(s) or cancer after baseline for models 1 (OR, 2.01; 95% CI, 1.04-3.90) and model 2 (OR, 3.17; 95% CI, 1.30-7.72). CONCLUSIONS: Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas. IMPACT: These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer.

An Avatar-Led Web-Based and SMS Text Message Smoking Cessation Program for Socioeconomically Disadvantaged Veterans: Pilot Randomized Controlled Trial.

BACKGROUND: Despite the declining prevalence of cigarette smoking in the United States, socioeconomically disadvantaged veterans receiving care from the Veterans Health Administration have a high prevalence of smoking. Currently, available treatment options for these veterans focus on tobacco users who are ready to quit and have limited reach. Consequently, there is a great need for accessible, effective smoking cessation interventions for veterans at all levels of readiness to quit smoking. OBJECTIVE: To address these needs, we developed Vet Flexiquit, a web-based Acceptance and Commitment Therapy program for veterans, and evaluated its acceptability (primary aim), efficacy, and impact on theory-based change processes relative to the National Cancer Institute's SmokefreeVET program in a pilot randomized controlled trial. METHODS: Participants (N=49) were randomized 1:1 to receive either the Vet Flexiquit (n=25) or SmokefreeVET (n=24) web program. Both groups received SMS text messages as part of the intervention for 6 weeks. Both interventions are fully automated and self-guided. Primary outcome data were collected at 3 months after the randomization. Self-reported smoking abstinence was biochemically verified using saliva cotinine. Multivariable logistic regression, negative binomial regression, and linear regression models were used to evaluate the association between the treatment arm and outcomes of interest. RESULTS: Acceptability, as measured by overall treatment satisfaction, was high and similar across treatment arms: 100% (17/17) for Vet Flexiquit and 95% (18/19) for SmokefreeVET. Acceptability, as measured by utilization, was more modest (log-ins: M=3.7 for Vet Flexiquit and M=3.2 for SmokefreeVET). There were no statistically significant differences between treatment arms for any acceptability measures. Similarly, there were no statistically significant differences between treatment arms in the secondary outcomes of smoking cessation or change in Acceptance and Commitment Therapy's theory-based processes. In open-ended survey responses, some veterans in both treatment arms expressed interest in having support from a professional or peer to enhance their experience, as well as an expanded SMS text messaging program. CONCLUSIONS: Both programs had high ratings of acceptability, limited utilization, and a similar impact on cessation and cessation processes. Taken together with the qualitative data suggesting that additional support may enhance participants' experience of both programs, these preliminary findings suggest that the programs may have similar outcomes among veterans who are looking for a digital cessation treatment option and that integrating provider or peer support and enhancing the SMS text messaging program holds promise as a means of boosting engagement and outcomes for both programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04502524; https://clinicaltrials.gov/ct2/show/NCT04502524.

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies.

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n = 1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n = 1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P = .001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n = 21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n = 192; 30%) or exercise (n = 139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda.

OBJECTIVE: Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response. METHODS: Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response. RESULTS: Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P  = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P  = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/µl; P  = 0.027), higher HIV viral load (HR = 2.22 per log 10  copies/ml; P  = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10  copies/ml; P  = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P  = 0.045), abnormal chest X-ray (HR = 8.41; P  = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10  copies/ml; P  < 0.001). CONCLUSIONS: Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

Assessment of Oncology Advanced Practice Professional Willingness to Participate in Medical Aid in Dying.

Importance: In 2021, New Mexico passed legislation allowing nurse practitioners and physician assistants (referred to herein as advanced practice professionals [APPs]) to prescribe medications for medical aid in dying (MAID). Other US states with existing MAID laws (eg, Washington) are also considering expanding MAID prescribing authority to APPs. There is a lack of research exploring APP knowledge of, willingness to, and comfort with acting as a prescribing or consulting clinician for MAID. Objective: To assess perspectives of oncology APPs regarding MAID, including their willingness to prescribe and/or consult for MAID and factors associated with willingness. Design, Setting, and Participants: This cross-sectional, self-report survey study used data collected from APPs working at a comprehensive cancer center in Washington State in fall 2021. Main Outcomes and Measures: The primary survey question was whether APPs would be willing to participate in death with dignity, the term used for MAID in Washington. Survey questions evaluated how influential specific factors were on APP views on MAID as well as respondents' knowledge of and comfort with aspects of the MAID process. Results: Of 167 eligible APPs, 77 (46.1%) responded to the survey. Most respondents (68 [88.3%]) reported their race and ethnicity as White; 72 (93.5%) identified as a woman. Medical oncology (28 [36.4%]) was the most common field of practice, and 21 respondents (27.3%) reported having practiced as an APP for 6 to 10 years. Of all respondents, 61 (79.2%) reported having at least 1 patient who inquired about MAID; depending on the question, less than a third of respondents (5.0%-27.0%) endorsed feeling knowledgeable or very knowledgeable about any aspect of the MAID process. In this study, 39 APPs (50.6%) endorsed being willing to participate in MAID either as a consulting or prescribing clinician, whereas 31 (40.3%) were uncertain of whether they would participate. Willingness to participate was associated with having had more patients pursue MAID (33 of the 39 willing participants [84.6%] vs 15 of the 31 unsure participants [48.4%] reported having 1 or more patients pursue MAID). Higher knowledge and comfort scores were both significantly associated with increased odds of being willing to participate (odds ratio, 1.14 per 1-point score increase [95% CI, 1.03-1.27]; P = .01) vs unsure (1.18 [95% CI, 1.07-1.30; P = .001). Conclusions and Relevance: The results of this survey study suggest that oncology APPs may require preparation for the addition of MAID to their scope of practice. This study also raises questions for future research regarding support for APPs who may be considering participation in MAID but question their role or want physician involvement.

