Operational Definition Research Articles

The Discrete, Fractional Order Model of a Two-Dimensional Temperature Field using Grünwald-Letnikov Definition

In the paper a new, fractional order, discrete model of a two-dimensional temperature field is addressed. The proposed model uses Grünwald-Letnikov definition of the fractional operator. Such a model has not been proposed yet. Elementary properties of the model: practical stability, accuracy and convergence are analysed. Analytical conditions of stability and convergence are proposed and they allow to estimate the orders of the model. Theoretical considerations are validated using exprimental data obtained with the use of a thermal imaging camera. Results of analysis supported by experiments point that the proposed model assures good accuracy and convergence for low order and relatively short memory length.

Abstract A002: Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma

Abstract Introduction and Objective: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with upper tract urothelial carcinoma (UTUC). The application of a robust urine-based multiplex assay, Oncuria-Detect®, to aid in the detection of UTUC has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis. Methods: To evaluate the performance of Oncuria-Detect®, a multiplex immunoassay capable of querying a voided urine sample for 10 protein biomarkers associated with urothelial carcinoma (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA). Its application to UTUC was evaluated in a multi-institutional cohort of 35 prospectively collected subjects presenting for evaluation of upper tract mass along with 46 prospective collected matched controls (i.e., non-tumor bearing). The ability of the test to identify patients harboring UTUC was assessed. UTCU status was confirmed by endoscopy and tissue biopsy or definitive surgery. Diagnostic performance was assessed using ROC curves. Results: Oncuria-Detect® provided an AUC of 0.886 (95% CI: 0.807-0.964) with an overall sensitivity of 91.4%, specificity of 73.9%, NPV 91.9% and PPV 72.7%. Sensitivity values of the diagnostic panel for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 86.7%, 90.9%, 88.9% and 94.1%, respectively. Urinary cytology or selective ureteral washing/cytology was associated with an overall sensitivity of 54.2%, specificity of 100%, NPV 63.3% and PPV 100%. Sensitivity values of cytology for low-grade UTUC, high-grade UTUC, non-invasive UTUC and invasive UTUC were 100%, 100%, 100%, and 77.8%, respectively. Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of UTUC and controls non-tumor bearing individuals. The multiplex Oncuria-Detect® test can achieve the efficient and accurate detection of UTUC in a non-invasive patient setting. Citation Format: Toru Sakatani, Sunao Tanaka, Kazutoshi Fujita, Jennifer Linehan, Kaoru Murakami, Riko Lee, Ian Pagano, Charles Rosser, Hideki Furuya. Assessment of the diagnostic accuracy of Oncuria-Detect® for detection of upper tract urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A002.

The Influence of the Language Used in the Lyrics on How People Perceive the Emotions in Music

According to the existing research, the part of the brain in charge of language is also linked with musical functions. Besides, it is not a secret that music can influence language development in the human brain. However, there is seldom research on how language can influence the processing of musics. Here, research is designed to measure how the presence of language can alter the perception of music and, specifically, how lyrics (language) can affect how people perceive the emotions in the music. The scores given by the participants about how strong the emotions perceived (including positive to negative ones) in the music will be the operational definition.

Definitive single-stage surgery for treating diabetic foot osteomyelitis: a protocolized pathway including antibiotic bone graft substitute use.

Diabetic foot ulcers (DFUs) are a challenging complication of diabetes mellitus, often leading to poor clinical outcomes and significant socioeconomic burdens. We evaluated the effectiveness of a definitive single-stage protocolized surgical management pathway, including the use of local antibiotic bone graft substitute, for the treatment of infected DFUs with associated osteomyelitis. A retrospective cohort study was conducted. Medical records were extracted (from January 2017 to December 2020) to establish a database consisting of patients who underwent surgical intervention for the treatment of an infected DFU with osteomyelitis. Patients were divided into conventional (control) and protocolized (intervention) surgical groups depending on the treatment received. Clinical outcomes were assessed over a 12-month follow-up period. A total of 136 consecutive patients were included (conventional = 33, protocolized = 103). The protocolized group demonstrated a statistically significant reduction in the mean number of operations performed per patient (1.2 vs. 3.5) (P < 0.001) and a shorter accumulative hospital length of stay (12.6 vs. 25.1 days) (P < 0.001) compared to the conventional group. Major amputation rates were significantly lower in the protocolized group (2% vs. 18%) (P < 0.001). Within 12 months of surgical intervention, the protocolized group exhibited an ulcer healing rate of 89%, with a low rate of recurrence (3%). The protocolized surgical pathway, including local antibiotic bone graft substitute use, demonstrated superior outcomes compared to conventional management for the treatment of infected DFUs with osteomyelitis. Further research is needed to evaluate the cost-effectiveness and generalizability of this approach.

