Operational Definition Research Articles

Competency model development: The backbone of successful stealth assessments

AbstractBackgroundStealth assessment is a learning analytics method, which leverages the collection and analysis of learners' interaction data to make real‐time inferences about their learning. Employed in digital learning environments, stealth assessment helps researchers, educators, and teachers evaluate learners' competencies and customize the learning experience to their specific needs. This adaptability is closely intertwined with theories related to learning, engagement, and motivation. The foundation of stealth assessment rests on evidence‐cantered design (ECD), consisting of four core models: the Competency Model (CM), Evidence Model, Task Model, and Assembly Model.ObjectiveThe first step in designing a stealth assessment entails producing operational definitions of the constructs to be assessed. The CM establishes a framework of latent variables representing the target constructs, as well as their interrelations. When developing the CM, assessment designers must produce clear descriptions of the claims associated with the latent variables and their states, as well as sketch out how the competencies can be measured using assessment tasks. As the designers elaborate on the assessment model, the CM definitions need to be revisited to make sure they work with the scope and constraints of the assessment. Although this is the first step, problems at this stage may result in an assessment that does not meet the intended purpose. The objective of this paper is to elucidate the necessary steps for CM development and to highlight potential challenges in the process, along with strategies for addressing them, particularly for designers without much formal assessment experience.MethodThis paper is a methodological exposition, showcasing five examples of CM development. Specifically, we conducted a qualitative retrospective analysis of the CM development procedure, wherein participants unfamiliar with ECD applied the framework and showcased their work. In a stealth assessment course, four groups of students (novice stealth assessment designers) engaged in developing stealth assessments for challenging‐to‐measure constructs across four distinct projects. During their CM development process, we observed various activities to pinpoint areas of difficulty.ResultsThis paper presents five illustrative examples, including one for assessing physics understanding and four for the development of CMs for four complex competencies: (1) systems thinking, (2) online information credibility evaluation, (3) computational thinking, and (4) collaborative creativity. Each example represents a case in CM development, offering valuable insights.ConclusionThe paper concludes by discussing several guidelines derived from the examples discussed. Emphasizing the importance of dedicating ample time to fine‐tune CMs can significantly enhance the accuracy of assessments related to learners' knowledge and skills. It underscores the significance of qualitative phases in crafting comprehensive stealth assessments, such as CMs, alongside the quantitative statistical modeling and technical aspects of these assessments.

High-Impact Pain Is Associated With Epigenetic Aging Among Middle-Aged and Older Adults: Findings From the Health and Retirement Study.

Chronic pain has been associated with accelerated biological aging, which may be related to epigenetic alterations. We evaluated the association of high-impact pain (ie, pain that limits activities and function) with epigenetic aging, a measure of biological aging, in a nationally representative sample of middle-aged and older adults in the United States. Cross-sectional analysis of adults 50 years of age and older from the 2016 Health and Retirement Study. Epigenetic aging was derived from 13 epigenetic clocks based on DNA methylation patterns that predict aging correlates of morbidity and mortality. Ordinary least squares regressions were performed to test for differences in the epigenetic clocks, adjusting for the complex survey design, as well as biological, social, and behavioral factors. The analysis consisted of 3855 adults with mean age of 68.5 years, including 59.8% with no pain and 25.8% with high-impact pain. Consistent with its operational definition, high-impact pain was associated with greater functional and activity limitations. High-impact pain was associated with accelerated epigenetic aging compared to no pain, as measured via second (Zhang, PhenoAge, GrimAge) and third (DunedinPoAm) generation epigenetic clocks. Additionally, GrimAge was accelerated in high-impact pain as compared to low-impact pain. High-impact pain is associated with accelerated epigenetic aging among middle-aged and older adults in the United States. These findings highlight aging-associated epigenetic alterations in high-impact chronic pain and suggest a potential for epigenetic therapeutic approaches for pain management and the preservation of physical function in older adults.

Persuasive Strategies in Email Marketing: An Analysis of Appeal and Influence in Business Communication

This study examines the employment of persuasive strategies in informational emails that market products and/or services, illustrating how these strategies influence target customers and persuade them to make purchases. A corpus of 850 emails, encompassing over a million words, was compiled and analyzed using a mixed-method approach that integrated both quantitative and qualitative measures. The emails were collected between 2020 and 2021. The categorization of persuasive strategies was directed by predefined operational definitions and criteria, informed by Aristotle's model of persuasion. The analysis identified 11 persuasive strategies utilized within the email corpus. Notably, the findings revealed that the offering appeal and the appeal to authority are the most commonly used strategies, whereas the contrasting appeal and romantic expressions are the least employed. These results underscore the importance of persuasive strategies in business communication, especially within informational emails. The insights derived from this study carry significant implications for businesses in crafting compelling marketing messages. Furthermore, the findings contribute to English for Business Purposes courses, particularly in English as a Foreign Language (EFL) contexts, by offering guidance on constructing persuasive business emails.

