Plasmonic nano-aperture label-free imaging of single small extracellular vesicles for cancer detection.

BACKGROUND: Small extracellular vesicle (sEV) analysis can potentially improve cancer detection and diagnostics. However, this potential has been constrained by insufficient sensitivity, dynamic range, and the need for complex labeling. METHODS: In this study, we demonstrate the combination of PANORAMA and fluorescence imaging for single sEV analysis. The co-acquisition of PANORAMA and fluorescence images enables label-free visualization, enumeration, size determination, and enables detection of cargo microRNAs (miRs). RESULTS: An increased sEV count is observed in human plasma samples from patients with cancer, regardless of cancer type. The cargo miR-21 provides molecular specificity within the same sEV population at the single unit level, which pinpoints the sEVs subset of cancer origin. Using cancer cells-implanted animals, cancer-specific sEVs from 20 µl of plasma can be detected before tumors were palpable. The level plateaus between 5-15 absolute sEV count (ASC) per µl with tumors ≥8 mm3. In healthy human individuals (N = 106), the levels are on average 1.5 ASC/µl (+/- 0.95) without miR-21 expression. However, for stage I-III cancer patients (N = 205), nearly all (204 out of 205) have levels exceeding 3.5 ASC/µl with an average of 12.2 ASC/µl (±9.6), and a variable proportion of miR-21 labeling among different tumor types with 100% cancer specificity. Using a threshold of 3.5 ASC/µl to test a separate sample set in a blinded fashion yields accurate classification of healthy individuals from cancer patients. CONCLUSIONS: Our techniques and findings can impact the understanding of cancer biology and the development of new cancer detection and diagnostic technologies.

Small extracellular vesicles (sEVs) are tiny particles derived from cells that can be detected in bodily fluids such as blood. Detecting sEVs and analyzing their contents may potentially help us to diagnose disease, for example by observing differences in sEV numbers or contents in the blood of patients with cancer versus healthy people. Here, we combine two imaging methods ­ our previously developed method PANORAMA and imaging of fluorescence emitted by sEVs­to visualize and count sEVs, determine their size, and analyze their cargo. We observe differences in sEV numbers and cargo in samples taken from healthy people versus people with cancer and are able to differentiate these two populations based on our analysis of sEVs. With further testing, our approach may be a useful tool for cancer diagnosis and provide insights into the biology of cancer and sEVs.

Acute Kidney Injury and Subsequent Kidney Failure With Replacement Therapy Incidence in Older Adults With Advanced CKD: A Cohort Study of US Veterans.

Rationale & Objective: Advanced age is a major risk factor for chronic kidney disease (CKD) development, which has high heterogeneity in disease progression. Acute kidney injury (AKI) hospitalization rates are increasing, especially among older adults. Previous AKI epidemiologic analyses have focused on hospitalized populations, which may bias results toward sicker populations. This study examined the association between AKI and incident kidney failure with replacement therapy (KFRT) while evaluating age as an effect modifier of this relationship. Study Design: Retrospective cohort study. Setting & Participants: 24,133 Veterans at least 65 years old with incident CKD stage 4 from 2011 to 2013. Exposures: AKI, AKI severity, and age. Outcomes: KFRT and death. Analytical Approach: The Fine-Gray competing risk regression was used to model AKI and incident KFRT with death as a competing risk. A Cox regression was used to model AKI severity and death. Results: Despite a nonsignificant age interaction between AKI and KFRT, a clinically relevant combined effect of AKI and age on incident KFRT was observed. Compared with our oldest age group without AKI, those aged 65-74 years with AKI had the highest risk of KFRT (subdistribution HR [sHR], 14.9; 95% CI, 12.7-17.4), whereas those at least 85 years old with AKI had the lowest (sHR, 1.71; 95% CI, 1.22-2.39). Once Veterans underwent KFRT, their risk of death increased by 44%. A 2-fold increased risk of KFRT was observed across all AKI severity stages. However, the risk of death increased with worsening AKI severity. Limitations: Our study lacked generalizability, was restricted to ever use of medications, and used inpatient serum creatinine laboratory results to define AKI and AKI severity. Conclusions: In this national cohort, advanced age was protective against incident KFRT but not death. This is likely explained by the high frequency of deaths observed in this population (51.1%). Nonetheless, AKI and younger age are substantial risk factors for incident KFRT.

