Neighborhood Disadvantage and Breast Cancer-Specific Survival in the US.

Importance: Despite improvements in breast cancer screening, treatment, and survival, disparate breast cancer-specific survival outcomes persist, particularly in disadvantaged neighborhoods. Most of these disparities are attributed to disparities in individual, tumor, and treatment characteristics. However, a critical knowledge gap exists as to whether disparities in breast cancer-specific survival remain after accounting for individual, tumor, and treatment characteristics. Objective: To evaluate if neighborhood disadvantage is associated with shorter breast cancer-specific survival after controlling for individual, tumor, and treatment characteristics in a national population. Design, Setting, and Participants: This national retrospective cohort study included patients with breast cancer diagnosed from 2013 to 2018 from the Surveillance, Epidemiology, and End Results 17 Census tract-level socioeconomic status and rurality database of the National Cancer Institute. Data analysis was performed from September 2022 to December 2023. Exposures: Neighborhood disadvantage measured by Yost index quintiles. Main Outcomes and Measures: Breast cancer-specific survival was evaluated using a competing risks cause-specific hazard model controlling for age, race, ethnicity, rurality, stage, subtype, insurance, and receipt of treatment. Results: A total of 350 824 patients with breast cancer were included; 41 519 (11.8%) were Hispanic, 39 631 (11.3%) were non-Hispanic Black, and 234 698 (66.9%) were non-Hispanic White. A total of 87 635 patients (25.0%) lived in the most advantaged neighborhoods (group 5) and 52 439 (14.9%) lived in the most disadvantaged neighborhoods (group 1). A larger number of non-Hispanic White patients (66 529 patients [76.2%]) lived in advantaged neighborhoods, while disadvantaged neighborhoods had the highest proportion of non-Hispanic Black (16 141 patients [30.9%]) and Hispanic patients (10 168 patients [19.5%]). Breast cancer-specific survival analysis found the most disadvantaged neighborhoods (group 1) had the highest risk of mortality (hazard ratio, 1.43; 95% CI, 1.36-1.50; P < .001) compared with the most advantaged neighborhoods. Conclusions and Relevance: In this national cohort study of patients with breast cancer, neighborhood disadvantage was independently associated with shorter breast cancer-specific survival even after controlling for individual-level factors, tumor characteristics, and treatment. This suggests potential unaccounted-for mechanisms, including both nonbiologic factors and biologic factors.

ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes.

OBJECTIVE: To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes. SUMMARY BACKGROUND DATA: ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS. METHODS: We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively. RESULTS: Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS. CONCLUSIONS: In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.

Unmet Social Needs and Breast Cancer Screening Utilization and Stage at Presentation.

Importance: Unmet social needs in local populations may hinder the development of targeted cancer control interventions aimed at improving screening utilization and early-stage breast cancer diagnosis to ultimately improve breast cancer survival disparities. Objective: To evaluate if (1) city-funded screening mammography is associated with utilization of screening mammography, (2) unmet social needs are associated with utilization of screening mammography, and (3) unmet social needs are associated with later-stage disease at diagnosis. Design, Setting, and Participants: This cohort study included patients with stages I-IV invasive ductal or lobular carcinoma treated at an academic medical center (including both an underserved safety-net hospital [SNH] and a National Cancer Institute-designated academic cancer center [ACC]) from 2020 to 2023. Eligible patients were aged 18 years or older and able to consent. Data were analyzed between July 2023 and September 2023. Exposure: The Health Leads Social Needs Screening Toolkit, a screening tool that gathers information on the most common social need domains affecting patient health. Main Outcomes and Measures: Univariable and multivariable logistic regression was utilized to evaluate the following primary outcomes: (1) routine screening mammography and (2) American Joint Committee on Cancer 8th edition clinical stage at presentation. Results: Of the 322 women who completed the Health Leads Social Needs Screening Toolkit, 201 (62%) self-identified as Hispanic, 63 (19%) as non-Hispanic Black, and 63 (19%) as non-Hispanic White. Two hundred fifty-five (76%) patients with access to city-funded screening mammography completed a screening mammogram. Patients who presented to the SNH were more likely to present with late-stage disease compared with early-stage disease (15 of 48 [31%] vs 50 of 274 [18%]; P = .04). On multivariable logistic regression, not completing a screening mammography was associated with having an increasing number of unmet social needs (OR, 0.74; 95% CI, 0.55-0.99; P = .047) and an increasing age at diagnosis (OR, 0.92; 95% CI, 0.89-0.96; P < .001). Moreover, increasing unmet social needs was significantly associated with late-stage diagnosis above and beyond screening mammography (OR, 1.38; 95% CI, 1.01-1.89; P = .04). Conclusions and Relevance: In this cohort study, access to screening mammography did not translate to utilization of screening mammography, increasing unmet social needs were significantly associated with lower rates of screening mammography, and those with increasing unmet social needs were more likely to present with late-stage disease. This association transcended recruitment site (SNH vs ACC), indicating that patients in either hospital setting may benefit from unmet social needs screening to overcome access to care barriers associated with late-stage disease at diagnosis.

