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Introduction TNBC is overrepresented in Black women, and Black patients with TNBC have worse clinical outcomes compared to non-Black patients. This disparity likely results from racial differences in clinical, biological, and demographic features of TNBC and social determinants of health. Neoadjuvant chemoimmunotherapy is current standard of care for high-risk TNBC. However, Black patients have been poorly represented in immunotherapy TNBC trials, making it difficult to assess comparative efficacy of immunotherapy in Black patients. Methods We utilized two TNBC neoadjuvant trials to assess racial differences in the tumor immune microenvironment composition and evaluate impact of race on response to chemotherapy vs chemoimmunotherapy. NeoSTOP trial (NCT02413320) randomized 100 stage I-III TNBC patients to receive neoadjuvant carboplatin/paclitaxel + doxorubicin/cyclophosphamide (CbP+AC) or carboplatin/docetaxel (CbD). NeoPACT trial (NCT03639948) enrolled 120 patients with stage I-III TNBC who received neoadjuvant CbD + pembrolizumab (CbD+P). sTILs were centrally quantified, and RNA extracted from pretreatment tissue was subjected to next-generation sequencing. Relative leukocyte fractions were computed by CIBERSORTx. Factors were tested as predictors of pathologic complete response (pCR) using logistic regression analysis. Event-free survival (EFS) was estimated by the Kaplan-Meier method and compared between groups by log-rank test, followed by Cox regression analysis. Results The study population includes 197 patients with known race, sTILs, and gene expression data (84 patients from NeoSTOP, 113 from NeoPACT). 15/84 (18%) patients in NeoSTOP and 20/113 (18%) patients in NeoPACT self-reported Black race. There was no significant difference in age, T or N stage, or germline BRCA1/2 mutation status by race in either study. Black patients had significantly higher sTILs than non-Black patients (median 40% vs 15%, P=0.048) and were more likely to have ≥20% sTILs than non-Black patients (66% vs 44%, P=0.026). There was no significant difference in pCR by race in NeoSTOP (OR=0.60, 95% CI 0.19-1.84, P=0.37; pCR 47% for Black vs 59% for non-Black). In contrast, in NeoPACT, Black patients had a significantly higher pCR compared to non-Black patients (OR=3.27, 95% CI 1.01-10.64, P=0.049; pCR 79% for Black vs 53% for non-Black). In NeoSTOP, EFS was similar for Black and non-Black patients (3-year EFS 92% and 94%, respectively, HR=0.88, 95% CI 0.11-7.28, P=0.90). In NeoPACT, EFS was numerically higher in Black vs non-Black patients (3-year EFS 93% and 81%, respectively, HR=0.43, 95% CI 0.05-3.36, P=0.40); NeoPACT survival follow-up is ongoing at the time of this report. On CIBERSORTx analysis, Black patients had relative depletion of immunosuppressive pro-tumorigenic M2 macrophages (P=0.005) and CD4+ memory resting T cells (P=0.021) compared to non-Black patients. Conclusions Compared to non-Black patients, Black patients with TNBC are more likely to have immune-enriched tumors with lower relative abundance of immunosuppressive leukocytes. These findings suggest potential for higher relative magnitude of benefit from checkpoint inhibitor therapy in Black compared to non-Black patients. Supporting this biological hypothesis, we noted that Black and non-Black patients had equivalent rates of pCR with neoadjuvant chemotherapy; however, pCR rate among Black patients was significantly higher than in non-Black patients when treated with neoadjuvant chemoimmunotherapy. These findings should be confirmed in other studies and can optimize utilization of neoadjuvant chemoimmunotherapy. Our findings also underscore the importance of efforts to address disparity in access and use of immunotherapy in Black patients. Citation Format: Shane R. Stecklein, Rachel Yoder, Roberto Salgado, Joshua M. Staley, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Andrew K. Godwin, Qamar Khan, Priyanka Sharma. Black patients with triple negative breast cancer (TNBC) have enriched stromal tumor infiltrating lymphocytes (sTILs) and receive preferential benefit from neoadjuvant immunotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-06.