Limitations of existing park quality instruments and suggestions for future research

Public parks are critical urban infrastructures offering health, environmental, social, and cultural benefits to people. However, the idea of park quality has lacked a clear operational definition and normative standard for measurement. We provide critical insights into existing park quality instruments and advocate for an alternative approach. First, due to the significant diversity in parks, inherent ambiguity and subjectivity in the idea of quality, and previous instruments’ inconsistent operationalizations of park quality, we recommend that future research shift its focus from creating instruments for universal application and standardized measurement to developing an inventory or list of park quality indicators that researchers and practitioners can selectively choose for their unique park contexts. Second, through our multidisciplinary examination, we identify five limitations in existing park quality instruments: (1) lack of attention to the histories of marginalized communities, (2) overemphasis on physical activities and public health, (3) lack of attention to ecological function and biodiversity, (4) lack of subjective measurements, and (5) insufficient consideration of multiple parks or a park system. Overall, a more flexible and site-specific approach to park quality measurement and the adoption of new indicators of park quality are expected to accomplish a more comprehensive and fairer assessment of park quality, contributing to park equity research and practice.

A systematic review of mobile brain/body imaging studies using the P300 event-related potentials to investigate cognition beyond the laboratory.

The P300 ERP component, related to the onset of task-relevant or infrequent stimuli, has been widely used in the Mobile Brain/Body Imaging (MoBI) literature. This systematic review evaluates the quality and breadth of P300 MoBI studies, revealing a maturing field with well-designed research yet grappling with standardization and global representation challenges. While affirming the reliability of measuring P300 ERP components in mobile settings, the review identifies significant hurdles in standardizing data cleaning and processing techniques, impacting comparability and reproducibility. Geographical disparities emerge, with studies predominantly in the Global North and a dearth of research from the Global South, emphasizing the need for broader inclusivity to counter the WEIRD bias in psychology. Collaborative projects and mobile EEG systems showcase the feasibility of reaching diverse populations, which is essential to advance precision psychiatry and to integrate varied data streams. Methodologically, a trend toward ecological validity is noted, shifting from lab-based to real-world settings with portable EEG system advancements. Future hardware developments are expected to balance signal quality and sensor intrusiveness, enriching data collection in everyday contexts. Innovative methodologies reflect a move toward more natural experimental settings, prompting critical questions about the applicability of traditional ERP markers, such as the P300 outside structured paradigms. The review concludes by highlighting the crucial role of integrating mobile technologies, physiological sensors, and machine learning to advance cognitive neuroscience. It advocates for an operational definition of ecological validity to bridge the gap between controlled experiments and the complexity of embodied cognitive experiences, enhancing both theoretical understanding and practical application in study design.

Impact of treatment approaches in patients with advance penile cancer: An analysis from a nationwide study.

e17024 Background: Advance penile cancer (APC) is a rare and aggressive malignancy, characterized by the presence of metastases to lymph nodes and/or distant organs. The rarity of patients with APC poses challenges in conducting comprehensive studies, with most existing evidence being small-scale, retrospective analyses from single institutions. Additionally, the absence of large clinical trials limits the evidence to compare the survival rates with different treatment approaches in patients with APC. Methods: Our study utilized the national cancer database (NCDB) from 2004 to 2021. Our primary analytic cohort included patients diagnosed with advance penile cancer based on the AJCC 8 th classification (T4 or N3 or M1). Treatment modalities comprised perioperative systemic therapy combined with definitive surgery (PST), concurrent chemoradiation (CCR), surgery only (S), and systemic therapy only (ST). We used Kaplan-Meier analysis and the cox proportional regression to evaluate the impact of these treatment modalities on survival outcomes. Results: We identified 1342 patients with advance penile cancer. The median overall survival (OS) was 22.24 months (CI: 15.87-27.86, P <0.001) for patients who received PST, 16.99 months (CI: 13.86-27.4) for those who underwent CCR, 11.99 months (CI: 9.2-15.01) for patients managed with surgery only, and 10.94 months (CI: 9.95-14.09) for those who received only ST. Our multivariate analysis revealed combining PST with surgery was associated with 27% reduction in the risk of death (HR: 0.73, P = 0.037) compared to systemic therapy after adjusting for age, race, tumor grade, comorbidities, distant metastasis and socioeconomic factors. Conclusions: Treatment approach with systemic therapy along with definitive penile surgery is associated with improved survival in patients with advanced penile cancer compared to other treatment modalities. Whenever feasible, this treatment approach should be considered as a management strategy in patients with APC. Further prospective studies are needed to validate our observations. [Table: see text]

Bloody stressed! A systematic review of the associations between adulthood psychological stress and menstrual cycle irregularity

Bloody stressed! A systematic review of the associations between adulthood psychological stress and menstrual cycle irregularity

Adjuvant chemotherapy guided by an integrated mRNA–lncRNA signature in triple-negative breast cancer (BCTOP-T-A01): A randomized, open-label, multicenter phase 3 trial.