Assessment of Safe Early Fixation Strategies in a Cohort Polytraumatized Patients – How is the Surgical Treatment Influenced by the Injury Pattern?

Abstract Background While the inital assessment and the intial treatment of potentially life-threatening injuries is well-described, the surgical treatment strategy following initial resuscitation remains controversial. Timepoint of surgery and type of surgery still reamin topic of discussions. Various, different strategies for optimal timing of fracture fixation in polytrauma patients exist. Aims This study tests the hypothesis that a concept of clearing patients for early definitive surgery that relies on anatomical and physiologic parameters is influenced by the injury distribution. Methods Polytrauma patients treated at a Level 1 trauma center (01.01.2016 - 31.12.2018). Inclusion: primary admission, injury severity score (ISS) ≥16points, requirement of surgical fixation of major extremity or a truncal injury. Exclusion: death &amp;lt;72h after admission, severe traumatic brain injury (TBI). Stratification according to surgical fixation concept: Early total care (ETC, all surgeries &amp;lt;24 h), safe definitive surgery (SDS, staged surgeries &amp;lt;72h), and damage control orthopaedics (DCO, definitive care after stabilization). Endpoints: mortality, complication rates. Parameters of interest: Injury severity and distribution (ISS/AIS), pathophysiologic parameters of hemorrhagic shock, coagulopathy, hypothermia, soft tissue trauma. Results 527 patients, mean age 54.8 SD19.9 years, mean ISS 26.9 SD9.0 points, mortality 20.5%. Group ETC (n=21, 3.9%), Group SDS (n = 284, 53.9%), Group DCO (n = 222, 42.1%). Abdominal and spinal injuries associated with ETC (AIS Abdomen; OR 2.1, 95%CI 1.1 to 4.0, p = 0.026: AIS Spine OR 2.0, 95%CI 1.2 to 3.4, p = 0.007). Extremity and pelvic injuries associated with SDS (OR 1.8, 95%CI 1.1 to 2.8, p = 0.012 and OR 1.3, 95%CI 1.0 to 1.7, p = 0.036), head injuries associated with DCO (OR1.5, 95%CI 1.3 to 1.8, p &amp;lt;0.001). Head injuries were most relevant for mortality and were associated with patients undergoing DCO (29.7%) (ETC; 23.8%, SDS; 13.0%). Conclusion The concept of staged early fixation for major extremity and axial injuries (SDS) was successfully applied in the majority of patients. Predominant head and abdominal injuries were associated with ETC or DCO. The injury distribution influences decision making towards surgical management that is associated with a low complication rate.

Unravelling the complexity of research capacity strengthening for health professionals in low- and middle-income countries: A concept analysis.

Research capacity strengthening (RCS) is crucial in enhancing healthcare outcomes, particularly in low- and middle-income countries (LMICs), which face challenges due to limited resources, unequal access to care and the need for evidence-based decision-making. We seek to move beyond a surface-level understanding of RCS, unearthing the core attributes, the factors that precede its implementation and the transformative outcomes it generates within the LMIC healthcare landscape. This study employs the Walker and Avant approach to concept analysis to comprehensively explore the dimensions and attributes of RCS as it pertains to allied and public health professionals in LMICs, propose empirical referents and suggest an operational definition. Ovid MEDLINE, Embase, CINAHL and Cochrane CENTRAL were searched from inception to 27 July 2023, to identify studies on RCS in LMICs. The Walker and Avant approach to concept analysis was selected because it provides a framework for systematically examining and clarifying the meaning and implications of RCS. This method involves a structured process of defining RCS, identifying its attributes, antecedents, consequences and cases, and ultimately providing a clear understanding of its meaning and implications. Identifying empirical referents offers measurable indicators that researchers and policymakers can use to assess the effectiveness of RCS initiatives in LMICs. RCS for health professionals in LMICs involves a sustainable process that equips them with essential research skills, fostering the ability to conduct high-quality research and improve healthcare delivery in resource-constrained settings. RCS aims to empower health professionals to apply evidence-based practices, reduce disparities and enhance the well-being of populations in LMICs. Ultimately, a concept analysis of RCS empowers us to harness the full potential of research to enhance healthcare delivery, improve patient outcomes and advance the well-being of populations worldwide.

On the distributional fractional derivative: From unidimensional to multidimensional

In this paper, we use the generalized notions of Riemann–Liouville (fractional calculus with respect to a regular function) to extend the definitions of fractional integration and derivative from the functional sense to the distributional sense. First, we give some properties of fractional integral and derivative for the functions infinitely differentiable with compact support. Then, we define the weak derivative, as well as the integral and derivative of a distribution with compact support, and the integral and derivative of a distribution using the convolution product. Then, we generalize those concepts from the unidimensional to the multidimensional case. Finally, we propose the definitions of some usual differential operators.

