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Background: HER2-targeted therapies have led to marked improvements in survival for patients with HER2-positive breast cancer. Despite the gains obtained with current HER2-targeted therapies, an unmet medical need remains for patients with HER2-expressing (high or low expression) advanced breast cancer that has progressed after prior treatments. Zanidatamab is a novel HER2-targeted bispecific antibody that has multiple mechanisms of action, including immune clearance of HER2-expressing tumor cells through antibody-dependent cellular phagocytosis. Zanidatamab has been shown to be well-tolerated and has demonstrated antitumor activity, both as monotherapy and in combination with chemotherapy, across HER2-expressing solid tumors in a Phase 1 study. ALX148 is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of anticancer therapies, including antibodies, with minimal added hematologic toxicity. Treatment with zanidatamab in combination with ALX148 has the potential to augment the immune clearance of HER2-expressing cancer cells by blocking the CD47-SIRPa interaction that inhibits phagocytosis of the same cancer cells. In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2-targeted therapies. Here, we describe a Phase 1b/2 study to investigate the safety and antitumor activity of a chemotherapy-free combination of zanidatamab plus ALX148 in advanced HER2-expressing cancers, including breast cancer. Methods: ZWI-ZW25-204 is a Phase 1b/2, 2-part, open-label, multicenter study to evaluate the safety and antitumor activity of zanidatamab administered in combination with ALX148 in patients with locally advanced/inoperable and/or metastatic HER2-expressing cancer. Part 1 of this study will evaluate safety and tolerability and will establish the recommended doses (RDs) of zanidatamab plus ALX148. It will include patients with either HER2-positive (defined per ASCO/CAP guidelines) or HER2-low (defined as immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization (ISH) negative) breast cancer. Part 2 will evaluate the antitumor activity of zanidatamab plus ALX148 (at their combination therapy RDs) in 3 expansion cohorts: HER2-positive breast cancer (Cohort 1), HER2-low breast cancer (Cohort 2) and other HER2-overexpressing advanced malignancies (Cohort 3). Other key eligibility criteria include: prior use of approved agents known to confer clinical benefit, disease progression on or after the most recent systemic therapy, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients will receive zanidatamab and ALX148, each administered intravenously once every 2 weeks in a 28-day treatment cycle. Response assessments will be performed every 8 weeks. Primary endpoints include safety and tolerability assessments (Part 1) and confirmed objective response rate per RECIST 1.1 (Part 2). Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139). Citation Format: Sara A. Hurvitz, Jorge Chaves, Adam Brufsky, Alberto J. Montero, Bruno Fang, Kay Yeung, Manish R. Patel, Ritesh Parajuli, Adam Omidpanah, Elaina Gartner, Abraham Fong, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204) [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 OT1-14-01.

Adolescent risk factors for pre-diabetes and diabetes in young adulthood were examined in three minority groups and compared to those in non-Hispanic Whites. Retrospective cohort study with data on 8337 adolescent respondents from Add Health (1994–2008). Participants included 5131 non-Hispanic Whites, 1651 non-Hispanic Blacks, 1223 Hispanics, and 332 American Indians/Alaska Natives. Diabetes was defined as: hemoglobin A1C ≥ 6.5%, glucose > 125 mg/dl, self-reported diabetes, or self-reported diabetes medication use, in Wave 4 data. Pre-diabetes was defined as hemoglobin A1C ≥ 5.7%. Relative risk regression models were used to evaluate the association between risk factors and risk of diabetes and pre-diabetes, controlling for body mass index, sedentary and physical activity habits, fast food consumption, and parental education, parental diabetes status, and financial stability. 484 participants developed diabetes; 2878 developed pre-diabetes between 1994 and 2008. Pre-diabetes and diabetes were more prevalent in non-Hispanic Blacks (55% and 12%, respectively) than in American Indians/Alaska Natives (43% and 11%), Hispanics (37% and 6%), and non-Hispanic Whites (27% and 3%). In all races, higher body mass index and parental diabetes were associated with higher risk of pre-diabetes and diabetes, while female sex was associated with lower risk of pre-diabetes. Efforts to reduce the risk of pre-diabetes and diabetes in adolescents should emphasize parental diabetes and BMI in all races, independent of physical activity, sedentary behaviors, or fast food consumption. Future interventions might be interested in targeting households, rather than individuals, to prevent pre-diabetes and diabetes in adolescents and young adults.

