Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging.

BACKGROUND: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac. METHODS: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. RESULTS: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. CONCLUSIONS: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.

UGT1A1*28 polymorphism and the risk of toxicity and disease progression in patients with breast cancer receiving sacituzumab govitecan.

BACKGROUND: Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2-negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. METHODS: In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). RESULTS: We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple-negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. CONCLUSION: This retrospective, real-world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.

Factors Associated With Additional Axillary Disease in Patients With Positive Sentinel Lymph Nodes After Neoadjuvant Chemotherapy for Breast Cancer.

Background: In previous studies, breast cancer patients with positive sentinel lymph node(s) (SLN) after neoadjuvant chemotherapy (NAC) frequently had additional nonSLN involvement. Per guidelines, residual SLN disease warrants completion axillary lymph node dissection (cALND), which has increased morbidity. Given recent improvements in NAC, we hypothesized that nonSLN positivity may be lower than previously reported for certain subgroups.Methods: We retrospectively reviewed breast cancer patients who received NAC and had positive lymph nodes on SLN biopsy or targeted axillary dissection and underwent cALND at one institution in 1/2018-8/2023. Associations between nonSLN positivity and clinicopathologic factors were assessed with Fisher's exact test and multivariable logistic regression.Results: There were 122 female patients. Median age was 48 years. Initially, 15 patients (12.3%) were cN0 and 107 patients (87.7%) were cN1. Largest SLN deposit was macrometastasis in 96 patients (78.7%), micrometastasis in 23 patients (18.9%), and isolated tumor cells in 3 patients (2.5%). Overall, 53 patients (43.4%) had nonSLN involvement. NonSLN positivity was higher in patients with cN1, ER+ HER2-, ypT2-3, SLN macrometastasis, and multiple positive SLN. On multivariable analysis, cN1 and ER+ HER2- remained associated with nonSLN positivity.Discussion: Among patients with positive SLN after NAC, clinically node positive and ER+ HER2- patients were more likely to have nonSLN involvement. Our findings support guidelines to consider omitting cALND in clinically node negative patients. With improving NAC, optimal axillary sampling, and radiation, omitting cALND may be safe in some clinically node positive triple negative or HER2+ patients with low volume residual disease, but further research is needed.

Differential response to neoadjuvant endocrine therapy for Black/African American and White women in NCDB.

PURPOSE: Compared to White women, there are higher mortality rates in Black/African American (BAA) women with hormone receptor-positive breast cancer (HR + BC) which may be partially due to differences in treatment resistance. We assessed factors associated with response to neoadjuvant endocrine therapy (NET). METHODS: The National Cancer Database (NCDB) was queried for women with clinical stage I-III HR + BC diagnosed 2006-2017 and treated with NET. Univariate and multivariate analyses described associations between the sample, duration of NET, and subsequent treatment response, defined by changes between clinical and pathological staging. RESULTS: The analytic sample included 9864 White and 1090 BAA women. Compared to White women, BAA women were younger, had more co-morbidities, were higher stage at presentation, and more likely to have > 24 weeks of NET. After excluding those with unknown pT/N/M, 3521 White and 365 BAA women were evaluated for NET response. On multivariate analyses, controlling for age, stage, histology, HR positivity, and duration of NET, BAA women were more likely to downstage to pT0/Tis (OR 3.0, CI 1.2-7.1) and upstage to Stage IV (OR 2.4, CI 1.002-5.6). None of the women downstaged to pT0/Tis presented with clinical stage III disease; only 2 of the women upstaged to Stage IV disease presented with clinical Stage I disease. CONCLUSION: Independent of NET duration and clinical stage at presentation, BAA women were more likely to experience both complete tumor response and progression to metastatic disease. These results suggest significant heterogeneity in tumor biology and warrant a more nuanced therapeutic approach to HR + BC.

A user-centered approach to the development of a diet education tool for older adults with tooth loss.

BACKGROUND: Tooth loss is associated with suboptimal nutrient intake and greater risk of malnutrition. OBJECTIVE: To develop and field-test a stakeholder-informed diet education tool that addresses the unique needs of older adults with tooth loss who do not wear dentures. METHODS: An iterative user-centered approach was used. Initial content was developed based on findings from previous research. Stakeholder panels of older adults with 20 or fewer teeth, and dentists, were conducted at two time points to obtain feedback on the tool, which was revised following each panel. The tool was field-tested in a dental school clinic and evaluated using the Patient Education Materials Assessment Tool; it was further revised based on feedback. RESULTS: A diet education tool entitled "Eating Healthier With Tooth Loss" was developed. Sections for fruits and vegetables, grains, and proteins food groups, and one addressing socioemotional aspects of eating with missing teeth were included. Panel members provided constructive, positive feedback; recommendations for editing text, images, design, and content were integrated. Field-testing in the dental clinic with 27 pairs of student dentists and their patients resulted in scores of 95.7% for understandability and 96.6% for actionability, with over 85% agreement with each item. The tool was revised based on field-testing feedback. CONCLUSION: A diet education tool for older adults with tooth loss was developed using a user-centered approach, integrating the 'patient voice' and patient experiences with US dietary guidelines. Use of this tool is feasible in a dental clinic setting. Future research should explore usage in larger settings.