525 Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with variable clinical outcomes. We have previously classified patients with TNBC into high- and low-risk groups based on a multigene signature. In this study, we aimed to evaluate the feasibility of utilizing a multigene signature to tailor individualized adjuvant therapy for patients with operable TNBC. Methods: This multicenter, open-label, randomized, phase 3 trial was conducted at 7 cancer centers in China. We included female patients aged 18-70 years with early TNBC after definitive surgery (histologically confirmed axillary lymph node-positive or lymph node-negative with tumor diameter >10 mm). After categorization using the integrated signature, high-risk patients were randomized (1:1) to receive an intensive adjuvant treatment comprising four cycles of docetaxel, epirubicin, and cyclophosphamide followed by four cycles of gemcitabine and cisplatin (TEC-GP; arm A), or the standard four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (EC-T; arm B). Low-risk patients received the same adjuvant chemotherapy as arm B (arm C). The primary endpoint was disease-free survival (DFS) in the intention-to-treat analysis of arm A versus arm B. Results: Between January 2016 and July 2023, 504 patients (336 high-risk and 168 low-risk; median age, 52 years; 488 with T1-2 tumors; 263 with node-positive disease) were recruited. At a median follow-up of 45.1 months, the 3-year DFS rates were 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.28 to 0.95; P = 0.030). Intensive chemotherapy improved DFS relative to standard therapy irrespective of tumor size and nodal status. The 3-year RFS was 92.6% in arm A and 83.2% in arm B (HR, 0.50; 95% CI, 0.25 to 0.98; P = 0.039). The groups did not differ in OS (HR, 0.58; 95% CI, 0.22 to 1.54; P = 0.267; 3-year OS, 98.2% vs 91.3%). Upon receiving the same chemotherapy regimen, patients in arm C had significantly higher DFS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.038; 3-year DFS, 90.1% vs 80.6%), RFS (HR, 0.42; 95% CI, 0.22-0.81; P = 0.007; 3-year RFS, 94.5% vs 83.2%) and OS (HR, 0.14; 95% CI, 0.03-0.61; P = 0.002; 3-year OS, 100% vs 91.3%) compared to patients in arm B. The incidence of grade 3 to 4 treatment-related adverse. events for arms A, B and C, respectively, were thrombocytopenia (14.1%, 2.5%, 1.8%), febrile neutropenia (9.9%, 4.3%, 4.9%), anemia (5.8%, 1.9%, 1.8%), nausea (7.0%, 3.7%, 4.9%), vomiting (8.3%, 4.3%, 4.9%) and myalgia (2.6%, 5.6%, 5.5%). There were no treatment-related deaths. Conclusions: The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable TNBC. Intensive regimens incorporating GP into anthracycline/taxane-based therapy improves survival with manageable toxicity. Clinical trial information: NCT02641847 .

Expert consensus recommendations on the daily clinical use of pembrolizumab for early triple-negative breast cancer.

e12521 Background: Triple-negative breast cancer (TNBC) accounts for 10–15% of all breast cancer cases and is associated with poor outcomes. Neoadjuvant chemotherapy is the standard treatment for early TNBC (eTNBC) to achieve a pathologic complete response which is associated with long-term clinical outcomes and to guide adjuvant treatment for residual disease after definitive surgery. Pembrolizumab, a programmed death 1 (PD-1) inhibitor, is approved for the peri-operative treatment of stage II and III TNBC. The Hong Kong Breast Cancer Foundation (HKBCF) convened a multi-disciplinary consensus consisting of surgeons, and clinical and medical oncologists to discuss the implementation of immunotherapy in the peri-operative setting and provide expert guidance on topics lacking definitive evidence from the KEYNOTE-522 study in daily clinical routine. Methods: The panel included 7 breast surgeons, 6 clinical oncologists, and 3 medical oncologists representing the academic, public, and private settings in Hong Kong. A modified Delphi panel was conducted, testing the panel on 7 different topics and 45 statements relating to the peri-operative treatment of eTNBC. Evidence was graded according to GRADE. Statements were initially voted by online form on a 6-point Likert scale, and the results were discussed during a consensus meeting. Consensus to accept was considered at a median ≥5 and an IQR ≤1.75 and consensus to reject at median ≤2 and an IQR ≤1.75. Results: Key findings are that the panel considered 1) the uncommon subtype “oestrogen receptor (ER)-low” does not formally meet the definition of TNBC but should be treated as TNBC; 2) pembrolizumab as a viable addition in the peri-operative setting; 3) guideline-recommended NAC for cT1c disease may be considered; but 4) this does not necessarily mean immunotherapy should be added, though it may be considered case-by-case. Furthermore, the panel 5) agreed that pembrolizumab prescription does not need to be guided by PD-L1 expression, and 6) that for patients with residual disease after NAC plus pembrolizumab, the addition of capecitabine to pembrolizumab is acceptable, however, 7) was divided about the addition of a PARPi to pembrolizumab for patients with a germline BRCA1/2 mutation (g BRCA1/2m) and residual disease — guided by the lack of routine g BRCA1/2m testing in Hong Kong. Finally, the panel 8) proposed to recommend adhering to the KEYNOTE-522 weekly paclitaxel regimen with a subclause to consider 3-weekly regimen as an alternative for specific technical or logistical challenges. Conclusions: The KEYNOTE-522 study has provided robust evidence on the efficacy and safety of peri-operative pembrolizumab in eTNBC patients. However, several clinical questions remain unanswered, and until further evidence is available, the HKBCF recommendations provide expert guidance on the use of pembrolizumab for eTNBC patients in daily clinical practice.