Spinal height for growth guidance treatment in early onset idiopathic scoliosis: analysis through final surgical treatment.

The growth guidance (GG) method for treatment of early onset scoliosis has as its primary goal the restoration of apical spinal alignment, facilitating normal spinal growth to achieve a suitable adult thoracic height. To evaluate whether GG surgical treatment achieves comparable thoracic and spinal height to distraction-based treatment (DBT) in idiopathic early onset scoliosis (I-EOS) patients. We hypothesized that GG would prove superior to DBT at the time of definitive fusion surgery. All I-EOS patients who underwent GG at a single center were reviewed. T1-L1 and T1-S1 heights were measured using the traditional coronal method as well as the Halifax sagittal spinal length (SSL) technique. The same measurements were obtained from a comparable control group obtained from a multi-center pediatric early onset scoliosis database who underwent treatment with traditional growing rods (TGR) or magnetically controlled growing rods (MCGR). Of the I-EOS patients who underwent GG 2004-2019, 15 patients underwent final fusion after GG completion, with a mean 5.5years of GG treatment prior to fusion (range 2.0-11.4years). Mean age at GG implantation was 8.4years (range 2.0-11.7years); 7 were male and 8 female. GG patients experienced a mean coronal thoracic height increase of 6.2cm during treatment through final fusion, and a mean coronal spinal height increase of 8.8cm. At the time of final fusion, GG patients achieved greater significant mean increases than DBT patients by 2.9cm in coronal thoracic height (p = 0.0023), 4.5cm in coronal spinal height (p = 0.001), and 4.0cm in SSL spinal height (p = 0.01). No GG patient concluded treatment with a thoracic height less than 18cm in either coronal or sagittal plane. Not only did 100% of GG patients reach minimum thoracic height of 18cm at time of final fusion, but GG also proved to be superior to distraction-based constructs in a comparison cohort on 3 of 4 spinal elongation measures. 3.

Multi-entropy at low Renyi index in 2d CFTs

For a static time slice of AdS_33 we describe a particular class of minimal surfaces which form trivalent networks of geodesics. Through geometric arguments we provide evidence that these surfaces describe a measure of multipartite entanglement. By relating these surfaces to Ryu-Takayanagi surfaces it can be shown that this multipartite contribution is related to the angles of intersection of the bulk geodesics. A proposed boundary dual [Phys. Rev. D 106, 126001 (2022), J. High Energy Phys. 08, 202 (2023), J. High Energy Phys. 05, 008 (2023)], the multi-entropy, generalizes replica trick calculations involving twist operators by considering monodromies with finite group symmetry beyond the cyclic group used for the computation of entanglement entropy. We make progress by providing explicit calculations of Renyi multi-entropy in two dimensional CFTs and geometric descriptions of the replica surfaces for several cases with low genus. We also explore aspects of the free fermion and free scalar CFTs. For the free fermion CFT we examine subtleties in the definition of the twist operators used for the calculation of Renyi multi-entropy. In particular the standard bosonization procedure used for the calculation of the usual entanglement entropy fails and a different treatment is required.

Critical Organ Dysfunction and Preoperative Mortality in Newborns with Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is fatal without surgical intervention. An important subset of HLHS patients die prior to surgical intervention, but this population is underevaluated. The neonatal sequential organ failure assessment score (nSOFA) is an operational definition of organ dysfunction that can identify those with a high risk of mortality among neonatal intensive care unit (NICU) patients. The utility of the nSOFA to predict preoperative mortality in the unique HLHS population is unknown and could inform care, particularly care provided by neonatology staff. We performed a multicenter retrospective cohort study of HLHS cases across three level IV NICUs from January 1, 2009 to December 3, 2023. Patients were classified as either survived or died prior to surgical intervention. Demographic variables were curated from medical records including the maximum nSOFA (nSOFAmax) before surgical intervention or death. We identified 265 patients with HLHS over the study period. The nSOFAmax was greater in patients who died preoperatively (14/265; 5%) compared with survivors to surgical intervention (median 8 [interquartile range, 6, 12] vs. 2 [0, 4]; p < 0.001). The area under receiver operating characteristics curve for the nSOFAmax to discriminate for mortality was 0.93 (95% confidence interval, 0.88-0.98; p < 0.001). Compared with an nSOFAmax of 0, the likelihood ratio for preoperative death doubled at 2, tripled at 4, and was 10-fold at 9. This is the first demonstration of nSOFA utility in specific to congenital heart disease and HLHS. The nSOFAmax represents a novel, electronic health record-compatible, and generalizable method to identify patient-level organ dysfunction and risk for preoperative mortality in HLHS patients. KEY POINTS: · An important subset of HLHS patients die preoperatively.. · nSOFA can be used to measure preoperative HLHS severity.. · nSOFA predicts preoperative mortality risk in HLHS patients..