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas.

BACKGROUND: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). MATERIALS AND METHODS: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. RESULTS: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. CONCLUSIONS: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

Safety and efficacy of transcranial direct current stimulation in upper extremity rehabilitation after tetraplegia: protocol of a multicenter randomized, clinical trial.

STUDY DESIGN: A multisite, randomized, controlled, double-blinded phase I/II clinical trial. OBJECTIVE: The purpose of this clinical trial is to evaluate the safety, feasibility and efficacy of pairing noninvasive transcranial direct current stimulation (tDCS) with rehabilitation to promote paretic upper extremity recovery and functional independence in persons living with chronic cervical spinal cord injury (SCI). SETTING: Four-site trial conducted across Cleveland Clinic, Louis Stokes Veterans Affairs Medical Center of Cleveland and MetroHealth Rehabilitation Rehabilitation Institute of Ohio, and Kessler Foundation of New Jersey. METHODS: Forty-four adults (age ≥18 years) with tetraplegia following cervical SCI that occurred ≥1-year ago will participate. Participants will be randomly assigned to receive anodal tDCS or sham tDCS given in combination with upper extremity rehabilitation for 15 sessions each over 3-5 weeks. Assessments will be made twice at baseline separated by at least a 3-week interval, once at end-of-intervention, and once at 3-month follow-up. PRIMARY OUTCOME MEASURE(S): Primary outcome measure is upper extremity motor impairment assessed using the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) scale. Functional abilities will be assessed using Capabilities of Upper Extremity-Test (CUE-T), while functional independence and participation restrictions will be evaluated using the self-care domain of Spinal Cord Independent Measure (SCIM), and Canadian Occupational Performance Measure (COPM). SECONDARY OUTCOME MEASURES: Treatment-associated change in corticospinal excitability and output will also be studied using transcranial magnetic stimulation (TMS) and safety (reports of adverse events) and feasibility (attrition, adherence etc.) will also be evaluated. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT03892746. This clinical trial is being performed at four sites within the United States: Cleveland Clinic (lead site), Louis Stokes Cleveland Veterans Affairs Medical Center (VAMC) and MetroHealth Rehabilitation Institute in Ohio, and Kessler Foundation in New Jersey. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office.

Clinical Outcomes After Proton Beam Therapy for Locally Advanced Non-Small Cell Lung Cancer: Analysis of a Multi-institutional Prospective Registry.

PURPOSE: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS AND MATERIALS: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS. RESULTS: A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality. CONCLUSIONS: PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

Status of medical genomics and genetics education in maternal-fetal medicine: survey of program directors and clinical fellows in the USA.

OBJECTIVE: The study aimed to assess the current state of medical genetics and genomics (MGG) education amongst maternal-fetal medicine (MFM) program directors (PDs) and clinical fellows. METHODS: An online questionnaire was generated and distributed to all current program directors and fellows in ACGME-accredited MFM fellowships across the USA in 2018. RESULTS: A total of 13 program directors and 54 MFM fellows responded to our survey. Of the respondents, 73% of the MFM fellows mentioned having dedicated structured MGG rotations as part of their training. Only 12% of fellows reported a high level of satisfaction with their programs' structured MGG rotations and almost 40% reported dissatisfaction, compared to 56% of PDs who reported very high satisfaction. Furthermore, 84% of PDs reported high levels of satisfaction with MGG didactics currently in place compared to only 24% of fellows sharing the same opinion. When compared to PDs, fellows reported a significantly lower satisfaction score toward their MGG rotations (p < .05) and didactic sessions (p < .05). More than 62% of PDs were satisfied with the number of MGG-faculty in their division compared to 80% of fellows who thought more faculty is needed. Thirty-eight percent of PDs quoted curricular overload and lack of time as the most important obstacles to MGG education, compared to 43% of fellows citing a limited number of genetics services providers as the most important obstacles to their MGG education. CONCLUSION: MFM fellows and PDs differ in their satisfaction with the current state of MGG didactics and rotations in their programs, the number of MGG faculty in their divisions, and the perceived obstacles to MGG education . Our study illustrates the need for MGG curriculum development in MFM fellowships as this subspecialty relies heavily on the use of genetics and genomics services.