CtDNA monitoring for breast cancer at high risk of recurrence: Interim analysis of JCOG1204A1.

518 Background: Monitoring ctDNA after definitive surgery has emerged as an accurate predictor of breast cancer (BC) recurrence. However, further data is needed to determine the proportion and dynamics of ctDNA positivity in different BC subtypes. Here we present ctDNA status and dynamics in patients from an ancillary study (A1) of the prospective randomized phase III JCOG1204 trial (UMIN000012429; Registration: November 2013 - January 2020, N = 1034) in which intensive post-operative follow-up is compared to standard follow-up in BC patients at high risk of recurrence. Methods: Eligible patients enrolled in JCOG1204 were required to have either (1) ≥4 lymph node metastases for estrogen receptor (ER)+ BC without neoadjuvant therapy, (2) ≥1 lymph node metastases for ER- without neoadjuvant therapy, or (3) ≥1 lymph node metastases after neoadjuvant therapy. Additional inclusion criteria for ancillary study JCOG1204A1 include no more than 4 years after surgery and relapse-free at the enrollment. A personalized, tumor-informed assay (Signatera, Natera Inc.) was used for ctDNA surveillance every 3 - 6 months for 2 years for ER- or 5 years for ER+ BC. ctDNA status, time of ctDNA detection and association with subtype were examined. The JCOG DSMC approved the publication of this interim analysis. Results: A total of 248 patients were enrolled (July 2020-October 2023) in JCOG1204A1. Personalized assays were successfully designed for 88% patients, the main reason for failure was insufficient tissue (83%; 25/30). A total of 1440 plasma ctDNA samples were collected from 211 patients. The median age at the time of surgery was 50 years. The most prevalent subtype was ER+ HER2- (Luminal; n = 130), followed by ER- HER2- (TN; n = 38), ER- HER2+ (HER2; n = 24), and ER+ HER2+ (Luminal-HER2; n = 18). 25 patients (11.8%) had at least one positive ctDNA result, with overall sample-level positivity proportion of 4.5% (65 / 1440); 76% (19/25) became detectable with longitudinal testing. Surveillance in TN [the first time point median 31.5 months (12.6-55.8) from surgery] did not result in ctDNA detection. Of the 130 patients with Luminal subtype [the first time point median 36.6 months (12-57) from surgery], 21 (16.2%) had ctDNA first detected at a median 43.5 months (18-72). Additionally, 5 patients (2.4%) had ctDNA detection for the first time after 5 years of surgery. The proportion of ctDNA positivity increased by ~2% annually in Luminal subtype; varied rates of ctDNA level increase have been observed. Conclusions: Monitoring ctDNA in high-risk BC reveals a detection proportion of 11.8% at the patient level (TNBC: 0%; Luminal: 16.2%) Longitudinal testing revealed ctDNA detection in patients with luminal subtype beyond 5 years from surgery, suggesting a correlation with late recurrence. Subsequent reports will focus on investigating the association of ctDNA status with relapse and overall survival.

Prospective evaluation of the breast microbiome and tumor microenvironment-related biomarkers of response to neoadjuvant systemic therapy in triple negative breast cancer.

TPS615 Background: Predictive biomarkers of response to combination chemotherapy and immune-checkpoint inhibitors are urgently needed to tailor treatment recommendations for patients with early-stage triple negative breast cancer (eTNBC). Our group has demonstrated that tumour-associated microbiota in primary breast tumours represent promising and novel candidate biomarkers for patients with breast cancer. We aim to prospectively interrogate the breast cancer microbiome and tumour microenvironment (TME) of eTNBC treated with neoadjuvant chemo-immunotherapy, and correlate with clinical outcome. Methods: Trial design: This prospective translational biomarker study is enrolling patients with eTNBC suitable for standard neoadjuvant systemic therapy followed by definitive surgery. The primary objective is to evaluate the change in breast cancer microbiome composition pre- and post-therapy. Secondary objectives include correlation of the breast microbiome with pathologic complete response (pCR) and survival outcomes, tumor infiltrating lymphocytes (TILs), PDL-1 and immune subset analysis, extracellular vesicles analysis and analysis of gut microbiome. Tumor tissue samples will be collected at baseline (mandatory research biopsy) and at the time of surgery. Microbiome evaluation will be conducted using metagenomic sequencing to assess changes in the relative abundance of microbial taxa. Blood and stool samples will be collected and analysed at baseline, on-treatment, at the time of surgery and post-operatively for secondary endpoints. Statistical analysis: Hierarchical clustering of samples based on relative abundance of the operational taxonomic units (OTUs) with sample composition at family and genus level will be performed. Alpha Diversity (Shannon Diversity Index) and Beta Diversity (Jaccard Similarity Index) will be analysed. Principal component analysis (PCA) and Random Forest analysis will be performed for classification and clustering analysis. Comparison of taxa or functions between clinical cohorts will be performed (two tailed Z test) and corrected using the false discovery rate to determine Q-values. Thirty patients will be recruited over 18-24 months. Current status: This University College Cork sponsored trial received ethics approval from the CREC in January 2024 and recruitment is ongoing. Those interested can contact uccctg@ucc.ie. This trial will provide a deeper insight into the potential role of the local breast microbiome as a predictive biomarker for response to neoadjuvant therapy in patients with eTNBC. The results will guide further studies exploring optimal immunomodulatory combinations for the treatment of TNBC and may provide evidence regarding future therapeutic targeting of the breast cancer microbiome.