Is there a role for suppression of infection in managing fracture-related infection following intra-medullary nailing?

BackgroundThe management of fracture-related infection has undergone radical progress following the development of international guidelines. However, there is limited consideration to the realities of healthcare in low-resource environments due to a lack of available evidence in the literature from these settings. Initial antimicrobial suppression to support fracture union is frequently used in low- and middle-income countries despite the lack of published clinical evidence to support its practice. This study aimed to evaluate the outcomes following initial antimicrobial suppression to support fracture union in the management of fracture-related infection. MethodsA retrospective review of consecutive patients treated with initial antimicrobial suppression to support fracture healing followed by definitive eradication surgery to manage fracture-related infections following intramedullary fixation was performed. Indications for this approach were; a soft tissue envelope not requiring reconstructive surgery, radiographic evidence of stable fixation with adequate alignment, and progression towards fracture union. ResultsThis approach was associated with successful treatment in 51/55 (93 %) patients. Fracture union was achieved in 52/55 (95 %) patients with antimicrobial suppression alone. Remission of infection was achieved in 54/55 (98 %) patients following definitive infection eradication surgery. Following antibiotic suppression, 6/46 (13 %) pathogens isolated from intra-operative samples demonstrated multi-drug resistance. ConclusionInitial antimicrobial suppression to support fracture healing followed by definitive infection eradication surgery was associated with successful treatment in 93 % of patients. The likelihood of remission of infection increases when eradication surgery is performed in a healed bone. This approach was not associated with an increased risk of developing multi-drug-resistant infections compared to contemporary bone infection cohorts in the published literature. Level of evidenceIV

Preexisting Diabetes and Breast Cancer Treatment Among Low-Income Women

Diabetes is associated with poorer prognosis of patients with breast cancer. The association between diabetes and adjuvant therapies for breast cancer remains uncertain. To comprehensively examine the associations of preexisting diabetes with radiotherapy, chemotherapy, and endocrine therapy in low-income women with breast cancer. This population-based cohort study included women younger than 65 years diagnosed with nonmetastatic breast cancer from 2007 through 2015, followed up through 2016, continuously enrolled in Medicaid, and identified from the linked Missouri Cancer Registry and Medicaid claims data set. Data were analyzed from January 2022 to October 2023. Preexisting diabetes. Logistic regression was used to estimate odds ratios (ORs) of utilization (yes/no), timely initiation (≤90 days postsurgery), and completion of radiotherapy and chemotherapy, as well as adherence (medication possession ratio ≥80%) and persistence (<90-consecutive day gap) of endocrine therapy in the first year of treatment for women with diabetes compared with women without diabetes. Analyses were adjusted for sociodemographic and tumor factors. Among 3704 women undergoing definitive surgery, the mean (SD) age was 51.4 (8.6) years, 1038 (28.1%) were non-Hispanic Black, 2598 (70.1%) were non-Hispanic White, 765 (20.7%) had a diabetes history, 2369 (64.0%) received radiotherapy, 2237 (60.4%) had chemotherapy, and 2505 (67.6%) took endocrine therapy. Compared with women without diabetes, women with diabetes were less likely to utilize radiotherapy (OR, 0.67; 95% CI, 0.53-0.86), receive chemotherapy (OR, 0.67; 95% CI, 0.48-0.93), complete chemotherapy (OR, 0.71; 95% CI, 0.50-0.99), and be adherent to endocrine therapy (OR, 0.71; 95% CI, 0.56-0.91). There were no significant associations of diabetes with utilization (OR, 0.95; 95% CI, 0.71-1.28) and persistence (OR, 1.09; 95% CI, 0.88-1.36) of endocrine therapy, timely initiation of radiotherapy (OR, 1.09; 95% CI, 0.86-1.38) and chemotherapy (OR, 1.09; 95% CI, 0.77-1.55), or completion of radiotherapy (OR, 1.25; 95% CI, 0.91-1.71). In this cohort study, preexisting diabetes was associated with subpar adjuvant therapies for breast cancer among low-income women. Improving diabetes management during cancer treatment is particularly important for low-income women with breast cancer who may have been disproportionately affected by diabetes and are likely to experience disparities in cancer treatment and outcomes.