A Multi-institutional Analysis of Factors Influencing the Rate of Positive MRI Biopsy Among Women with Early-Stage Breast Cancer.

BACKGROUND: The use of preoperative magnetic resonance imaging (MRI) for early-stage breast cancer (ESBC) is increasing, but its utility in detecting additional malignancy is unclear and delays surgical management (Jatoi and Benson in Future Oncol 9:347-353, 2013. https://doi.org/10.2217/fon.12.186 , Bleicher et al. J Am Coll Surg 209:180-187, 2009. https://doi.org/10.1016/j.jamcollsurg.2009.04.010 , Borowsky et al. J Surg Res 280:114-122, 2022. https://doi.org/10.1016/j.jss.2022.06.066 ). The present study sought to identify ESBC patients most likely to benefit from preoperative MRI by assessing the positive predictive values (PPVs) of ipsilateral and contralateral biopsies. METHODS: A retrospective cohort study included patients with cTis-T2N0-N1 breast cancer from two institutions during 2016-2021. A "positive" biopsy result was defined as additional cancer (PositiveCancer) or cancer with histology often excised (PositiveSurg). The PPV of MRI biopsies was calculated with respect to age, family history, breast density, and histology. Uni- and multivariate logistic regression determined whether combinations of age younger than 50 years, dense breasts, family history, and pure ductal carcinoma in situ (DCIS) histology led to higher biopsy yield. RESULTS: Of the included patients, 447 received preoperative MRI and 131 underwent 149 MRI-guided biopsies (96 ipsilateral, 53 contralateral [18 bilateral]). PositiveCancer for ipsilateral biopsy was 54.2%, and PositiveCancer for contralateral biopsy was 17.0%. PositiveSurg for ipsilateral biopsy was 62.5%, and PositiveSurg for contralateral biopsy was 24.5%. Among the contralateral MRI biopsies, patients younger than 50 years were less likely to have PositiveSurg (odds ratio, 0.02; 95% confidence interval, 0.00-0.84; p = 0.041). The combinations of age, density, family history, and histology did not lead to a higher biopsy yield. CONCLUSION: Historically accepted factors for recommending preoperative MRI did not appear to confer a higher MRI biopsy yield. To prevent delays to surgical management, MRI should be carefully selected for individual patients most likely to benefit from additional imaging.

Genetic Ancestry-specific Molecular and Survival Differences in Admixed Patients With Breast Cancer.