Introduction: The TNBC-DX risk score includes the 14-gene immunoglobulin (IGG) immune signature, tumor size, and nodal status and has shown prognostic value for survival in early-stage TNBC (B. Conte et al., ESMO Breast 2021). However, currently unknown are the value of the TNBC-DX risk score and IGG immune signature in 1) predicting pathologic complete response (pCR) following neoadjuvant therapy, and 2) predicting outcomes the context of neoadjuvant anti-PD1 treatment. Here, we assessed the IGG signature and the TNBC-DX risk score in patients with TNBC treated with neoadjuvant chemoimmunotherapy (NeoPACT; NCT03639948) and neoadjuvant chemotherapy without immunotherapy (NeoSTOP; NCT02413320). Methods: NeoPACT trial enrolled 120 patients with stage I-III TNBC who received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. NeoSTOP randomized 100 patients with stage I-III TNBC to two chemotherapy regimens; Arm B of NeoSTOP was included in this correlative study as the chemotherapy regimen was identical to NeoPACT. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. The 14-gene IGG immune signature and TNBC-DX risk score were calculated in silico as previously described. Evaluation of stromal tumor-infiltrating lymphocytes (sTILs) was performed as previously described. Markers were tested for prediction of pCR. Logistic regression analysis was used to examine the effect of multiple variables. Event-free survival (EFS) curves were assessed by the Kaplan-Meier method and groups compared by the log-rank test, followed by Cox regression analysis. Results: In this analysis, 112 patients were treated with chemoimmunotherapy on NeoPACT (node-positive = 38%, pCR rate = 58%). In the NeoPACT trial, the 14-gene IGG signature (as a continuous variable) was significantly associated with improved pCR (odds ratio [OR]=1.105, 95% CI 1.019-1.197, P=0.015 for every 0.2 increment). The pCR rates in IGG-high (≥ median) and IGG-low (< median) groups were 71% and 44%, respectively (OR=3.152, 95% CI 1.420-6.996, P=0.005). In terms of EFS, the 14-gene IGG signature was not prognostic (hazard ratio [HR]=0.507, 95% CI 0.148-1.735, p=0.269). In contrast, TNBC-DX risk score was strongly associated with EFS (HR=5.684, 95% CI 1.226-26.356, P=0.012), even when adjusted for sTILs and pCR status (HR=8.415, 95% CI 1.054-67.169, P=0.044). Estimated 3-year EFS rates in TNBC-DX high and low risk groups (above and below median) were 77% and 89%, respectively (P=0.012). In 43 NeoSTOP patients treated with neoadjuvant chemotherapy only (node-positive = 33%, pCR rate = 53%), no association of IGG signature with pCR or TNBC-DX score with EFS was observed. Finally, we observed a moderate correlation between IGG signature and sTILs in both trial datasets combined (r=0.642, P< 0.001). Conclusions: High expression of the 14-gene IGG immune signature in baseline pretreatment tumor samples in early-stage TNBC is significantly associated with pCR following pembrolizumab-based neoadjuvant chemotherapy. The combination of this signature with tumor burden as assessed by TNBC-DX is prognostic for long-term outcomes. Availability of biomarkers that can predict both pathological response and survival with chemoimmunotherapy can optimize this therapy, and evaluation of this biomarker in larger studies is warranted. Citation Format: Priyanka Sharma, Shane R. Stecklein, Rachel Yoder, Joshua M. Staley, Roberto Salgado, Laia Paré, Benedetta Conte, Fara Brasó-Maristany, Anne O’Dea, Lauren Nye, Manana Elia, Deepti Satelli, Gregory Crane, Richard McKittrick, Qamar Khan, Andrew K. Godwin, Aleix Prat. PD11-07 Association of TNBC-DX scores with outcomes in triple-negative breast cancer (TNBC) treated with neoadjuvant pembrolizumab and chemotherapy: a correlative analysis from NeoPACT and NeoSTOP trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-07.

NeoSTOP study schema

Purpose:Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens.Patients and Methods:Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS).Results:One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02).Conclusions:The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.