Angioplasty with ductal stent: experience at Garrahan Hospital

To describe and evaluate the outcomes of ductal angioplasty with stent placement at a single high-complexity center during the period 2016-2022. A retrospective descriptive cross-sectional study was conducted, including patients under 3 months of age who underwent ductal stent implantation as initial palliative treatment. Demographic, clinical, and anatomical data were collected before the intervention. Mortality, intra- and post-procedural complications, need for re-intervention, intensive care requirements, and hospital stay were recorded. The characteristics at the time of definitive surgery are described. Discrete variables are presented as percentages, and continuous variables are presented with their medians and respective interquartile ranges. Twenty patients who underwent this treatment were reviewed, revealing a success rate of 80%. Complications due to stent dysfunction required surgical resolution. 95% of patients were dischargedfrom the institution after the procedure, and 17 patients reached a second definitive surgical stage. Three patients died afterthe procedure, but with no direct relation to it. Indications for ductal angioplasty with stent as an alternative treatment to systemic-pulmonary anastomosis by surgery are not yet fully defined; the strategy represents a valid alternative in appropriately selected patients. The presented experience shows results similar to international reference centers.

Chondrosarcoma of the Mobile Spine: An Update on Patients Treated at a Single Institution.

Retrospective study. The objective is to report the clinical data for patients treated with mobile spine chondrosarcoma. Chondrosarcoma of the mobile spine is a rare and challenging entity. A handful of case series have been published that report the clinical results of treatment, largely influenced by chondrosarcoma of the appendicular skeleton and pelvis. The clinical results of patients treated for chondrosarcoma of the mobile spine from our institution were published over ten years ago and this represents and update since that publication. Inclusion criteria were adults patients treated for chondrosarcoma of the mobile spine at Massachusetts General Hospital between 2007-2020. Patients with large sacral tumors extending into the lumbar spine were excluded. Further, we excluded patients with metastatic chondrosarcoma undergoing palliative decompressions for neurologic instability or instrumented procedures for biomechanical instability. Therefore, only patients undergoing definitive surgery at the primary site of disease in the mobile spine were included. Twenty-four patients were included for review in this series. Seventeen of the 24 patients had their tumors excised with negative (R0) margins. Three of these 17 patients (18%) were dead of disease at final follow-up. There were two patients with R1 resections and five patients with R2 resections. Three of the 7 patients (43%) with positive margins were dead of disease at final follow-up. A Cox proportional hazard analysis indicated total radiation dose was a significant covariate (HR 1.18, 95% CI 1.01 - 1.39, P=0.03). We found higher percentages of overall survival with R0 tumor resection and lower histologic grade whereas development of metastatic disease was closely associated with local recurrence and poor survival. Despite the improvements in treatment paradigms, it is sobering that our findings largely mirror those of previous work considering patients treated between 1984 and 2006.

Clinicopathological profile and management challenges of congenital encephaloceles in a tertiary hospital in southwest Nigeria.

A congenital encephalocele is the herniation of intracranial contents through skull defects of various sizes. Depending on the site, content, and size, it is associated with significant morbidity and mortality in children. There is a paucity of recent and comprehensive local clinical data regarding this anomaly. Understanding the peculiarities, clinical-pathologic profiles, and management challenges will help prevent and effectively manage congenital encephalocele to improve outcomes. This was a retrospective study of all cases of congenital encephalocele managed between July 2000 and December 2023 at a tertiary hospital in the southwest region of Nigeria. Relevant demographic, clinicopathological, and management data were retrieved and analysed. There were 31 females and 11 males. Their ages ranged from 3hours to 24years. Sixteen (35.3%) were delivered in a non-health facility. Birth asphyxia was reported in 5 babies. Few mothers (4.8%) used preconception folic acid. Anaemia (n = 5) and sepsis (n = 4) were the common preoperative morbidities. All patients had definitive surgery, with 18 operated on within the first month of life. Cerebrospinal fluid (CSF) leak was the most common postoperative complication and was significantly observed in the sincipital group (p = 0.018). Thirty-one patients (73.8%) presented for follow-up after surgery, and the mean follow-up duration was 26.6weeks. Mortality was recorded in a patient (2.4%) due to Klebsiella meningitis. Congenital encephaloceles are relatively common in our setting. Therefore, there is a need to address the associated poor maternal and neonatal health conditions. Early surgery can be performed with a favourable outcome.

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p &amp;lt; 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p &amp;lt; 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-04.