OBJECTIVE: We aim to determine whether incremental changes in genetic ancestry percentages influence molecular and clinical outcome characteristics of breast cancer in an admixed population. BACKGROUND: Patients with breast cancer are predominantly characterized as "Black" or "White" based on self-identified race/ethnicity or arbitrary genetic ancestry cutoffs. This limits scientific discovery in populations that are admixed or of mixed race/ethnicity as they cannot be classified based on historical race/ethnicity boxes or genetic ancestry cutoffs. METHODS: We used The Cancer Genome Atlas cohort and focused on genetically admixed patients that had less than 90% European, African, Asian, or Native American ancestry. RESULTS: Genetically admixed patients with breast cancer exhibited improved 10-year overall survival relative to those with >90% European ancestry. Within the luminal A subtype, patients with lower African ancestry had longer 10-year overall survival compared to those with higher African ancestry. The correlation of genetic ancestry with gene expression and DNA methylation in the admixed cohort revealed novel ancestry-specific intrinsic PAM50 subtype patterns. In luminal A tumors, genetic ancestry was correlated with both the expression and methylation of signaling genes, while in basal-like tumors, genetic ancestry was correlated with stemness genes. In addition, we took a machine-learning approach to estimate genetic ancestry from gene expression or DNA methylation and were able to accurately calculate ancestry values from a reduced set of 10 genes or 50 methylation sites that were specific for each molecular subtype. CONCLUSIONS: Our results suggest that incremental changes in genetic ancestry percentages result in ancestry-specific molecular differences even between well-established PAM50 subtypes which may influence disparities in breast cancer survival outcomes. Accounting for incremental changes in ancestry will be important in future research, prognostication, and risk stratification, particularly in ancestrally diverse populations.

Impact of Neighborhood Disadvantage on Tumor Biology and Breast Cancer Survival.

OBJECTIVE: The aim of this study was to evaluate the association between neighborhood disadvantage and Oncotype DX score, a surrogate for tumor biology, among a national cohort. BACKGROUND: Women living in disadvantaged neighborhoods have shorter breast cancer (BC) survival, even after accounting for individual-level, tumor, and treatment characteristics. This suggests unaccounted social and biological mechanisms by which neighborhood disadvantage may impact BC survival. METHODS: This cross-sectional study included stage I and II, ER + /HER2 - BC patients with Oncotype DX score data from the National Cancer Database (NCDB) from 2004 to 2019. Multivariate regression models tested the association of neighborhood-level income on Oncotype DX score controlling for age, race/ethnicity, insurance, clinical stage, and education. Cox regression assessed overall survival. RESULTS: Of the 294,283 total BC patients selected, the majority were non-Hispanic White (n=237,197, 80.6%) with 7.6% non-Hispanic Black (n=22,495) and 4.5% other (n=13,383). 27.1% (n=797,254) of the population lived in the disadvantaged neighborhoods with an annual neighborhood-level income of <$48,000, while 59.62% (n=175,305) lived in advantaged neighborhoods with a neighborhood-level income of >$48,000. On multivariable analysis controlling for age, race/ethnicity, insurance status, neighborhood-level education, and pathologic stage, patients in disadvantaged neighborhoods had greater odds of high-risk versus low-risk Oncotype DX scores compared with those in advantaged neighborhoods [odds ratio=1.04 (1.01-1.07), P =0.0067]. CONCLUSION AND RELEVANCE: This study takes a translational epidemiologic approach to identify that women living in the most disadvantaged neighborhoods have more aggressive tumor biology, as determined by the Oncotype DX score.

A Multiscale Spatiotemporal Epidemiological Analysis of Neighborhood Correlates of Triple-Negative Breast Cancer.

BACKGROUND: Women living in disadvantaged neighborhoods present with increased prevalence rates of triple-negative breast cancer (TNBC). This study takes a spatiotemporal epidemiological approach to understand the impact of socioenvironmental contextual factors on TNBC prevalence rates. METHODS: We analyzed 935 TNBC cases from a major cancer center registry, between 2005 and 2017, to explore spatial and space-time clusters of TNBC prevalence rates at the census tract and neighborhood scales. Spatial regression analysis was performed to examine relationships between nine socioenvironmental factors and TNBC prevalence rates at both ecological scales. RESULTS: We observed spatial clustering of high TNBC prevalence rates along a north-south corridor of Miami-Dade County along Interstate 95, a region containing several majority non-Hispanic Black neighborhoods. Among the ecologic measures, the percent of a region designated as a brownfield was associated with TNBC prevalence rates at the tract-level (ß = 4.27; SE = 1.08; P < 0.001) and neighborhood-level (ß = 8.61; SE = 2.20; P < 0.001). CONCLUSIONS: Our spatiotemporal analysis identified robust patterns of hot spots of TNBC prevalence rates in a corridor of several disadvantaged neighborhoods in the northern half of the county. These patterns of TNBC align with the literature regarding at-risk groups and neighborhood-level effects on TNBC; however, remain to be validated in a population-based sample. IMPACT: Spatial epidemiological approaches can help public health officials and cancer care providers improve place-specific screening, patient care, and understanding of socioenvironmental factors that may shape breast cancer subtype through gene-environment and epigenetic interactions.