Clinicopathologic features of patients with breast cancer in a single tertiary hospital in the Philippines.

e23313 Background: Breast cancer incidence in the Philippines is among the highest in Asia - the WHO reported it to be as high as 33,079 in 2022. Data provided by the Philippine Cancer Society and Department of Health Rizal Cancer Registry in 2009 included 1,615 breast cancer patients and noted a significant increase in breast cancer incidence from the year 1980 to 2002 in 7 cities in Metro Manila. This retrospective study aims to describe and analyze clinicopathologic and treatment data of Filipino breast cancer patients in a tertiary hospital. This study represents the largest pooled data in the Philippines on breast cancer demographics. Methods: Patients diagnosed with invasive breast cancer in St. Luke’s Medical Center (SLMC) from 2009 to 2020 were included. Patients diagnosed with other breast histopathologic results [i.e. ductal and lobular carcinoma in situ without invasive component] and double primaries were excluded. The study was approved by the Ethics Review Committee (Reference No.: SL-19157). Results: A total of 5,462 breast cancer patients were included. Majority of the patients were late perimenopausal (50-59 yo, 30.06%), menopausal (60-69 yo, 23.03%), and premenopausal (below 44 yo, 19.28%,) at the time of diagnosis. Patients were diagnosed with stage II (N = 1,816, 47.24%), followed by stage I (N = 943, 24%), and stage III (N = 662, 17%). Sixty four percent (N = 1,498) were node negative while 46% (N = 1,300) were node positive. Among patients with de novo metastasis, 14.6% metastasized to the bone while visceral sites include chest wall (17.4%), lung (16.6%), liver (11.5%) and brain (7.45%). Luminal her2- (48.9%) was the most common clinical subtype followed by non-luminal her2+ (15.6%) and triple negative (6.7%). Definitive surgery was the mainstay of treatment – 94% (N = 4116) underwent modified radical mastectomy (MRM) while 5% (N = 223) underwent breast conserving surgery (BCS). Eight hundred patients (19%) received neoadjuvant treatment (hormonal and/or systemic chemotherapy) while 2,246 patients (54%) received adjuvant treatment. Total number of breast cancer patients who underwent adjuvant radiation was 1,399 (25.6%). Conclusions: Compared to middle-high income countries, data suggests that MRM is the preferred surgical technique over BCS. Majority of patients in the study are luminal her2-. However, only 54% received adjuvant treatment. Another observation is the low rate of neoadjuvant treatment by the study population. Further research on the risk factors or reasons for not receiving treatment as well as the outcomes of these patient cohorts is needed to shed light on these cancer care gaps.

The impact of adjuvant endocrine therapy (AET) omission in ER-low (1-10%) early-stage breast cancer.

513 Background: Adjuvant endocrine therapy (AET) improves overall survival (OS) in patients (pts) with hormone receptor (HR) positive early-stage breast cancer (BC). For pts with estrogen receptor (ER)-low BC (defined as ER 1-10%), there is controversy regarding AET benefit, given tumor heterogeneity (>40% basal; (1)), and similar chemotherapy response and prognosis to ER-negative (neg) BC. Current guidelines categorize ER-low BC as a separate entity and suggest equipoise regarding AET benefit. We previously determined that AET omission in chemotherapy-treated pts with ER+ BC resulted in a nearly 2-fold increase in death (2). However, the impact of AET omission in patients with ER-low BC is unknown. Methods: Beginning in 2018, the National Cancer Database (NCDB) began to abstract ER as a continuous variable, allowing classification of ER+ tumors as 1-10% or >10%. Therefore, we queried the NCDB 2018-2020 for patients with stage I-III ER+BC treated with neoadjuvant or adjuvant chemotherapy, as these pts have the highest risk of recurrence. ER was assessed as ER-neg (0%), low (1-10%) and ER >10%. OS was analyzed with AET as a time-dependent covariate using Cox proportional hazards regression. Results: 357,085 pts with stage I-III ER+BC were identified, with 10,396 (3%) classified as ER-low. Among pts with ER-low disease, 69% had PR-neg BC and 67% had HER2-neg BC. The majority (77%) were treated with chemotherapy (32% neoadjuvant, 44% adjuvant, 1% unknown timing) and formed our analysis cohort. Among these 7,956 pts, AET was omitted in 3,233 (41%). AET omission was more common for pts with tumors that were PR-neg vs positive (46% vs 30%, p<0.001), HER2-neg vs positive (44% vs 37%, p<0.001), and Ki67≥20% (44% vs 35%, p<0.001). With median follow-up of 3 years, 648 deaths were observed. OS was 94.3% (95% CI: 93.8-94.9%) at 2 years and 87.6% (95% CI: 86.5-88.7%) at 4 years. In unadjusted analysis, omission of AET was associated with worse OS (HR 1.40, 95% CI: 1.19-1.65, p<0.001), with similar effects regardless of PR, HER2, or Ki67 (each interaction test p>0.3). When controlling for age, comorbidity score, year of diagnosis, PR, HER2, and pathologic stage, the adjusted effect of AET omission on OS was HR 1.22 (95% CI: 1.00-1.48, p=0.05). Given assessment of OS was performed during pandemic years, with 1/3 of deaths occurring during the first year of follow-up, we performed a sensitivity analysis to analyze pts who survived to one year after definitive surgery. In this analysis, the adjusted effect of AET omission on OS was 1.24 (95% CI: 1.02-1.51, p=0.03). Conclusions: Omission of AET in pts treated with chemotherapy for ER-low, early-stage BC is associated with significantly worse OS. These data strongly suggest that pts with ER low BC should be counseled regarding the benefit of AET and practice guidelines should recommend AET in this setting. 1. Benefield JNCI 2020. 2. Choong SABCS 2022.