Abstract PO2-22-06: MRI response Assessment of Single Fraction Pre-operative Stereotactic Radiotherapy: Preliminary results

Abstract Background: Pre-operative stereotactic breast irradiation (SPBI) improves targeting precision and has the potential to decrease treatment-related toxicity while downstaging or eliminating cancer. Accurate pCR prediction may allow omission of surgery. We are reporting initial interim results of the performance of multiparametric breast MRI in identifying pathologic response rate after single-fraction pre-operative SPBI in early stage estrogen receptor-positive (ER+), HER-2 negative breast cancer. Methods: In an ongoing single center prospective single-arm trial 22 patients with ER+/HER2-negative, cN0, unifocal, invasive breast cancer ≤3 cm underwent single-dose ablative SPBI, followed by definitive surgery per standard of care. Residual disease vs complete imaging response to SPBI was assessed on baseline and post-SPBI/pre-operative breast MRI. Pathologic response was categorized using MDACC Residual Cancer Burden (RCB) Categories. Wilcoxon rank sum test was used to assess the correlation of pathologic complete response (pCR) or RCB status on final path with MRI lesion size, volume, diffusion weighted imaging apparent diffusion coefficient (ADC) value, and when available, presence of residual enhancement on pre-operative MRI. MRI volume and ADC values were obtained using a dedicated CAD software. Area under the receiver operating Curve(AUC) was constructed to assess the diagnostic performance of pre-operative MRI on predicting pathologic response. Results Mean patient age was 64.9 (SD±7.3) years, tumor diameter 1.2(± 0.6) cm, pre-SPBI volume 6.4 ± 9.1 cm3, post SPBI volume 1.8 ± 5.6 cm3, ADC 0.91 ×10-3 mm2/s. At surgical pathology, 6(27.2%) achieved pCR/RCB-0, 9(41%) RCB-I, 7(31.8%) RCB-II. Mean baseline MRI size (1.2 ± 0.7 vs 1.3 ± 0.6, p=0.88), enhancement volumes (6.0±6.2 vs 7.9±9.9 cm3, p=0.59), DWI ADC values (1.1 ± 0.3 vs 0.9 ± 0.2 mm2/s, p-0.48) were not significantly different between tumors that showed pCR vs RCB I-II at surgical pathology. Time elapsed from SBRT to surgery were significantly longer in patients with pCR (264.3 ± 74.2 vs 183.7 ± 68.3 days, p=0.04) On pre-op MRI, mean enhancement volume was smaller in cancers that had pCR, however it did not reach significance (0.1 ± 0.1 vs 2.1 ± 6.0 cm3, p=0.2). Of 18 patients with available pre-operative MRI, residual enhancement was present in 7, of these 6/7(87%) had RCB I-II, and 1/7(13%) RCB-0 at surgical pathology. Conversely, in 11 patients with no residual enhancement on MRI, pathology showed pCR/RCB-0 in 5(45.5%), while 6(54.5%) had RCB I or II. Presence of residual enhancement on pre-operative MRI had an AUC of 0.68 (95%CI 0.43; 0.93, p=0.2) in predicting residual cancer after SPBI. Conclusion: Detecting residual enhancement on pre-operative MRI is a strong indicator of residual disease after SPBI, while lack of enhancement is not a reliable predictor of pCR. Our preliminary results do not indicate an association between baseline MRI enhancement volume, DWI ADC and pathologic response. Citation Format: Baṣak Dogan, Sunati Sahoo, Marilyn Leitch, Prasanna Alluri, Robert Timmerman, Deborah Farr, Asal Rahimi. MRI response Assessment of Single Fraction Pre-operative Stereotactic Radiotherapy: Preliminary results [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-06.