Older adults are at risk of acute kidney injury (AKI) and subsequent nonrecovery from AKI, resulting in long-term dialysis. Hospitalized patients have often been used in the past to study AKI. This could lead to biased conclusions when inferring from sicker populations. That is why we created a national cohort of 24,133 Veterans at least 65 years old with incident chronic kidney disease (CKD) stage 4 to examine the relationship between AKI and age and subsequent kidney failure with replacement therapy (KFRT). The data have showed that AKI and younger age are substantial risk factors for incident KFRT. As for older age, it appears to be protective against KFRT but not death. This is likely explained by the high frequency of deaths observed in our cohort.

Increasing Preterm Delivery and Small for Gestational Age Trends in South Carolina during the COVID-19 Pandemic.

Preterm delivery (PTD) complications are a major cause of childhood morbidity and mortality. We aimed to assess trends in PTD and small for gestational age (SGA) and whether trends varied between race-ethnic groups in South Carolina (SC). We utilized 2015-2021 SC vital records linked to hospitalization and emergency department records. PTD was defined as clinically estimated gestation less than (<) 37 weeks (wks.) with subgroup analyses of PTD < 34 wks. and < 28 wks. SGA was defined as infants weighing below the 10th percentile for gestational age. This retrospective study included 338,532 (243,010 before the COVID-19 pandemic and 95,522 during the pandemic) live singleton births of gestational age ≥ 20 wks. born to 260,276 mothers in SC. Generalized estimating equations and a change-point during the first quarter of 2020 helped to assess trends. In unadjusted analyses, pre-pandemic PTD showed an increasing trend that continued during the pandemic (relative risk (RR) = 1.04, 95% CI: 1.02-1.06). PTD < 34 wks. rose during the pandemic (RR = 1.07, 95% CI: 1.02-1.12) with a significant change in the slope. Trends in SGA varied by race and ethnicity, increasing only in Hispanics (RR = 1.02, 95% CI: 1.00-1.04) before the pandemic. Our study reveals an increasing prevalence of PTD and a rise in PTD < 34 wks. during the pandemic, as well as an increasing prevalence of SGA in Hispanics during the study period.

The Spectrum of Non-neoplastic Changes Associated With Breast Implants: Histopathology, Imaging, and Clinical Significance.

Breast implant-associated anaplastic large cell lymphoma has been recognized as a distinct entity in the World Health Organization classification of hematolymphoid neoplasms. These neoplasms are causally related to textured implants that were used worldwide until recently. Consequently, there is an increased demand for processing periprosthetic capsules, adding new challenges for surgeons, clinicians, and pathologists. In the literature, the focus has been on breast implant-associated anaplastic large cell lymphoma; however, benign complications related to the placement of breast implants occur in up to 20% to 30% of patients. Imaging studies are helpful in assessing patients with breast implants for evidence of implant rupture, changes in tissues surrounding the implants, or regional lymphadenopathy related to breast implants, but pathologic examination is often required. In this review, we couple our experience with a review of the literature to describe a range of benign lesions associated with breast implants that can be associated with different clinical presentations or pathogenesis and that may require different diagnostic approaches. We illustrate the spectrum of the most common of these benign disorders, highlighting their clinical, imaging, gross, and microscopic features. Finally, we propose a systematic approach for the diagnosis and handling of breast implant specimens in general.

Geographic, Patient, and VA Medical Center Variation in the Receipt and Mode of Primary Care in a National Sample of Veterans with Diabetes during 2020.