Impact of the COVID-19 pandemic on disease progression in patients with hepatobiliary and pancreatic cancer.

e16246 Background: The COVID-19 pandemic has posed challenges to healthcare systems, notably impacting cancer care. For patients with Hepatobiliary and Pancreatic Cancer, there has been a reported decline in median survival. The etiology of this decline, whether it is attributed to an escalation in disease severity or to delays in diagnosis and treatment remains unclear. Methods: This retrospective study analyzed the National Cancer Database (NCDB 2004-2020) data from 2018 to 2020. We compared time from diagnosis to initial treatment, AJCC (2017) TNM clinical stage distribution, and pathological variables suggestive of tumor aggression between the pre-pandemic and pandemic periods, as well as within COVID-19 positive (C19+) and negative (C19-) patients. Results: The study included 17,429 liver cancer (LC), 37,185 pancreatic cancer (PC), 1,684 gallbladder cancer (GC), and 3,651 intrahepatic biliary cancer (IBC) patient’s pre-pandemic, and 14,420 LC and 35,456 PC, 1,457 GC, and 3,792 IBC patients during the pandemic. The time to initial treatment did not significantly differ in the before and during the pandemic groups for all types of cancer. However, for GC, there was a significant increase in days to definitive surgery during the pandemic 54 ±73 days compared to pre-pandemic 28±53 days (p < 0.01). There was also a notable increase in the time to initial treatment and definitive surgery for pancreatic cancer in C19+ patients (46±51, 118±104 days) compared to C19- patients (35±37, 97±89 respectively) (p < 0.01). For LC and GC, there was a significant increase in late-stage diagnoses during the pandemic period. LC (stage III: 23.67% and stage IV: 21.10%) compared to pre-pandemic (stage III: 22.71% and stage IV: 19.02%, p < 0.01). GC (stage IV: 77.0%) compared to pre-pandemic (stage IV: 71.85%, p < 0.01). Lympho-vascular invasion rates and node positivity ratios in HC, GC, and IBC patients remained unchanged. For PC there was no change in late stage distribution and IBC there were no significant differences in overall stage distribution or lympho-vascular invasion rates. However, a significant increase in node positive/node harvested ratio was observed in stage III C19+ PC patients (0.308±0.322) compared to C19- (0.134±0.181, p < 0.01). Conclusions: Cancer screening delays during the pandemic led to an increase in late-stage diagnoses for LC and GC but stage distributions for PC and IBC were largely unchanged. However, the pandemic's impact was subtly observed in the form of increased node positivity in stage III C19+ pancreatic cancer patients possibly due to their delay in initial treatment and surgery. There was also an increase in time to definitive surgery in gallbladder cancer. These findings underscore the importance of maintaining robust cancer care pathways, particularly for high-risk groups, to prevent adverse stage migration and ensure timely management, even in the face of global health emergencies.

Analysis of ctDNA assay as a strategy for watchful waiting in locally advanced esophageal cancer.

e16126 Background: Standard treatment for locally advanced esophagogastric (EG) cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. The treatment goal is curative in order to control the tumor in the thorax, prevent regional recurrence, and to help prevent or delay metastatic progression. Despite achieving pathologic complete response (pCR) after surgery, patients with supposed local control may have recurrence up to a third of the time. Circulating tumor DNA (ctDNA) is an evolving tool in the field of oncology used as an informative biomarker. We provide longitudinal, real world observation of ctDNA minimal residual disease (MRD) to predict pCR and risk of recurrence. Methods: 22 participants with newly diagnosed locoregional EG cancer were enrolled under single institution approved protocol [IRB#1864127-7]. CtDNA-based MRD levels were obtained by Natera SignateraTM bespoke mPCR-NGS assay. Additionally, Natera Altera TM was used as a non-invasive biopsy to provide the comprehensive tumor-specific genomic profile. We evaluated thirteen participants who underwent definitive surgery and those who did not. Non-invasive plasma samples were surveilled at various timepoints which included the time of diagnosis, during neoadjuvant CRT, after definitive surgery. The primary outcome is a comparison of assay recurrence (AR) to disease recurrence (DR) defined as radiologic or clinical disease recurrence in participants with locoregional disease. Exploratory endpoints examine the profile of tumor. Results: Baseline levels were detected (n = 22) at new diagnoses. Longitudinal results demonstrated ctDNA clearance in eight participants while undergoing neoadjuvant chemoradiaton. Residual ctDNA were found in five participants for which two had clinical disease recurrence. Esophagectomy was done in three participants achieving pCR. Post procedural ctDNA were detected in one participant. Conclusions: The clearance of ctDNA favors less clinical disease recurrence in this study. This may indicate that ctDNA clearance confers lower risk of relapase. However, a larger cohort prospective study will be needed to validate the application of ctDNA as an early biomarker. The future application of ctDNA can be used to identify patients who may benefit from a watchful waiting adjuvant strategy instead of proceeding with invasive esophagectomy.

Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Change in tumor microenvironment and PD-L1 expression with rucaparib treatment in triple-negative breast cancer.

e12569 Background: Triple-Negative Breast Cancers (TNBCs) represent a diverse subset of tumors characterized by varied responses to therapies including immunotherapy (IO). While IO is approved in early-stage and advanced TNBC, responses are modest. Modulation of the tumor microenvironment to improve responses to IO is an active area of research. In-vitro and in-vivo studies have shown Poly-ADP Ribose Polymerase inhibitors (PARPi) to increase PD-L1 expression in sporadic, BRCA1 and BRCA2 mutated TNBC cell lines improving response to IO. In addition, TNBCs have diverse mechanisms leading to Homologous Recombination Deficiency and the role of PARPi in sporadic TNBCs is still unclear. Methods: To further investigate the role of PARPi in tumor immuno-modulation we conducted a single-arm, open-label, window of opportunity (WOO) trial in patients with early-stage TNBC (NCT03911453). This study was approved by our institutional review board. Patients with histologically documented stage I-III TNBC were eligible for definitive surgery were enrolled. Patients were treated with 600mg BID rucaparib for 21 days. Pre- and post-treatment tumor biopsies were collected. Post-treatment, patients went to surgery or proceeded with neoadjuvant chemotherapy (NAC) followed by definitive surgery. Our primary endpoint was to assess change in PD-L1 expression. In addition, change in tumor microenvironment was by evaluating change in percentage of B cells, T cells and macrophages was calculated. Results: Twenty patients were enrolled. Nineteen patients completed 21 days and 1 patient went on extended duration PARPi during the COVID19 pandemic. Almost 50% of patients went to surgery while the rest went onto NAC after PARPi therapy. Pre-treatment tumor samples were obtained from the diagnostic core biopsies while post-treatment, fresh frozen and Formalin Fixed Paraffin Embedded were obtained either at time of surgery or a research biopsy prior to NAC initiation. Primary biomarkers data was successfully done in 14 paired samples. Treatment with rucaparib has increased expression of PD-L1 from median of 15% in pre-treatment tumor samples to a median of 26% in post-treatment tumor samples. Table below summarizes our results. Conclusions: Our study revealed that treatment with PARPi, rucaparib, changed the tumor microenvironment as noted by changes in expression of PD-L1, and immune milieu in and around the tumor. This could lead to change in responsiveness to therapies including CKI. This strategy should be further investigated to evaluate improving responses to immunotherapies. Clinical trial information: NCT03911453 . [Table: see text]

Cytomegalovirus-Associated Colitis as a Cause of Lower Gastrointestinal Bleeding in Kidney Transplant Recipients: A Single-Centered Study.

Introduction Cytomegalovirus (CMV) is the most common viral pathogen affecting patients undergoing solid organ transplantation. It is often the most important infection for patients who have undergone kidney transplantation. Clinical presentations of cytomegalovirus infection range from asymptomatic infection to organ-specific involvement. This study aimed to determine the frequency of cytomegalovirus-associated colitis in kidney transplant recipients (KTRs) presenting with lower gastrointestinal bleeding. Methods After the approval of the ethical review committee of the Sindh Institute of Urology and Transplantation (ERC-SIUT), this cross-sectional study was conducted at the Department of Hepatogastroenterology at the Sindh Institute of Urology and Transplantation from January 2021 to December 2021. All the KTRs (six months after the transplantation) of either gender and aged between 18 and 65 years, presenting with lower gastrointestinal (GI) bleeding as per the operational definition, were enrolled in the study. Those patients who were either unfit for the endoscopy or refused to give consent were excluded from the study. Colonic biopsies were reviewed by a consultant histopathologist for the features of CMV infection. Results A total of 95 renal transplant recipients of either gender or age above 18 to 65 years with lower GI bleeding were included in the study. Among them, 84 (88.4%) were males, while 11 (11.6%) were females. The mean age of the patients included in the study was 37±11 years. The most common presenting complaint was fresh bleeding per rectum, which was observed in 73 (76.8%). The most common findings observed on colonoscopy in KTRs with bleeding per rectum were colonic ulcers and erosions noted in 41 (43.1%) and 36 (37.3%) patients, respectively. On histopathology, CMV colitis was noted in 21 (22.1%) patients. On comparison of different baseline variables, the presence of fresh bleeding per rectum and the presence of both ulcers and erosions on colonoscopy were the factors significantly associated with CMV colitis in KTRs. Conclusion CMV colitis is a prevalent condition in KTRs, presenting with lower GI bleeding. Despite the significant occurrence, the levels of CMV viremia were not associated with CMV colitis, suggesting that diagnosis should rely on histopathological confirmation. Prophylaxis during periods of high immunosuppression is crucial to reducing the incidence of CMV infections and improving both graft function and patient survival.