Neutrophils are an integral component of the innate immune system and key regulators of cell-mediated defense against bacterial and fungal pathogens. The potential of granulocyte transfusions has been investigated to temporarily replenish innate immune function to prevent and/or treat infections in patients with severe neutropenia or neutrophil dysfunction. However, evidence has been largely theoretical, experimental, and/or inconclusive. Clinical efficacy has yet to be confirmed by large-scale randomized controlled clinical trials. Performing such trials has been hampered by low granulocyte collection yield and poor patient accrual. We provide a practical summary of the current literature surrounding the practice of granulocyte transfusion.

Behavioural diversity may serve as a positive indicator of animal welfare that can be applied in long-term monitoring schemes in managed settings (eg zoos, laboratories, farms). Behavioural diversity is often higher when animals live in stimulating environments and experience positive events. Unfortunately, welfare researchers have not adopted consistent, standardised approaches to measuring behavioural diversity. The goal of this exploratory study was to utilise data from 41 adult chimpanzees (Pan troglodytes) housed across 16 zoological institutions to examine various models of Shannon's Diversity Index. Specifically, we investigated the impact of: combining versus splitting behaviours, including only positive behaviours, including human interaction, and considering recipient behaviours. We evaluate how the inclusion or exclusion of different behaviours impacts the relationship of behavioural diversity with: (i) concentrations of faecal glucocorticoid metabolites (GCM), a common indicator of adrenal activity; (ii) concentrations of immunoglobulin-A (IgA), an indicator of immune function and potential indicator of positive welfare; and (iii) stereotypic behaviour, a validated indicator of poor welfare. Most indices had significant negative relationships with faecal GCM. Animals that express a variety of behaviours from their species-typical repertoire have lower average faecal GCM concentrations and are likely experiencing better welfare. We did not find significant relationships between the behavioural diversity indices and IgA concentrations. Two indices were inversely associated with stereotypic behaviour. Our findings provide additional support for using Shannon's Diversity Index to calculate behavioural diversity as a robust, valid measure of positive welfare. However, future publications must justify the process for including or excluding behaviours from calculations.

Enhancing communicative competence of healthcare providers (HCPs) is a critical initiative for improving the healthcare experience of sexual and gender minority (SGM) cancer patients. This study presents the development, implementation, and preliminary efficacy of a new training curriculum for improving oncology HCPs’ skills in providing a safe and welcoming environment for SGM cancer patients (SGM Comskil training). Thirty-three (N= 33) oncology HCPs including nurses, nurse leaders, and nurse practitioners participated in a 4.25-hour SGM Comskil Training between July and August 2019. Overall, participants reported highly favorable evaluations of the training, with more than 80% of the participants reacting positively to 12 of the 15 evaluation items assessing engagement and reflectiveness for experiential role-plays with lesbian, gay, bisexual (LGB) and transgender standardized patients (SPs), respectively. Participants also demonstrated significant improvements in SGM healthcare knowledge, self-efficacy, beliefs toward LGB and transgender persons, and SGM-sensitive language use skills following the training. Encouraged by the feasibility of conducting this experiential training with busy cancer care HCPs and the initial favorable participant evaluation of the SGM Comskil training, results clearly indicate that this training can be rolled out into clinical settings to ensure its translational potential. The next steps should assess observable changes in communication skills and SGM-sensitive language skills with SGM patients and improvements in SGM patients’ healthcare experience.

Purpose: Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens. Patients and Methods: Patients aged ≥18 years with stage I–III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS). Results: One hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%–69%] in arm A and 54% (95% CI, 40%–68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02). Conclusions: The two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.