While telemedicine infrastructure was in place within the Veterans Health Administration (VHA) healthcare system before the onset of the COVID-19 pandemic, geographically varying ordinances/closures disrupted vital care for chronic disease patients such as those with type 2 diabetes. We created a national cohort of 1,647,158 non-Hispanic White, non-Hispanic Black, and Hispanic veterans with diabetes including patients with at least one primary care visit and HbA1c lab result between 3.5% and 20% in the fiscal year (FY) 2018 or 2019. For each VAMC, the proportion of telehealth visits in FY 2019 was calculated. Two logistic Bayesian spatial models were employed for in-person primary care or telehealth primary care in the fourth quarter of the FY 2020, with spatial random effects incorporated at the VA medical center (MC) catchment area level. Finally, we computed and mapped the posterior probability of receipt of primary care for an "average" patient within each catchment area. Non-Hispanic Black veterans and Hispanic veterans were less likely to receive in-person primary care but more likely to receive tele-primary care than non-Hispanic white veterans during the study period. Veterans living in the most socially vulnerable areas were more likely to receive telehealth primary care in the fourth quarter of FY 2020 compared to the least socially vulnerable group but were less likely to receive in-person care. In summary, racial minorities and those in the most socially vulnerable areas were less likely to receive in-person primary care but more likely to receive telehealth primary care, potentially indicating a disparity in the impact of the pandemic across these groups.

The Association of Hypertensive Disorders of Pregnancy with Infant Mortality, Preterm Delivery, and Small for Gestational Age.

Gestational hypertension, preeclampsia, eclampsia, and chronic hypertension (CHTN) are associated with adverse infant outcomes and disproportionately affect minoritized race/ethnicity groups. We evaluated the relationships between hypertensive disorders of pregnancy (HDP) and/or CHTN with infant mortality, preterm delivery (PTD), and small for gestational age (SGA) in a statewide cohort with a diverse racial/ethnic population. All live, singleton deliveries in South Carolina (2004-2016) to mothers aged 12-49 were evaluated for adverse outcomes: infant mortality, PTD (20 to less than <37 weeks) and SGA (<10th birthweight-for-gestational-age percentile). Logistic regression models adjusted for sociodemographic, behavioral, and clinical characteristics. In 666,905 deliveries, mothers had superimposed preeclampsia (HDP + CHTN; 1.0%), HDP alone (8.0%), CHTN alone (1.8%), or no hypertension (89.1%). Infant mortality risk was significantly higher in deliveries to women with superimposed preeclampsia, HDP, and CHTN compared with no hypertension (relative risk [RR] = 1.79, 1.39, and 1.48, respectively). After accounting for differing risk by race/ethnicity, deliveries to women with HDP and/or CHTN were more likely to result in PTD (RRs ranged from 3.14 to 5.25) or SGA (RRs ranged from 1.67 to 3.64). As CHTN, HDP and superimposed preeclampsia confer higher risk of adverse outcomes, prevention efforts should involve encouraging and supporting mothers in mitigating modifiable cardiovascular risk factors.

Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40-49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.

Effect of Delirium on Interhospital Transfer Outcomes.

OBJECTIVES: Interhospital transfer (IHT) and in-hospital delirium are both independently associated with increased length of stay (LOS), mortality, and discharge to facility. Our objective was to investigate the joint effects between IHT and the presence of in-hospital delirium on the outcomes of LOS, discharge to a facility, and in-hospital mortality. METHODS: This was a single-center retrospective cohort study of 25,886 adult hospital admissions at a tertiary-care academic medical center. Staged multivariable logistic and linear regression models were used to evaluate the association between IHT status and the outcomes of discharge to a facility, LOS, and mortality while considering the joint impact of delirium. The joint effects of IHT status and delirium were evaluated by categorizing patients into one of four categories: emergency department (ED) admissions without delirium, ED admissions with delirium, IHT admissions without delirium, and IHT admissions with delirium. The primary outcomes were LOS, in-hospital mortality, and discharge disposition. RESULTS: The odds of discharge to a facility were 4.48 times higher in admissions through IHT with delirium when compared with ED admissions without delirium. IHT admissions with delirium had a 1.97-fold (95% confidence interval 1.88-2.06) longer LOS when compared with admission through the ED without delirium. Finally, admissions through IHT with delirium had 3.60 (95% confidence interval 2.36-5.49) times the odds of mortality when compared with admissions through the ED without delirium. CONCLUSIONS: The relationship between IHT and delirium is complex, and patients with IHT combined with in-hospital delirium are at high risk of longer LOS, discharge to a facility, and mortality.

Breast Implant Associated Anaplastic Large Cell Lymphoma: Evidence-Based Consensus Conference Statement From The American Association of Plastic Surgeons.