Pathologic response rates to neoadjuvant pembrolizumab in locally advanced (LA) resectable cutaneous squamous cell carcinoma (cSCC).

9591 Background: Cutaneous squamous cell carcinoma (cSCC) is the second commonest cutaneous malignancy, accounting for 20% of cutaneous malignancies and 75% of non-melanoma skin cancer deaths. Anti-PD-1 is approved in unresectable and metastatic cSCC, and is associated with high rates of pathologic response in resectable locally advanced (LA) cSCC. We conducted a phase II single-arm neoadjuvant trial of pembrolizumab (P) in patients with PD-1 naïve resectable LA cSCC. Methods: Patients with AJCC/UICC ≥T3 (or T2 with ≥2 BWH high-risk features) and/or N+ disease were eligible. Patients received 2 cycles of P (200mg Q3W) prior to definitive surgery, and 15 cycles post-surgery (NCT04808999). The primary endpoint was pathologic complete response (pCR, defined as 0% residual viable tumor, RVT) per independent central pathology review. Key secondary endpoints included incidence of adverse events (AEs), recurrence-free survival (RFS), overall survival (OS), safety and unbiased spatial biomarkers. A selected panel of multiplex immunofluorescence imaging biomarkers were used by PredxBio Inc.’s computational pipeline to reveal spatial intratumor heterogeneity in the tumor microenvironment (TME). Results: Thirty patients were enrolled and received at least 1 cycle of P. The median age was 79 (59-93) years and patients were predominantly male (77%). One patient withdrew consent prior to surgery. Three patients died prior to definitive surgery: 2 from COVID-19, a third from a NSTEMI possibly related to P. Of the 26 response-evaluable patients, AJCC/UICC stage at baseline was high-risk T2, T3, N1, and N2 in 2 (8%), 12 (46%), 9 (34.5%), and 3 (11.5%) patients, respectively. We observed pCR in 15 (57%), pathologic partial response (pPR, 10% < %RVT <50%) in 2 (8%) and pathologic non-response (pNR, >50%RVT) in 8 (31%) patients. One patient is pending surgery. Postoperative radiotherapy (RT) was de-escalated in 54% of the patients (14/15 in pCR). Median RFS was 13 (pCR) versus 10.5 (non-pCR) months. One Grade 5 (NSTEMI) and two Grade 3 (hepatitis, colitis) treatment-related AEs were observed. Computational analysis identifies key spatial interactions between PDL-1+/CD68+ cells implicated in response to P. Conclusions: Neoadjuvant P is efficacious in resectable LA cSCC with a high pCR rate (57%). Three deaths were observed, including 2 unrelated to treatment and 1 possible Grade 5 cardiac irAE, reflecting the inherent risks of perioperative therapy in this patient population. RT was de-escalated in 93% of pCR patients. No relapse events in pCR patients. Spatial interactions between PDL-1+ cells and CD68+ macrophages have a role in therapeutic response and will be detailed along with other spatial analyses of the TME compartment that have an impact on outcomes. Clinical trial information: NCT04808999 .

Disease monitoring using plasma-based circulating tumor DNA (ctDNA) assays in rare malignancies.

e15046 Background: ctDNA assays can be used to assess molecular residual disease, and the value of ctDNA monitoring in disease surveillance and treatment response assessment has been demonstrated in colon, breast, lung, and bladder cancers. However, the data of ctDNA in rare cancers has been lacking. We conducted this retrospective study to investigate the potential roles of ctDNA monitoring in rare tumors in both surveillance and response evaluation. Methods: ctDNA assay results of 12 patients (pts) with rare cancers including adrenocortical carcinoma (ACC) (4 pts), salivary gland cancers (3 pts), pleural or peritoneal malignant mesothelioma (4 pts), and anaplastic thyroid cancer (ATC) (1pt) undergoing treatment or surveillance in 2023 at Mayo Clinic Florida were analyzed. The trends of ctDNA levels were correlated with radiographic images findings. Results: Among the 12 patients, ctDNA was detected in at least one time point in 9 (75%) pts, including 1 (100%) ATC pt, 2 (66%) salivary gland pts, 3 (75%) malignant mesothelioma pts, and 3 (75%) ACC pts. Among these 9 pts, 5 pts had ctDNA collected at more than one timepoints, and the trends of ctDNA levels were consistent with image findings in all 5 pts. Among these 5 pts, one pt received definitive surgery for ACC with clearance of ctDNA after the surgery and one salivary gland cancer pt was undergoing surveillance and later developed disease progression. The other 3 pts were undergoing palliative systemic therapy and had responded to treatments. Conclusions: ctDNA was detectable in majority of the patients with rare malignancies reviewed in this study, including ACC, ATC, pleural or peritoneal malignant mesothelioma, and salivary gland cancers. Further study is warranted to investigate the role of ctDNA monitoring in surveillance and treatment response evaluation in rare malignancies.