Associations Between Neighborhood-Level Income and Triple-Negative Breast Cancer in a Majority-Minority Population.

BACKGROUND: Previous studies on disparities in triple-negative breast cancer (TNBC) focus on race/ethnicity, with few exploring the impact of contextual factors such as neighborhood-level income. This study evaluates the effect of neighborhood-level income on disparities in TNBC among a racially and ethnically diverse cohort, after accounting for granular individual-level risk factors of TNBC. PATIENTS AND METHODS: Patients with stage I-IV breast cancer from 2005 to 2017 were identified from our local tumor registry. The primary outcome was diagnosis of TNBC. Using 5-years estimates from the American Community Survey, we obtained median household income for each census tract which was categorized into quartiles. Mixed effects logistic regression was conducted and stratified by race and ethnicity, controlling for individual-level sociodemographic, comorbidities, and tumor characteristics. RESULTS: Among 5377 breast cancer registry patients, 16.5% were diagnosed with TNBC. The majority were Hispanic (50.1%) followed by non-Hispanic Black (NHB) (28.0%). After controlling for individual-level covariables including race and ethnicity, comorbidities, and tumor characteristics, women from low-income neighborhoods had increased odds of TNBC compared with other breast cancer subtypes, compared with those in high-income neighborhoods [odds ratio (OR) 1.33; 95% confidence interval (CI) 1.04, 1.70, p < 0.001]. In stratified analyses, NHB patients from low-income neighborhoods had two times the odds of TNBC diagnosis compared with those from high-income neighborhoods (OR 2.11; 95% CI 1.02, 4.37). CONCLUSION: We found that living in a low-income neighborhood is associated with an increased odds of TNBC independent of granular individual-level TNBC risk factors, particularly NHB race. More striking, NHB living in low-income neighborhoods had increased odds of TNBC compared with NHB living in high-income neighborhoods. Our results suggest potential unaccounted gene-environment and/or social (api)genomic interactions between neighborhood-level income and TNBC subtype development.

Time to Cancer Treatment and Chemotherapy Relative Dose Intensity for Patients With Breast Cancer Living With HIV.

Importance: Patients with breast cancer and comorbid HIV experience higher mortality than other patients with breast cancer. Objective: To compare time to cancer treatment initiation and relative dose intensity (RDI) of neoadjuvant and adjuvant chemotherapy among patients with breast cancer with vs without HIV. Design, Setting, and Participants: A retrospective, matched cohort study enrolled women who received a diagnosis of breast cancer from January 1, 2000, through December 31, 2018. The electronic medical records of 3 urban, academic cancer centers were searched for women with confirmed HIV infection prior to or simultaneous with diagnosis of stage I to III breast cancer. Tumor registry data were used to identify 2 control patients with breast cancer without HIV for each participant with HIV, matching for study site, stage, and year of cancer diagnosis. Statistical analysis was performed from December 2022 to October 2023. Exposure: HIV infection detected before or within 90 days of participants' breast cancer diagnosis. Main Outcomes and Measures: The primary outcome was time to breast cancer treatment initiation, defined as the number of days between cancer diagnosis and first treatment. The secondary outcome was overall RDI for patients who received chemotherapy. These outcomes were compared by HIV status using Cox proportional hazards regression and linear regression modeling, respectively, adjusting for confounding demographic and clinical factors. Exploratory outcomes included instances of anemia, neutropenia, thrombocytopenia, and liver function test result abnormalities during chemotherapy, which were compared using Fisher exact tests. Results: The study enrolled 66 women with comorbid breast cancer and HIV (median age, 51.1 years [IQR, 45.7-58.2 years]) and 132 with breast cancer alone (median age, 53.9 years [IQR, 47.0-62.5 years]). The median time to first cancer treatment was not significantly higher among patients with HIV than those without (48.5 days [IQR, 32.0-67.0 days] vs 42.5 days [IQR, 25.0-59.0 days]; adjusted hazard ratio, 0.78, 95% CI, 0.55-1.12). Among the 36 women with HIV and 62 women without HIV who received chemotherapy, the median overall RDI was lower for those with HIV vs without HIV (0.87 [IQR, 0.74-0.97] vs 0.96 [IQR, 0.88-1.00]; adjusted P = .01). Grade 3 or higher neutropenia during chemotherapy occurred among more women with HIV than those without HIV (13 of 36 [36.1%] vs 5 of 58 [8.6%]). Conclusions and Relevance: This matched cohort study suggests that patients with breast cancer and HIV may have experienced reduced adjuvant chemotherapy RDI, reflecting greater dose reductions, delays, or discontinuation. Strategies for supporting this vulnerable population during chemotherapy treatment are necessary.