BACKGROUND: In the absence of high-quality evidence, there is a need to provide guidelines and multidisciplinary consensus recommendations on Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis, and management of BIA-ALCL caused by textured implants. The aim is to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL. METHODS: A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, supplemented by manual searches of relevant English language articles and "related articles" sections. Studies focusing on breast surgery and lymphoma associated with breast implants were included for analysis. Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons by a Delphi consensus method. RESULTS: 840 articles between January 2011 and January 2023 were initially identified and screened. Full-text of 188 articles were assessed. An additional 43 articles were excluded for focus, and 145 articles were included in the synthesis of results, with 105 of them being case reports or case series. The analysis encompassed a comprehensive examination of the selected articles to determine the incidence, risk factors, clinical presentation, diagnostic approaches, and treatment modalities related to BIA-ALCL. CONCLUSIONS: Plastic surgeons should be aware of the elevated risks by surface type, implement appropriate patient surveillance, and follow the recommendations outlined in this statement to ensure patient safety and optimize outcomes. Ongoing research on pathogenesis, genetic drivers, and preventative and prophylactic measures is crucial for improving patient care.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

High Community-Level Social Vulnerability is Associated with Worse Recurrence-Free Survival (RFS) After Resection of Extremity and Truncal Soft Tissue Sarcoma.

BACKGROUND: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. METHODS: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. RESULTS: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). CONCLUSION: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.

Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics.

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.

Diffusion Tensor Imaging for Characterizing Changes in Triple-Negative Breast Cancer During Neoadjuvant Systemic Therapy.

BACKGROUND: Assessment of treatment response in triple-negative breast cancer (TNBC) may guide individualized care for improved patient outcomes. Diffusion tensor imaging (DTI) measures tissue anisotropy and could be useful for characterizing changes in the tumors and adjacent fibroglandular tissue (FGT) of TNBC patients undergoing neoadjuvant systemic treatment (NAST). PURPOSE: To evaluate the potential of DTI parameters for prediction of treatment response in TNBC patients undergoing NAST. STUDY TYPE: Prospective. POPULATION: Eighty-six women (average age: 51 ± 11 years) with biopsy-proven clinical stage I-III TNBC who underwent NAST followed by definitive surgery. 47% of patients (40/86) had pathologic complete response (pCR). FIELD STRENGTH/SEQUENCE: 3.0 T/reduced field of view single-shot echo-planar DTI sequence. ASSESSMENT: Three MRI scans were acquired longitudinally (pre-treatment, after 2 cycles of NAST, and after 4 cycles of NAST). Eleven histogram features were extracted from DTI parameter maps of tumors, a peritumoral region (PTR), and FGT in the ipsilateral breast. DTI parameters included apparent diffusion coefficients and relative diffusion anisotropies. pCR status was determined at surgery. STATISTICAL TESTS: Longitudinal changes of DTI features were tested for discrimination of pCR using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC). A P value <0.05 was considered statistically significant. RESULTS: 47% of patients (40/86) had pCR. DTI parameters assessed after 2 and 4 cycles of NAST were significantly different between pCR and non-pCR patients when compared between tumors, PTRs, and FGTs. The median surface/average anisotropy of the PTR, measured after 2 and 4 cycles of NAST, increased in pCR patients and decreased in non-pCR patients (AUC: 0.78; 0.027 ± 0.043 vs. -0.017 ± 0.042 mm2 /s). DATA CONCLUSION: Quantitative DTI features from breast tumors and the peritumoral tissue may be useful for predicting the response to NAST in TNBC. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Hypertensive Disorders of Pregnancy and Pre-Pregnancy Hypertension with Subsequent Incident Venous Thromboembolic Events.