Objective To examine the feasibility of implementing a standardized, clinically relevant genitourinary examination for both men and women, and to identify physical examination findings characteristic of urologic chronic pelvic pain syndrome (UCPPS). Materials and Methods This study analyzed 2 samples: men and women with UCPPS who participated in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping (EP) Study, and age-matched controls who were either positive for chronic fatigue syndrome or healthy (pain-free). We compared physical examination findings in both positive and healthy controls with UCPPS cases: findings from both the EP examinations and from an extended genitourinary examination. Results EP and extended examinations were performed on 143 participants: 62 UCPPS cases (30 women, 32 men), 42 positive controls (15 women, 27 men), and 39 healthy controls (22 women, 17 men). EP examinations showed that pelvic floor tenderness was more prevalent in cases (55.0%) than in positive (14.6%) or healthy controls (10.5%). Extended examinations revealed specific areas of tenderness in the pelvic floor musculature. Cases were also more likely than healthy controls to report tenderness in multiple areas, including suprapubic, symphysis pubis, and posterior superior iliac spine, and on bimanual examination. No comparative findings were specific to biological sex, and no evidence of pudendal neuropathy was observed on extended examination of cases or controls. Conclusion The extended genitourinary examination is an easily administered addition to the assessment of men and women during evaluation for UCPPS. Physical findings may help to better categorize patients with UCPPS into clinically relevant subgroups for optimal treatment.

Left ventricular mass (LVM) has been shown to serve as a measure of target organ damage resulting from chronic exposure to several risk factors. Data on the association of midlife LVM with later cognitive performance are sparse. We studied 721 adults (mean age 56 years at baseline) enrolled in the Strong Heart Study (SHS, 1993–1995) and the ancillary CDCAI (Cerebrovascular Disease and Its Consequences in American Indians) Study (2010–2013), a study population with high prevalence of cardiovascular disease. LVM was assessed with transthoracic echocardiography at baseline in 1993 to 1995. Cranial magnetic resonance imaging and cognitive testing were undertaken between 2010 and 2013. Generalized estimating equations were used to model associations between LVM and later imaging and cognition outcomes. The mean follow-up period was 17 years. A difference of 25 g in higher LVM was associated with marginally lower hippocampal volume (0.01%; 95% confidence interval, 0.02–0.00; P =0.001) and higher white matter grade (0.10; 95% confidence interval, 0.02–0.18; P =0.014). Functionally, participants with higher LVM tended to have slightly lower scores on the modified mini-mental state examination (0.58; 95% confidence interval, 1.08–0.08; P =0.024). The main results persisted after adjusting for blood pressure levels or vascular disease. The small overall effect sizes are partly explained by survival bias because of the high prevalence of cardiovascular disease in our population. Our findings emphasize the role of cardiovascular health in midlife as a target for the prevention of deleterious cognitive and functional outcomes in later life.

American Indians and Alaska Natives have the highest obesity prevalence in the United States, but the influence of early childhood variables on body mass index (BMI; calculated as kg/mThis study investigated the association between breastfeeding in infancy and BMI in American Indians and Alaska Native and non-Hispanic white adolescents and young adults.Longitudinal analysis based on data from the National Longitudinal Study of Adolescent to Adult Health (1994 to 2008).Adolescent respondents who self-identified as American Indians and Alaska Native or non-Hispanic white, and whose parents completed the parental questionnaire, reported their height and weight. The final sample included 655 American Indians and Alaska Native and 10,305 non-Hispanic white respondents.Generalized estimating equations were used to measure the mean differences, 95% CIs, and P values of the association between breastfeeding in infancy and offspring BMI in adolescence, stratifying by race, and adjusting for demographic and socioeconomic variables.The length of breastfeeding was inversely associated with BMI in both populations. American Indians and Alaska Natives that were breastfed for 6 to 12 months or for more than 12 months had a mean BMI of 2.69 (95% CI -3.46 to -1.92; P0.01) and 1.54 (95% CI -2.75 to -0.33; P0.05) units lower than those that were never breastfed. Non-Hispanic whites that were breastfed for 3 to 6 months, 6 to 12 months, or more than 12 months had a mean BMI of 0.71 (95% CI -0.93 to -0.50; P0.01), 0.68 (95% CI -0.87 to -0.50; P0.01), and 0.85 (95% CI -1.09 to -0.62; P0.01) units lower than those that were never breastfed. The association between the length of breastfeeding and offspring BMI varied by race (P0.01).Breastfeeding in infancy is associated with lower mean BMI. Future research should investigate causal pathways and whether interventions promoting breastfeeding in American Indians and Alaska Natives can prevent increasing BMI.