Post-Mastectomy Implant Complications in the Hispanic Breast Cancer Patient Population.

BACKGROUND/AIM: The purpose was to analyze the impact of post-mastectomy radiation therapy (PMRT) on implant-based breast reconstruction (IBR) in self-identified Hispanic patients compared to non-Hispanic counterparts. PATIENTS AND METHODS: We retrospectively reviewed patients who underwent IBR between January 1, 2017 and December 31, 2019 at a single hospital system. Patients were cisgender women, assigned female at birth, 18 years or older, and underwent mastectomy with immediate IBR +/- PMRT. We compared characteristics between Hispanic and non-Hispanic patients, assessing capsular contracture and implant loss rates. Multivariable analysis was performed to identify factors associated with complications. RESULTS: A total of 317 patients underwent mastectomy and reconstruction. Of these patients, 302 underwent a total of 467 mastectomies with IBR, and these 467 procedures were included in the analysis of complications. Complications occurred in 175 breasts (37.5%), regardless of PMRT. Seventy-two of the 302 patients (24%) received PMRT to one breast. The overall rates of capsular contracture, implant loss, and overall complications did not vary significantly between Hispanic and non-Hispanic patients (p=0.866, 0.974, and 0.761, respectively). When comparing only irradiated patients, there was a trend towards increased implant loss and overall complication rates in Hispanic versus non-Hispanic patients (p=0.107 and 0.113, respectively). Following PMRT the rate of any complication was 71% in Hispanic women and 53% in non-Hispanic women. CONCLUSION: Our study illuminates a trend towards higher complication rates after PMRT in Hispanic versus non-Hispanic patients. Further studies are needed to understand why Hispanic patients may have more side effects from radiation therapy.

Genomic Characterization of Aggressive Breast Cancer in Younger Women.

PURPOSE: Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in younger women. METHODS: Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40-60 years, > 60 years) in female BC patients were investigated in two large cohorts [AACR-GENIE8.1 (n = 11,594) and METABRIC (n = 2509)]. Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups. RESULTS: Survival analysis showed that women < 40 years had shorter DSS [hazard ratio (HR): 1.52, p = 0.005], RFS (HR: 1.4, p = 0.006), and PFS (HR: 1.82, p = 0.0003) compared with women 40-60 years, and shorter RFS (HR: 1.5, p = 0.001) and PFS (HR: 2.95, p < 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (p < 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with TP53 mutations (FDR < 0.0001), BRCA1 mutations (FDR = 0.01), ERBB2 amplifications (FDR < 0.001), CDK12 amplifications (FDR < 0.001), and PPM1D amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with PIK3CA, KMT2C, and CDH1 mutations (FDR < 0.0001). CONCLUSIONS: BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in TP53 and BRCA1, and amplifications in ERBB2 and CDK12. These findings have the potential to impact clinical trial design and treatment.

Translational Epidemiology: Genetic Ancestry in Breast Cancer: What Is the Role of Genetic Ancestry and Socioeconomic Status in Triple-Negative Breast Cancer?

Racial/ethnic and socioeconomic disparities seen in triple-negative breast cancer (TNBC) have prompted questions regarding the role of genetic ancestry in breast cancer (BC) subtype development, tumor biology, and ultimately prognosis. The causes of disparities in TNBC are influenced greatly by both sociopolitical factors and genetic ancestry, and now, the potential genomic underpinnings of social factors. To comprehensively understand disparities in TNBC, it is critical to take a translational epidemiologic approach that takes into account genomic and non-genomic factors. Understanding the interplay between genetic ancestry and social genomics and their proportional influence on outcomes can guide our priorities for screening, diagnosis, and interventions for this aggressive BC subtype.