Hypertensive disorders of pregnancy (HDP) and pre-pregnancy hypertension contribute to maternal morbidity and mortality. We examined the association of HDP and pre-pregnancy hypertension with subsequent venous thromboembolic (VTE) events. The retrospective cohort study included 444,859 women with ≥1 live, singleton birth in South Carolina (2004-2016). Hospital and emergency department visit and death certificate data defined incident VTE, HDP, and pre-pregnancy hypertension. Birth certificate data also defined the exposures. Adjusted Cox proportional hazards methods modeled VTE events risk. Of the cohort, 2.6% of women had pre-pregnancy hypertension, 5.8% had HDP, 2.8% had both pre-pregnancy hypertension and HDP (both conditions), and 88.8% had neither condition. The risk of incident VTE events within one year of delivery was higher in women with HDP (hazard ratio [HR] = 1.62, 95% confidence interval [CI]: 1.15-2.29) and both conditions (HR = 2.32, 95% CI: 1.60-3.35) compared to those with neither condition as was the risk within five years for women with HDP (HR = 1.35, 95% CI: 1.13-1.60) and for women with both conditions (HR = 1.82, 95% CI: 1.50-2.20). One- and five-year risks did not differ in women with pre-pregnancy hypertension compared to women with neither condition. Compared to non-Hispanic White (NHW) women with neither condition, the incident VTE event risk was elevated within five years of delivery for NHW (HR = 1.29, 95% CI: 1.02-1.63; HR = 1.59, 95% CI: 1.16-2.17) and non-Hispanic Black (NHB; HR = 1.51, 95% CI: 1.16-2.96; HR = 2.08, 95% CI: 1.62-2.66) women with HDP and with both conditions, respectively, and for NHB women with pre-pregnancy hypertension (HR = 1.50, 95% CI: 1.09-2.07). VTE event risk was highest in women with HDP, and the event rates were higher in NHB women than in NHW women in the same exposure group.

Circulating Lipoprotein Sphingolipids in Chronic Kidney Disease with and without Diabetes.

Abnormalities of sphingolipid metabolism play an important role in diabetes. We compared sphingolipid levels in plasma and in isolated lipoproteins between healthy control subjects and two groups of patients, one with chronic kidney disease without diabetes (ND-CKD), and the other with type 2 diabetes and macroalbuminuria (D-MA). Ceramides, sphingomyelins, and sphingoid bases and their phosphates in LDL were higher in ND-CKD and in D-MA patients compared to controls. However, ceramides and sphingoid bases in HDL2 and HDL3 were lower in ND-CKD and in D-MA patients than in controls. Sphingomyelins in HDL2 and HDL3 were lower in D-MA patients than in controls but were normal in ND-CKD patients. Compared to controls, lactosylceramides in LDL and VLDL were higher in ND-CKD patients but not in D-MA patients. However, lactosylceramides in HDL2 and HDL3 were lower in both ND-CKD and D-MA patients than in controls. Plasma hexosylceramides in ND-CKD patients were increased and sphingoid bases decreased in both ND-CKD and D-MA patients. However, hexosylceramides in LDL, HDL2, and HDL3 were higher in ND-CKD patients than in controls. In D-MA patients, only C16:0 hexosylceramide in LDL was higher than in controls. The data suggest that sphingolipid measurement in lipoproteins, rather than in whole plasma, is crucial to decipher the role of sphingolipids in kidney disease.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial.

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease. Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions: Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures: The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results: Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance: In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT01953588.

A Bayesian zero-inflated beta-binomial model for longitudinal data with group-specific changepoints.

Timeline followback (TLFB) is often used in addiction research to monitor recent substance use, such as the number of abstinent days in the past week. TLFB data usually take the form of binomial counts that exhibit overdispersion and zero inflation. Motivated by a 12-week randomized trial evaluating the efficacy of varenicline tartrate for smoking cessation among adolescents, we propose a Bayesian zero-inflated beta-binomial model for the analysis of longitudinal, bounded TLFB data. The model comprises a mixture of a point mass that accounts for zero inflation and a beta-binomial distribution for the number of days abstinent in the past week. Because treatment effects appear to level off during the study, we introduce random changepoints for each study group to reflect group-specific changes in treatment efficacy over time. The model also includes fixed and random effects that capture group- and subject-level slopes before and after the changepoints. Using the model, we can accurately estimate the mean trend for each study group, test whether the groups experience changepoints simultaneously, and identify critical windows of treatment efficacy. For posterior computation, we propose an efficient Markov chain Monte Carlo algorithm that relies on easily sampled Gibbs and Metropolis-Hastings steps. Our application shows that the varenicline group has a short-term positive effect on abstinence that tapers off after week 9.