Objectives The first coronavirus disease 2019 (COVID-19) case in the United States was reported in Washington State. The pandemic caused drastic disruptions to medical institutions, including medical education. The Department of Laboratory Medicine at the University of Washington responded by rapidly implementing substantial changes to medical student clerkships. Methods In real time, we converted one ongoing case- and didactic-based course, LabM 685, to remote learning. Results Fifteen of 17 scheduled sessions proceeded as planned, including two sessions for student presentations. Two didactics were canceled as the functions of the teleconferencing platform were not sufficient to proceed. One grand rounds speaker canceled due to COVID-19 precautions. Elements of an immersive clinical laboratory clerkship, LabM 680, were repurposed to accommodate 40 medical students per class via remote learning, highlighting clinical laboratory activities that continue throughout the outbreak. A new remote clerkship, MedSci 585C, was developed incorporating distance learning and guided small-group sessions. This coincided with parallel efforts to make resident and fellow service work, conferences, and didactics available remotely to comply with social distancing. Conclusions The changes in medical education described reflect the dynamic interplay of current events affecting the world of clinical pathology. Throughout this, technology—while with some limitations—has provided the platform for innovative learning.

In the semiarid Southwestern USA, wildfires are commonly followed by runoff-generated debris flows because wildfires remove vegetation and ground cover, which reduces soil infiltration capacity and increases soil erodibility. At a study site in Southern California, we initially observed runoff-generated debris flows in the first year following fire. However, at the same site three years after the fire, the mass-wasting response to a long-duration rainstorm with high rainfall intensity peaks was shallow landsliding rather than runoff-generated debris flows. Moreover, the same storm caused landslides on unburned hillslopes as well as on slopes burned 5 years prior to the storm and areas burned by successive wildfires, 10 years and 3 years before the rainstorm. The landslide density was the highest on the hillslopes that had burned 3 years beforehand, and the hillslopes burned 5 years prior to the storm had low landslide densities, similar to unburned areas. We also found that reburning (i.e., two wildfires within the past 10 years) had little influence on landslide density. Our results indicate that landscape susceptibility to shallow landslides might return to that of unburned conditions after as little as 5 years of vegetation recovery. Moreover, most of the landslide activity was on steep, equatorial-facing slopes that receive higher solar radiation and had slower rates of vegetation regrowth, which further implicates vegetation as a controlling factor on post-fire landslide susceptibility. Finally, the total volume of sediment mobilized by the year 3 landslides was much smaller than the year 1 runoff-generated debris flows, and the landslides were orders of magnitude less mobile than the runoff-generated debris flows.

Laboratory tests are an integral part of the diagnosis and management of patients; however, these tests are far from perfect. Their imperfections can be due to patient health condition, specimen collection, and/or technological difficulty with performing the assay and/or interpretation. To be useful clinically, testing requires calculation of positive predictive values (PPVs) and negative predictive values (NPVs). During the current global pandemic of COVID-19 (coronavirus disease 2019), multiple assays with unknown clinical sensitivity and specificity have been rapidly developed to aid in the diagnosis of the disease. Due to a lack of surveillance testing, the prevalence of COVID-19 remains unknown. Hence, using this situation as an clinical example, the goal of this article is to clarify the key factors that influence the PPV and NPV yielded by diagnostic testing, By doing so, we hope to offer health-care providers information that will help them better understand the potential implications of utilizing these test results in clinical patient management.

This article surveys the linear temporal logic (LTL) literature and presents all the LTL theorems from the survey, plus many new ones, in a calculational deductive system. Calculational deductive systems, developed by Dijkstra and Scholten and extended by Gries and Schneider, are based on only four inference rules—Substitution, Leibniz, Equanimity, and Transitivity. Inference rules in the older Hilbert-style systems, notably modus ponens, appear as theorems in this calculational deductive system. This article extends the calculational deductive system of Gries and Schneider to LTL, using only the same four inference rules. Although space limitations preclude giving a proof of every theorem in this article, every theorem has been proved with calculational logic.