Effects of neighborhood disadvantage on cortisol and interviewer-rated anxiety symptoms in breast cancer patients initiating treatment.

PURPOSE: Shorter breast cancer (BC) survival outcomes persist by neighborhood disadvantage independent of patient, tumor, and treatment characteristics. This suggests unaccounted mechanisms by which neighborhood disadvantage "gets under the skin" to impact BC survival outcomes. Here, we evaluate the relationship between neighborhood disadvantage and clinical and neuroendocrine markers of stress in BC patients. METHODS: Women with stage 0-III BC were enrolled 2-10 weeks post-surgery and before initiating adjuvant treatment in a study examining stress and stress management processes. Women provided an afternoon-evening (PM) serum cortisol sample and were administered the Hamilton Anxiety Rating Scale (HAM-A). Home addresses were used to determine the Area Deprivation Index (ADI), a validated measure of neighborhood disadvantage. Multiple regression assessed the relationship between ADI and PM serum cortisol and the presence of elevated HAM-A symptoms. RESULTS: Our sample (n = 225) was predominately middle-aged (M = 50.4 years; range 23-70 years), non-Hispanic White (64.3%), with stage I (38.1%), or II (38.6%) disease. The majority (n = 175) lived in advantaged neighborhoods (ADI 1-3). After controlling for age, stage, and surgery type, women from high ADI (4-10) (vs low ADI) neighborhoods had higher PM cortisol levels (ß = 0.19, 95% CI [0.24, 5.00], p = 0.031) and were nearly two times as likely to report the presence of elevated anxiety symptoms (OR = 1.96, 95% CI [1.00, 3.86], p = 0.050). CONCLUSION: Neighborhood disadvantage is significantly associated with higher levels of PM cortisol and elevated anxiety symptoms suggesting stress pathways could potentially contribute to relationships between neighborhood disadvantage and BC survival.

Omission of Completion Lymph Node Dissection in Sentinel Node Biopsy Positive Head and Neck Cutaneous Melanoma Patients.

BACKGROUND: Recent studies evaluating patients with a positive sentinel lymph node biopsy (SLNB+) show no melanoma-specific survival difference between patients undergoing lymph node basin surveillance and completion lymph node dissection (CLND). This has been broadly applied, despite underrepresentation of head and neck (HN) cutaneous melanoma patients. We evaluated whether this was upheld in the HN melanoma cohort. METHODS: Patients with HN melanoma with a SLNB+ were selected from the National Cancer Database (NCDB) from 2012 to 2019. Overall survival (OS) of patients who underwent SLNB only versus SLNB + CLND were compared. Subgroup analyses were performed based on pathologic N (pN) and receipt of immunotherapy. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were calculated. RESULTS: Analysis of 634 patients with multivariable Cox regression showed no difference in OS in SLNB only versus SLNB + CLND cohorts (hazard ratio [HR] 1.13; 95% confidence interval [CI] 0.71-1.81; p = 0.610). Charlson-Deyo score (CDS) 1 versus 0 (HR 1.70; 95% CI 1.10-2.63; p = 0.016), pN2+ versus pN1 (HR 1.74; 95% CI 1.23-2.45; p = 0.002), and lymphovascular invasion (LVI) versus no (HR 2.07; 95% CI 1.34-3.19; p = 0.001) were associated with worse prognosis. Subgroup analysis by pN showed no OS benefit for CLND in either pN1 (HR 1.04; 95% CI 0.51-2.10; p = 0.922) or pN2+ (HR 1.31; 95% CI 0.67-2.57; p = 0.427) patients or in patients who received immunotherapy (HR 1.32; 95% CI 0.54-3.22; p = 0.549). CONCLUSIONS: This study of SLNB + HN melanoma patients showed no OS difference in SLNB only versus SLNB + CLND. Further studies need to be performed to better define the role of CLND.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.