Evidence-Based Interventions Implemented into HIV Primary Care Clinics to Make Sexually Transmitted Infection Screening and Testing Routine: Outcomes of a Multi-Site Study.

In response to rising rates of bacterial sexually transmitted infections (STIs) in the United States, this evaluative study of the implementation of four evidence-based interventions was developed and implemented. In three STI and HIV high-incidence jurisdictions of the United States, nine federally funded Health Resources and Services Administration Ryan White HIV/AIDS Program clinical demonstration sites implemented (1) audio computer-assisted self-interview sexual history taking, (2) patient self-collection of urogenital and extragenital site chlamydia/gonorrhea nucleic acid amplification test specimens, (3) sexual and gender minority welcoming indicators, and (4) provider training, to make STI screening, testing, and treatment routine in their HIV primary care clinics. The priority populations of young adults, men who have sex with men, and sexual and gender minority patients were found to have risk behaviors identified in the self-interview sexual history, to prefer to self-collect urogenital and extragenital site specimens for STI testing, and to notice and like the sexual and gender minority welcoming indicators. Testing positive for a bacterial STI was significantly associated with using alcohol or recreational drugs before sex, being younger than 50 years, and having two or more sexual partners with other concurrent sexual partners. Of 255 cases of chlamydia, gonorrhea, and syphilis infections, only 13.73% of patients reported related symptoms when screened and tested.

Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer.

Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40-60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474R and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease.

Impact of Federal, State, and Local Housing Policies on Disparities in Cardiovascular Disease in Black/African American Men and Women: From Policy to Pathways to Biology.

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies - "redlining," zoning, and the construction of highways - which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer.

Cutaneous metastasectomy: Is there a role in breast cancer? A systematic review and overview of current treatment modalities.

Cutaneous metastases (CM) are neoplastic lesions involving the dermis or subcutaneous tissues, originating from another primary tumor. Breast cancer is commonest primary solid tumor, representing 24%-50% of CM patients. There is no "standard of care" on management. In particular, the role of surgery in the treatment of cutaneous metastases from breast carcinoma (CMBC) remains controversial. This systematic review evaluates the role of cutaneous metastasectomy in breast cancer and provides an overview of existing treatment types.

Family Systems Cultural and Resilience Dimensions to Consider in Nutrition Interventions: Exploring Preschoolers' Eating and Physical Activity Routines During COVID-19.

OBJECTIVE: To describe the weight-related family functioning of racial minority families with low income using family systems theory as an interpretive framework. DESIGN: Primarily a qualitative study with interviews plus; descriptive demographics, anthropometrics, a family functioning measure, and food insecurity screening. SETTING: Telephone interviews with families of preschool-aged children in an urban setting. PARTICIPANTS: Primary caregivers of preschool-aged children. PHENOMENON OF INTEREST: Cultural impacts on family systems. ANALYSIS: Interviews were audio-recorded, transcribed verbatim, and loaded into NVivo 12 for thematic analysis. Descriptive statistics. RESULTS: The 23 participants were mothers and 2 maternal grandmothers. Seventy-four percent were African American, most children were normal weight (n = 15, 65%), mean family function scores were high, and more than half the families were at risk for food insecurity (n = 13, 56%). Acculturation and intergenerational eating-related cultural dimensions were discerned as the overarching themes influencing family cohesion. Family cohesion appeared to have helped the families adapt to the impact of coronavirus disease 2019. CONCLUSIONS AND IMPLICATIONS: Cultural dimensions such as acculturation and intergenerational influences appeared to be associated with social cohesion and family functioning around weight-related behaviors for these families. These findings add cultural and family resilience dimensions to family systems theory in nutrition interventions.

Upstage Rate of Complex Sclerosing Lesions/Radial Scars.