The human X and Y chromosomes evolved from a pair of autosomes approximately 180 million years ago. Despite their shared evolutionary origin, extensive genetic decay has resulted in the human Y chromosome losing 97% of its ancestral genes while gene content and order remain highly conserved on the X chromosome. Five ‘stratification’ events, most likely inversions, reduced the Y chromosome’s ability to recombine with the X chromosome across the majority of its length and subjected its genes to the erosive forces associated with reduced recombination. The remaining functional genes are ubiquitously expressed, functionally coherent, dosage-sensitive genes, or have evolved male-specific functionality. It is unknown, however, whether functional specialization is a degenerative phenomenon unique to sex chromosomes, or if it conveys a potential selective advantage aside from sexual antagonism. We examined the evolution of mammalian orthologs to determine if the selective forces that led to the degeneration of the Y chromosome are unique in the genome. The results of our study suggest these forces are not exclusive to the Y chromosome, and chromosomal degeneration may have occurred throughout our evolutionary history. The reduction of recombination could additionally result in rapid fixation through isolation of specialized functions resulting in a cost-benefit relationship during times of intense selective pressure.

Neutrophils are an integral component of the innate immune system and key regulators of cell-mediated defense against bacterial and fungal pathogens. The potential of granulocyte transfusions has been investigated to temporarily replenish innate immune function to prevent and/or treat infections in patients with severe neutropenia or neutrophil dysfunction. However, evidence has been largely theoretical, experimental, and/or inconclusive. Clinical efficacy has yet to be confirmed by large-scale randomized controlled clinical trials. Performing such trials has been hampered by low granulocyte collection yield and poor patient accrual. We provide a practical summary of the current literature surrounding the practice of granulocyte transfusion.

The safety and integrity of the blood supply is of paramount importance for delivering optimal medical care. Additionally, blood safety is of utmost importance to the United States public. Pathogen testing of donated blood products has been adapted and developed with the goal of eliminating the risk of transfusion-transmitted infectious disease. Currently, blood safety interventions are focused on excluding persons at risk for transfusion-transmissible infections from donating blood and on detecting the presence of transfusion-transmissible agents in donated blood. These interventions are intended to be complementary and function to isolate, and ideally, eliminate, the risk of exposure to known pathogenic agents by transfused blood components. We provide an overview of the strategies and techniques utilized to ensure the safety of the blood supply in the U.S.

Shortly before the beginning of the 2017–2018 winter rainy season, one of the largest fires in California (USA) history (Thomas fire) substantially increased the susceptibility of steep slopes in Santa Barbara and Ventura Counties to debris flows. On 9 January 2018, before the fire was fully contained, an intense burst of rain fell on the portion of the burn area above Montecito, California. The rainfall and associated runoff triggered a series of debris flows that mobilized ∼680,000 m3 of sediment (including boulders >6 m in diameter) at velocities up to 4 m/s down coalescing urbanized alluvial fans. The resulting destruction (including 23 fatalities, at least 167 injuries, and 408 damaged homes) underscores the need for improved understanding of debris-flow runout in the built environment, and the need for a comprehensive framework to assess the potential loss from debris flows following wildfire. We present observations of the inundation, debris-flow dynamics, and damage from the event. The data include field measurements of flow depth and deposit characteristics made within the first 12 days after the event (before ephemeral features of the deposits were lost to recovery operations); an inventory of building damage; estimates of flow velocity; information on flow timing; soil-hydrologic properties; and post-event imagery and lidar. Together, these data provide rare spatial and dynamic constraints for testing debris-flow runout models, which are needed for advancing post-fire debris-flow hazard assessments. Our analysis also outlines a framework for translating the results of these models into estimates of economic loss based on an adaptation of the U.S. Federal Emergency Management Agency’s Hazus model for tsunamis.

The American Society for Apheresis (ASFA) regularly publishes evidence-based guidelines, with the most recent edition in 2016, to assist the requesting and/or apheresis physicians with the evaluation of therapeutic apheresis. Given that therapeutic plasma exchange (TPE) is one of the most common therapeutic apheresis procedures, in this review, we discuss the rationale of TPE in both ASFA category I (first-line therapy) and II (second-line therapy) indications. However, the ASFA Guidelines usually provide little guidance with regard to scheduling/urgency issues. Given that mobilizing resources to perform apheresis after-hours may be expensive and challenging, we classified the urgency of the procedures in this review into 3 distinct groups: emergent (i.e. TPE should be started as soon as possible, preferably within 4–6 h upon request), urgent (i.e. TPE should be initiated within 24 h of request), and routine (i.e. TPE may be performed during regular working hours) based on our experiences in clinical practices. A brief discussion of the technical aspects as well as important considerations for an apheresis consultation is also provided.