Abstract PO4-08-10: Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer

Abstract Background: Combination treatment with chemotherapy and immunotherapy remains the standard of care for high risk, early-stage triple negative breast cancer (TNBC). Although the addition of immunotherapy improves rates of pathologic complete response (pCR) and event-free survival, approximately 50% of patients achieve pCR with neoadjuvant chemotherapy alone suggesting that some patients may safely avoid the potential toxicities of immunotherapy without compromising outcomes.1,2 Markers of immune activation including PD-L1 expression and tumor infiltrating lymphocytes have demonstrated prognostic significance; however, identifying a predictive biomarker to aid in selecting those patients most likely to benefit from immunotherapy remains an unmet need.3,4 Genetic mutations are suggestive of DNA susceptibility to damage and the role they may play as a potential marker of immune response is unclear.5,6 This study explores genetic analysis and mutation rates among a diverse cohort of patients with TNBC to identify patterns associated with and without pCR. Methods: We evaluated 105 women diagnosed with Stage I-III TNBC and treated with combination neoadjuvant chemotherapy and immunotherapy at Ochsner Cancer Center between December 2019 through June 2022. Exclusion criteria included ER+, PR+, HER2+, or unknown receptor status, no pembrolizumab in the neoadjuvant setting, no definitive surgery following neoadjuvant treatment, absence of documented race and age less than 18 years of age. Data was collected utilizing Epic Slicer Dicer program, in addition to chart review. Genetic analysis was performed using a variety of DNA-based next generation sequencing analysis platforms. Results: 91 patients met inclusion criteria. 17 patients were found to have pathogenic mutations (BRCA1/2, POLE and ATM), 38 patients had variants of undetermined significance (VUS) and 36 patients had neither. Among patients with pathogenic genetic mutations, 81.25% had a pCR following neoadjuvant treatment compared to 58.33% of those with a VUS and 47.06% of those with no known mutation (p=0.07). Before adjusting for age and stage, patients with a pathogenic mutation were 73% more likely to achieve pCR than those with no known genetic mutations (crude RR: 1.73, 95% CI: 1.13-2.65). After adjusting for age and stage, the relationship was not statistically significant (aRR: 1.15, 95% CI: 0.78-1.34). Among the 47 Black patients, 5 were found to have a pathogenic mutation and 29 had a VUS. 11 of the 39 White patients were found to have a pathogenic mutation while only 6 had a VUS. Across all genetic mutation categories, Black patients experienced lower rates of pCR than White patients. White patients with a known pathogenic mutation had the highest rate of pCR at 90.91%, while Black patients with no identified mutation had the lowest rate of pCR at 38.46%. The generalizability of these results may be limited due to small sample size. Conclusion: Our results demonstrating higher rates of genetic variants among patients achieving pCR regardless of race highlight the importance of better understanding how these variants correlate with tumor mutational burden (TMB) and further, the role this may play in predicting immune-response. Larger studies are needed to assess TMB as a predictive biomarker in early-stage TNBC as this may provide opportunities to further individualize treatment and minimize toxicity among this group of patients. Additionally, given differences in the prevalence of pathogenic mutations and VUS among Black patients, better understanding the relationship between mutation status and immune response is imperative to optimize outcomes in this high-risk population. Table. Citation Format: Caitlin Taylor, Melanie Sheen, Rabia Cattie, Victoria Chung, Melyssa Bratton, Meredith Lakey, Erin Biggs. Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-10.

Abstract PO3-13-09: Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes

Abstract Background: Molecular residual disease (MRD) describes detectable circulating tumor DNA (ctDNA) after definitive surgery and is an expanding field in breast oncology. Multiple studies have demonstrated detectable MRD to be poorly prognostic, and clinical trials are now underway assessing the efficacy of therapeutic interception. However, most retrospective studies did not obtain baseline imaging at the time of MRD detection, such that the proportion of patients with detectable ctDNA and concurrent radiographically evident recurrent disease is not known. Furthermore, the role of serial ctDNA testing in the adjuvant setting remains unclear. Meanwhile, tumor-informed assays such as the SignateraTM platform are now covered by Medicare. To address these outstanding clinical questions, we aimed to determine the temporal dynamics of MRD detection in HR+/HER2- breast cancer, association with radiographic recurrence, and impact on clinical outcomes. Methods: Patients with HR+/HER2- breast cancer who underwent MRD testing either as part of a clinical trial or via an expanded access program were reviewed for MRD positivity and assessed alongside clinically annotated data. All patients completed surgical resection prior to MRD testing. Whole exome sequencing of primary tumor tissue and personalized ctDNA primers were designed for multiplex PCR targeting up to 16 single nucleotide variants for MRD testing via the SignateraTM platform. Clinical data was determined through focused chart review. Results: Among 185 patients with HR+/HER2- breast cancer who underwent MRD testing, 37 patients (20%) did not complete testing due to factors including tumor tissue not meeting pathology parameters, insufficient quantity of primary tissue, or tumor/normal discordance. 14 patients (8%) had detectable ctDNA (1, 5, and 8 patients had stage I, II, and III breast cancer, respectively). Among the 6 patients who did not have stage III disease, 3 had other high-risk features (Oncotype 40; grade 3 disease x2). Overall, 71% (n=10) of the +MRD population tested positive at the first test, while 29% (n=4) tested positive only on serial sampling. Median time from surgery to positive test was 3.5 years (range: 1 month – 10.2 years). Twelve patients (86%) were on adjuvant endocrine therapy at the time of detectable MRD. Among the 14 +MRD patients, 9 underwent staging scans shortly after positive MRD testing, and among these patients, 3 (33%) had radiographic evidence of asymptomatic metastatic recurrence (2 bone-only; 1 visceral); two of these pts had 1 MRD test, while the other had a negative test followed by a positive test 11 months later. The other 3 patients with radiographic recurrences had scans prompted only by clinical symptoms &amp;gt;6 months after +MRD. Among the 4 patients with serial data after first +MRD testing, none experienced subsequent ctDNA clearance. Serial testing occurred over a median of 11.5 months (range 1.1-21.7 months). With median follow up of 8.6 months, 43% (n=6) of patients with +MRD had distant disease recurrence. Conclusions: Personalized tumor-informed ctDNA testing identified patients with high risk of recurrence, including patients without classic high-risk clinical, pathologic, or genomic features, suggesting a complementary role of MRD testing for risk assessment. Serial monitoring was necessary to identify MRD in more than a quarter of patients. Furthermore, one-third of patients with +MRD disease had asymptomatic metastatic recurrence, highlighting the importance of staging scans in studies and clinical trials assessing therapeutic interception in the adjuvant setting. Citation Format: Arielle Medford, Elyssa Denault, Zanta Ephrem, Douglas Micalizzi, Yael Bar, Rachel Abelman, Amy Comander, Justine Knape, Minetta Liu, Angel Rodriguez, Steven Isakoff, Beverly Moy, Laura Spring, Aditya Bardia. Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-09.