BACKGROUND: Radial scars (RS) and complex sclerosing lesions (CSL) are breast radiologic findings described as small, stellate lesions causing architectural distortion. This can mimic malignancy. Core needle biopsy (CNB) is often performed. Advances in breast imaging have led to increased detection of RS/CSL. The upstage rate of RS/CSL to in situ or invasive disease is 0-40%. We sought to determine the upstaging rate of RS/CSL to in situ, invasive disease, or high-risk lesion at our institution to create excision guidelines. METHODS: The pathology database of a single center was searched for RS/CSL, from January 2013 to September 2020. We included CNB without malignancy or high-risk lesion (eg, atypical ductal hyperplasia). Patient demographics, indications for biopsy, imaging findings, biopsy procedure, and final pathology were collected. RESULTS: Forty-four patients were included. 52.3% had CNB for architectural distortion on mammography, 18.2% for mass, 11.4% for calcifications, 2.3% for abnormal MRI, and 15.9% for multiple reasons (eg, calcifications and mass). Most had an ultrasound: 43.2% had no abnormality and 34.1% had a mass. All CNB were vacuum assisted, 65.9% with 9-gauge needle, and averaged 10.0 cores. 77.3% were stereotactic biopsies, 13.6% ultrasound, and 6.8% MRI. 59.1% had excision after CNB. 82.1% of patients did not upstage. One patient upstaged to invasive ductal carcinoma (3.6%) and two patients to high-risk lesion (7.1%). DISCUSSION: There was low upstage rate of RS/CSL on excisional biopsy. Centers could consider close surveillance for RS/CSL on CNB. Longer follow-up in cases of deferred excision is needed to ensure oncologic safety.

Short Stay Management of Locally Advanced Breast Cancer Using Immediate Local Thoracoabdominal Advancement Flap and Enhanced Recovery After Surgery Protocol.

BACKGROUND: Patients with locally advanced invasive breast cancer (LABC) are often considered inoperable, because of the anticipated chest wall defect and need for complex reconstruction. We present a series of patients who underwent mastectomy with extensive skin resection and immediate chest wall reconstruction using a local thoracoabdominal advancement flap (TAAF). All patients were managed after surgery with an ERAS (Enhanced Recovery After Surgery) protocol, to decrease length of stay in hospital. We also present 1 patient who subsequently had satisfactory bilateral delayed breast reconstruction with pedicled latissimus dorsi myocutaneous flaps with prepectoral silicone implants. METHODS: This is a single-surgeon, single-institution retrospective chart review of patients with LABC who underwent mastectomy with skin resection and local TAAF from May 2017 to October 2019, with minimum 3-month follow-up. RESULTS: Thirteen patients met inclusion criteria. Twelve of 13 patients presented with stage III or IV invasive breast cancer, with skin involvement. The mean chest wall defect measured 248.7 cm2 (140-336 cm2; SD, 63.2 cm2), and all were successfully reconstructed with immediate local TAAF. There were no intraoperative complications, but 1 patient developed a postop hematoma. The mean hospital stay was 1.3 nights, with 9 patients (69.2%) staying less than 23 hours and 4 patients (30.8%) staying 2 nights. Nine patients (69.2%) underwent adjuvant therapy, beginning on average 32 days (13-55 days; SD, 13.1 days) after surgery. The mean follow-up time was 13.8 months (4.5-31.6 months; SD, 9.2 months). One patient underwent successful delayed bilateral breast reconstruction with pedicled latissimus dorsi myocutaneous flaps and silicone implant placement. CONCLUSIONS: Our study demonstrates that reconstruction with local TAAF is an outpatient procedure that reliably provides durable, immediate chest wall coverage, after mastectomy in patients with LABC. This technique has a short operative time, low blood loss, and low complication rate, allowing timely adjuvant therapy. Using an ERAS postop protocol we were able to reduce mean hospital stay to 1.3 days. Compared with other described techniques of reconstruction, the additional scars and donor site morbidity are minimal, allowing for delayed breast reconstruction. We also present survival outcomes data on these surgically managed patients.

Racial disparities in diabetes prevalence among cancer patients.

Introduction: Cancer inequity is one of the most critical public health issues faced by ethnic minorities and people of lower socioeconomic status. The disparate burden of cancer is caused by poor access to care and inadequate delivery of cancer treatment, as well as comorbid and co-occurring conditions. Diabetes is a common and serious comorbid condition of cancer. Methods: To better understand diabetes prevalence among diverse cancer patients, this study analyzed and described characteristics of cancer patients with diabetes from local-level Service Planning Area (SPA) data using City of Hope Comprehensive Cancer Center data, and United States national-level data from The National Health Interview Survey. Results: Findings from national level data showed that patients in racial/ethnic minority groups had a higher occurrence of being diagnosed with diabetes, especially for non-Hispanic Blacks (OR=1.76, 95% CI=1.51, 2.03) and Hispanic/Latino individuals (OR=1.34, 95% CI=1.18, 1.52). Cancer patients who are older, ethnic minority, overweight/obese and with lower educational levels were more likely to have co-occurring diabetes. SPA-level patient data found similar results. Discussion: In response to our findings and other reports, clinicians and health system including health coverage organizations should routinely assess cancer patients for cooccurring chronic illnesses, in particular diabetes. Interventions improving coordinated care that integrates oncology, endocrinology and primary care, targeting cancer patients --especially racial/ethnic minorities, overweight/obese, and older patients who are at increased risk for diabetes -- ought to be considered as best practice Whole Person care. With coordinated care management, ethnic disparities in cancer may be better addressed and reduced. Additionally, policymakers can contribute by enacting policies improving access to and coverage of integrated oncology, chronic disease prevention, and associated specialty care i.e., endocrinology to equalize quality care for ethnic minority, lower educated, overweight/obese and older cancer patients who are more likely to suffer greater comorbidity, and inadequate oncology and coordinated care to reduce disparities.