Immune-mediated thrombotic thrombocytopenic purpura is characterized by severe thrombocytopenia and microangiopathic hemolytic anemia. It is primarily caused by immunoglobin G type autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. However, reliable markers predictive of patient outcomes are yet to be identified. Seventy-three unique patients with a confirmed diagnosis of immune-mediated thrombotic thrombocytopenic purpura between April 2006 and December 2017 were enrolled from the Univeristy of Alabama at Birmingham Medical Center. Clinical information, laboratory values, and a panel of special biomarkers were collected and/or determined. The results demonstrated that the biomarkers associated with endothelial injury (e.g., von Willebrand factor antigen and collagen-binding activity), acute inflammation (e.g., human neutrophil peptides 1-3 and histone/deoxyribonucleic acid complexes), and activation of the complement alternative pathway (e.g., factors Bb and iC3b) were all significantly increased in patients with acute immune-mediated thrombotic thrombocytopenic purpura compared to those in the healthy controls. Moreover, failure to normalize platelet counts within 7 days or failure to markedly reduce serum lactate dehydrogenase by day 5, low total serum protein or albumin, and high serum troponin levels were also predictive of mortality, as were the prolonged activated partial thromboplastin time, high fibrinogen, and elevated serum lactate dehydrogenase, Bb, and sC5b-9 on admission. These results may help to stratify patients for more intensive management. The findings may also provide a framework for future multicenter studies to identify valuable prognostic markers for immune-mediated thrombotic thrombocytopenic purpura.

513 Background: Addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in TNBC. Aim of this study was to assess the efficacy of the anthracycline free neoadjuvant regimen of pembrolizumab plus carboplatin plus docetaxel (Cb+D) in TNBC. Methods: In this multicenter study, eligible patients with stage I-III TNBC received carboplatin (AUC 6) + docetaxel (75 mg/m2) + pembrolizumab (200 mg) every 21 days x 6 cycles. The primary endpoint was pCR (no evidence of invasive tumor in breast and axilla). Secondary endpoints were residual cancer burden (RCB), EFS, toxicity, and immune response biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next generation sequencing. Samples were classified as DNA Damage Immune Response (DDIR) signature and DetermaIO signature positive/negative using predefined cutoffs. Evaluation of stromal tumor infiltrating lymphocytes (sTILs) was performed using standard criteria. Results: 117 patients were enrolled from September 2018 to January 2022. 18% were African American, 39% had node positive disease, 88% had stage II/III disease and 15% had ER/PR 1-10%. Pathologic response information is available for 105 patients. pCR and RCB 0+1 rates were 60% (95% CI 51%-70%) and 71% (95% CI 62%-80%), respectively. Treatment related adverse events led to discontinuation of any trial drug in 12% of patients. Immune adverse events were observed in 28% of patients (Grade ≥3=6%). 47% of patients had sTILs ≥30%, 48% were DetermaIO positive, and 61% DDIR positive. The table describes the impact of these biomarkers on pCR and RCB. The areas under the prediction curve (AUC) for pCR were 0.660, 0.709, and 0.719 for DDIR, sTILs, and DetermaIO respectively. At a median follow up of 21 months, 2-year EFS is 88% in all patients; 98% in pCR group and 82% in no pCR group. Conclusions: Neoadjuvant pembrolizumab plus Cb+D regimen yields pCR of 60% and 2-year EFS of 88% in the absence of adjuvant pembrolizumab. The regimen was well tolerated, and no new toxicity signals were noted. Immune enrichment identified by sTILs or DetermaIO signature was associated with high pCR rates approaching or exceeding 80%. PD-L1 and additional biomarker analyses are ongoing. Clinical trial information: NCT03639948. [Table: see text]