Measurement error and reliability of TMS metrics collected from biceps and triceps in individuals with chronic incomplete tetraplegia.

Transcranial magnetic stimulation (TMS) is used to investigate corticomotor neurophysiology associated with functional recovery in individuals with spinal cord injury (SCI). There is insufficient evidence about test-retest measurement properties of TMS in SCI. Therefore, we investigated test-retest agreement and reliability of TMS metrics representing corticomotor excitability, output, gain, map (representation), and inhibition in individuals with cervical SCI. We collected TMS metrics from biceps and triceps muscles because of the relevance of this proximal muscle pair to the cervical SCI population. Twelve individuals with chronic C3-C6 SCI participated in two TMS sessions separated by ≥ 2 weeks. Measurement agreement was evaluated using t tests, Bland-Altman limits of agreement and relative standard error of measurement (SEM%), while reliability was investigated using intra-class correlation coefficient (ICC) and concordance correlation coefficient (CCC). We calculated the smallest detectable change for all TMS metrics. All TMS metrics except antero-posterior map coordinates and corticomotor inhibition were in agreement upon repeated measurement though limits of agreement were generally large. Measures of corticomotor excitability, output and medio-lateral map coordinates had superior agreement (SEM% < 10). Metrics representing corticomotor excitability, output, and inhibition had good-to-excellent reliability (ICC/CCC > 0.75). The smallest detectable change for TMS metrics was generally high for a single individual, but this value reduced substantially with increase in sample size. We recommend use of corticomotor excitability and recruitment curve area owing to their superior measurement properties. A modest group size (20 or above) yields more stable measurements, which may favor use of TMS metrics in group level modulation after SCI.

An Avatar-Led Digital Smoking Cessation Program for Sexual and Gender Minority Young Adults: Intervention Development and Results of a Single-Arm Pilot Trial.

BACKGROUND: Sexual and gender minority young adults have a high prevalence of smoking and unique barriers to accessing tobacco treatment. OBJECTIVE: To address these challenges as well as their preferences for sexual and gender minority-targeted interventions and digital programs, we developed and evaluated the acceptability, preliminary efficacy, and impact on theory-based change processes of an acceptance and commitment therapy-based digital program called Empowered, Queer, Quitting, and Living (EQQUAL). METHODS: Participants (n=22) of a single-arm trial conducted to evaluate the program were young adults, age 18 to 30 years, who self-identified as sexual and gender minority individuals and smoked at least one cigarette per day. All participants received access to the EQQUAL program. Participants completed web-based surveys at baseline and at a follow-up 2 months after enrollment. We verified self-reported smoking abstinence with biochemical testing; missing data were counted as smoking or using tobacco. RESULTS: For young adults who logged in at least once (n=18), the mean number of log-ins was 5.5 (SD 3.6), mean number of sessions completed was 3.1 (SD 2.6), and 39% (7/18) completed all 6 sessions. Overall, 93% of participants (14/15) were satisfied with the EQQUAL program, 100% (15/15) found it easy to use, and 100% (15/15) said it helped them be clearer about how to quit. Abstinence from smoking or using tobacco was confirmed with biochemical testing for 23% of participants (5/22). Both quantitative and qualitative results suggested a positive overall response to the avatar guide, with areas for future improvement largely centered on the avatar's appearance and movements. CONCLUSIONS: Treatment acceptability of EQQUAL was very promising. The rate of abstinence, which was biochemically confirmed, was 3 times higher than that of the only other digital program to date that has targeted sexual and gender minority young adults and 6 to 13 times higher than those of nontargeted digital smoking interventions among sexual and gender minority young adults. Planned improvements for the next iteration of the program include making the avatar's movements more natural; offering multiple avatar guides with different on characteristics such as race, ethnicity, and gender identity from which to choose; and providing a support forum for users to connect anonymously with peers.