A Cross-Sectional Study of Distress Levels in Patients with Newly Diagnosed Breast Cancer: The Impact of Race, Ethnicity, and Language Preference.

PURPOSE: Our objective was to assess distress levels in female breast cancer patients as a function of race, ethnicity, and preferred language. We hypothesized minority patients and non-English screen-takers would report higher distress levels compared to English screen-takers and non-Hispanic whites. METHODS: We conducted a retrospective observational study of female breast cancer patients at an NCI designated cancer center from 2009 to 2016 who were administered a validated biopsychosocial distress screening questionnaire. Self-reported data on race and ethnicity was collected. RESULTS: A total of 3,156 patients were included in the analysis; mean age of 56.3 (SD 12.25) years. The racial/ethnic cohort distribution included 54% non-Hispanic white (NHW), 19% Hispanic, 16% Asian, 7% Black/African American, and 4% other. On multivariable analysis only Hispanic patients were significantly more likely to report overall distress compared to NHW (OR [1.39; CI [1.03-1.87; p=0.03). Asians were significantly less likely to report distress in the functional domain (OR 0.71, CI [0.58-0.88]; p=0.002), while Black patients were significantly more likely to report highest distress levels in the physical (OR 1.53, CI [1.11-2.12]; p=0.01) domain. Hispanic Spanish screen-takers reported significantly more distress compared to Hispanic English screen-takers across all four domains of distress (p<0.05 for all). CONCLUSIONS: Top sources of distress in female breast cancer patients vary as a function of race, ethnicity, and preferred language. Future studies should focus on identifying effective, culturally appropriate targeted interventions to mitigate emotional distress levels in ethnic and racial minorities as well as non-English speaking patients with breast cancer.

Calling Attention to the Role of Race-Driven Societal Determinants of Health on Aggressive Tumor Biology: A Focus on Black Americans.

Blacks have the highest incidence and mortality from most cancers. The reasons for these disparities remain unclear. Blacks are exposed to adverse social determinants because of historic and contemporary racist polices; however, how these determinants affect the disparities that Blacks experience is understudied. As a result of discriminatory community policies, like redlining, Blacks have higher exposure to air pollution and neighborhood deprivation. Studies investigating how these factors affect tumor biology are emerging. We highlight the literature that connects racism-related community exposure to the tumor biology in breast, lung, prostate, and colorectal cancer. Further investigations that clarify the link between adverse social determinants that result from systemic racism and aggressive tumor biology are required if health equity is to be achieved. Without recognition that racism is a public health risk with carcinogenic impact, health care delivery and cancer care will never achieve excellence. In response, health systems ought to establish corrective actions to improve Black population health and bring medical justice to marginalized racialized groups.

Improving sexually transmitted infection screening, testing, and treatment among people with HIV: A mixed method needs assessment to inform a multi-site, multi-level intervention and evaluation plan.

Bacterial sexually transmitted infections (STIs) continue to be a worsening public health concern in the United States (US). Though the national incidence of HIV infection has decreased over recent years, that of chlamydia, gonorrhea, and syphilis have not. Despite national recommendations on prevention, screening, and treatment of these STIs, these practices have not been standardized. Nine Health Resources and Services Administration Ryan White HIV/AIDS Program funded clinics across 3 US jurisdictions (Florida, Louisiana, and Washington, DC), were selected as clinical demonstration sites to be evaluated in this mixed method needs assessment to inform a multi-site, multi-level intervention to evaluate evidence-based interventions to improve STI screening and testing of bacterial STIs among people with or at risk for HIV. These 3 US jurisdictions were selected due to having higher than national average incidence rates of HIV and bacterial STIs. Descriptive statistics and deductive analysis were used to assess quantitative and qualitative needs assessment data. Results indicate the following needs across participating sites: inconsistent and irregular comprehensive sexual behavior history taking within and among sites, limited routine bacterial STI testing (once/year and if symptomatic) not in accordance with CDC recommendations, limited extragenital site gonorrhea/chlamydia testing, limited annual training on STI-related topics including LGBTQ health and adolescent/young adult sexual health, and limited efforts for making high-STI incidence individuals feel welcome in the clinic (primarily LGBTQ individuals and adolescents/young adults). These findings were used to identify interventions to be used to increase routine screenings and testing for bacterial STIs.