INTRODUCTION AND OBJECTIVES:Active surveillance is the preferred treatment strategy for patients with stage 1A and 1B seminoma as reflected in the National Comprehensive Cancer Network (NCCN) guide...

Objectives To estimate the prevalence of lifetime traumatic experiences, describe related symptoms of traumatic stress, and examine their association with perceived social support and physical and mental health among older American Indians. Method Analyses of existing interview data from the Native Elder Care Study, a random age-stratified sample of 505 tribal members ≥55 years of age conducted in partnership with a large Southeastern tribe. Interviews assessed trauma exposure, traumatic stress, measures of social support, and physical and mental health status. Results Overall, 31% of participants had experienced a traumatic event; of these, 43% reported traumatic stress at the time of the interview. Higher perceived social support was associated with a reduced prevalence of traumatic stress. Compared to their counterparts without traumatic stress, women participants reporting traumatic stress reported more symptoms of depression, and both symptomatic men and women had a higher prevalence of cardiovascular disease and chronic pain. Discussion Traumatic stress was associated with less perceived social support and poorer health. Social support was not found to moderate the relationship between traumatic stress and physical and mental health.

Objectives Insulin resistance is a substantial health issue for American Indians, with type 2 diabetes overrepresented in this population as compared with non-Hispanic whites. Insulin resistance and its related conditions in turn increase risk for dementia and cognitive impairment. The aim of the current study was to determine whether type 2 diabetes and insulin resistance at midlife was associated with later-life cognitive testing in a large sample of older American Indians, aged 65 and older. Methods American Indian participants who underwent both fasting blood draw as part of the Strong Heart Study and had subsequent cognitive testing as part of the later adjunct Cerebrovascular Disease and its Consequences in American Indians study were included (n = 790). Regression models examined type 2 diabetes and impaired fasting glucose and subsequent cognitive test performance as part of a longitudinal study design. The relationship between a continuous measure of insulin resistance and later cognitive test performance was assessed using generalized estimating equations. Results Controlling for demographic and clinical factors, verbal fluency and processing speed/working memory were significantly negatively associated with having type 2 diabetes and with insulin resistance, but not with impaired fasting glucose. Conclusion In this sample of American Indians, type 2 diabetes at midlife was associated with subsequent lower performance on measures of executive function. These results may have important implications for future implementation of diagnostic and intervention services in this population.

BACKGROUND Estimates of hippocampal volume by magnetic resonance imaging have clinical and cognitive correlations and can assist in early Alzheimer disease diagnosis. However, little is known about the relationship between global or regional brain volumes and cognitive test performance in American Indians. MATERIALS AND METHODS American Indian participants (N=698; median age, 72 y) recruited for the Cerebrovascular Disease and its Consequences in American Indians study, an ancillary study of the Strong Heart Study cohort, were enrolled. Linear regression models assessed the relationship between magnetic resonance imaging brain volumes (total brain and hippocampi) and cognitive measures of verbal learning and recall, processing speed, verbal fluency, and global cognition. RESULTS After controlling for demographic and clinical factors, all volumetric measurements were positively associated with processing speed. Total brain volume was also positively associated with verbal learning, but not with verbal recall. Conversely, left hippocampal volume was associated with both verbal learning and recall. The relationship between hippocampal volume and recall performance was more pronounced among those with lower scores on a global cognitive measure. Controlling for APOE e4 did not substantively affect the associations. CONCLUSIONS These results support further investigation into the relationship between structural Alzheimer disease biomarkers, cognition, genetics, and vascular risk factors in aging American Indians.