Abstract PS14-05: Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC)

Abstract Background: In KEYNOTE-522 (NCT03036488), neoadjuvant (neoadj) pembrolizumab (pembro) + chemotherapy (chemo) followed by adjuvant (adj) pembro led to statistically significant and clinically meaningful improvements in the primary endpoints, pCR and EFS, vs neoadj placebo (pbo) + chemo followed by adj pbo in patients (pts) with newly diagnosed, high-risk, early TNBC. In the safety population at preplanned interim analysis 4 (IA4), treatment-related AEs in the combined phases (neoadj + adj) occurred in 98.9% of pts with pembro + chemo/pembro and 99.7% of pts with pbo + chemo/pbo; immune-mediated AEs of any grade occurred in 33.5% and 11.3% of pts, respectively. We report additional safety findings, beyond the already reported safety results, on immune-mediated AEs and management in the combined phases from IA4 of KEYNOTE-522. Methods: Eligible pts were randomized 2:1 to receive neoadj pembro 200 mg or pbo Q3W + paclitaxel-carboplatin for 4 cycles and then doxorubicin or epirubicin + cyclophosphamide for 4 cycles. After definitive surgery, pts received radiation therapy as indicated + adj pembro 200 mg or pbo Q3W for up to 9 cycles. Safety was assessed in all randomized pts who received ≥1 dose, underwent surgery, or both. AEs were monitored throughout the study and for 30 d post-treatment (90 d for serious AEs). Results: At IA4 (data cut-off: March 23, 2021), median treatment duration was 13.3 (range, 0-21.9) mo with pembro + chemo/pembro (n = 783) and 13.6 (range, 0-19.8) mo with pbo + chemo/pbo (n = 389). Of 341 pts with immune-mediated AEs and infusion reactions in the pembro + chemo/pembro arm (most events occurred in neoadj phase), 224 had grade 1-2 events and 117 had grade 3–5 events. The most common immune-mediated AEs with pembro + chemo/pembro were hypothyroidism (15.1%) and severe skin reactions (5.7%); infusion reactions occurred in 18.0% of pts (table). Of 118 pts with hypothyroidism, median time to onset was 105 d (range, 7–510 d) and 106 were treated with thyroid replacement, suggesting an endocrine abnormality and need for continued thyroid replacement. Of 45 pts with severe skin reactions, median time to onset was 64 d (range, 4–479 d) and 28 were treated with corticosteroids. Of 141 pts with infusion reactions, median time to onset was 16 d (range, 1–458 d) and 85 were treated with corticosteroids. Other immune-mediated AEs of interest with pembro + chemo/pembro were adrenal insufficiency (2.6%), pneumonitis (2.2%), and hypophysitis (1.9%); most of these events were grade 2–3. All 20 pts with adrenal insufficiency were treated with hormone replacement. Of 17 pts with pneumonitis, median time to onset was 167 d (range, 22-537 d) and 12 were treated with corticosteroids; median episode duration was 92 d. Of 15 pts with hypophysitis, 14 were treated with corticosteroids. Conclusion: In pts with newly diagnosed, high-risk, early TNBC, neoadj pembro + chemo followed by adj pembro had a manageable safety profile that was generally consistent with the known safety profiles of pembro and the chemo regimens. Most immune-mediated AEs and infusion reactions were grade 1-2, manageable with treatment interruption, corticosteroids, and/or hormone replacement therapy, and did not result in treatment discontinuation. Together with the efficacy findings, our results support neoadj pembro + chemo followed by adj pembro as a standard of care regimen for these pts. Table Citation Format: Javier Cortés, Rebecca Dent, Lajos Pusztai, Heather McArthur, Sherko Kuemmel, Carsten Denkert, Yeon Hee Park, Rina Hui, Masato Takahashi, Carlos Barrios, Yalin Zhu, Xiaoli Zhang, Wilbur Pan, Vassiliki Karantza, Joyce O'Shaughnessy, Peter Schmid. Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-05.