Introduction . Cancer is among the leading causes of death in American Indians and Alaska Natives (AI/ANs), with rates increasing over the last two decades. Barriers in accessing cancer screening and treatment likely contribute to this situation. Methods . We administered structured clinical interviews and conducted descriptive and multiple linear regression analyses of demographic, health, spiritual, and treatment factors associated with self-reported barriers to cancer care among 143 adult AI/AN oncology patients. Results . High levels of satisfaction with cancer care, older age, positive mental health quality of life, and positive physical health quality of life were all significantly associated with lower scores for cancer care barriers, explaining 27% of the total model variance. Conclusion . Addressing barriers to cancer care might help to reduce health disparities among AI/AN oncology patients. Future research should determine whether reducing barriers improves engagement with cancer treatment and overall health outcomes.

The mastectomy rate in rural areas of the Northern Plains of the U.S. was 64 percent from 2000 through 2005. We implemented a breast cancer patient navigation (BPN) program in May 2007 to increase breast conservation (BC) rates.We analyzed mastectomy and BC rates among our 1,466 patients with either ductal carcinoma in situ (DCIS) or stage I/II invasive breast cancer treated from 2000 through 2012. We used interrupted time series (ITS) to compare rates in treatment following implementation of BPN. In addition, breast conservation rates were compared to population data from the Surveillance, Epidemiology, and End Results (SEER) database.The BC rates were 56 percent for navigated patients versus 37 percent for non-navigated patients (95 percent CI for difference: 14.8 to 25.6 percent). There was a consistent annual increase in treatment with BC versus a mastectomy (+2.9 percent/year, p-trend0.001). The BC rate of 60 percent in 2012 now mirrors those observed in the SEER database. The ITS did not find that the change in BC rates over time was significantly attributable to implementation of the BPN. Other secular trends may have contributed to the change in BC rates over time.A number of factors may have contributed to an increase of BC rates over time, including physician and patient education, more radiation therapy options, and possibly a dedicated breast cancer PN program. This analysis demonstrates that overall breast cancer care among this rural and medically-underserved population is improving in our region and now parallels other regions of the country.

Objective: To examine the relationship between health care access and diabetes management among a geographically diverse sample of American Indians (AIs) aged 50 and older with type 2 diabetes. Method: We examined the relationship between access to care and diabetes management, as measured by HbA1c, using 1998-1999 data from the Strong Heart Family Study. A series of bivariate and multivariate linear models examined the relationships between nine access-related variables and HbA1c levels. Results: In bivariate analyses, out-of-pocket costs were associated with higher HbA1c levels. No other access-related characteristics were significantly associated with diabetes management in bivariate or in multivariate models. Discussion: Access-related barriers were not associated with worse diabetes management in multivariate analyses. The study concludes with implications for clinicians working with AI populations to enhance opportunities for diabetes management.

Objective:This study examined the role of English language use in the reported frequency of musculoskeletal pain among Hispanic and non-Hispanic White youth. Method: This is a secondary data analysis using a cross-sectional sample of 12,189 Hispanic and non-Hispanic White adolescents recruited for the National Longitudinal Study of Adolescent to Adult Health. Respondents were classified into three groups: (a) English-speaking non-Hispanic Whites, (b) English-speaking Hispanics, and (c) Spanish-speaking Hispanics. Results: After controlling for body mass index and demographic, socioeconomic, and behavioral variables, Spanish-speaking Hispanics reported the least frequent musculoskeletal pain ( OR = 0.415, 95% CI [0.361, 0.477]; p < .001), followed by English-speaking Hispanics ( OR = 0.773, 95% CI [0.690, 0.865]; p < .001). Conclusion: The experience of musculoskeletal pain is a physiological as well as a cultural phenomenon. Implications for Practice: Health care providers should consider the role of language use in reports of pain in Hispanic and non-Hispanic White adolescents.

SummaryUsing data from The National Epidemiologic Survey on Alcohol and Related Conditions, the strength of social networks and the association of self-reported health among American Indians and Alaska Natives (AI/AN) and non-Hispanic Whites (NHW) were compared. Differences in social network–health relationships between AI/ANs and NHWs were also examined. For both groups, those with fewer network members were more likely to report fair or poor health than those with average or more network members, and persons with the fewest types of relationships had worse self-reported health than those with the average or very diverse types of relationships. Furthermore, small social networks were associated with much worse self-reported health in AI/ANs than in NHWs.