Citations

Background: Long-term outcomes of lead management strategies of lead abandonment (LA) or transvenous lead extraction (TLE) during cardiac implantable electronic devices (CIED) procedures requiring lead addition or replacement remain unclear. Hypothesis: We hypothesized that there is no difference in long-term (10-year) outcomes of LA versus TLE during CIED procedures requiring lead addition. Methods: We performed a retrospective cohort study of a population residing in seven adjacent counties of southeastern Minnesota with follow-up at the Mayo Clinic and its health systems. Patients who underwent LA or TLE for sterile leads from January 1, 2000, to January 1, 2011, and had follow-up for at least 10-years or until their death were included. Outcomes were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system. Results: A total of 172 patients were included in the study with 153 patients who underwent LA and 19 who underwent TLE for sterile leads. In long-term follow-up, indications for subsequent lead extraction arose in 9.1% (n=14) of patients with initial LA and 5.3% (n=1) in patients with initial TLE, after an average of 7-years. Moreover, out of 14 patients, who required secondary extraction in the LA cohort, 28.6% did not proceed with the extraction. Of the remaining 10 patients, 60% had clinical success and 40% had a clinical failure with the extraction. Subsequent device upgrades or revisions were performed in 18.3% of patients in the LA group and 31.6% in the TLE group, with no significant differences in procedural challenges such as requiring balloon venoplasty or serial dilation (5.2% vs. 5.3%, P=1.0). There was no difference in 10-year survival probability among LA group and TLE group (P=0.64). Conclusion: Indications for subsequent extraction arose in 9.1% of patients with the initial LA approach for sterile leads after an average of 7.3 years and 28.6% did not proceed with the extraction. Of the patients who underwent the subsequent extraction, 60% had clinical success and 40% had a clinical failure. There was no difference in 10-year survival probability between patients with the initial LA approach or TLE approach.

Background: Recognition of the causes of early mortality after atrial fibrillation (AF) catheter ablation is essential for the improvement of patient safety. Objective: This study sought to determine the causes of early mortality (≤90-days) after AF ablation and to further understand the circumstances surrounding death after the procedure. Methods: We performed a retrospective analysis of AF ablation from January 1, 2013, to December 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a comprehensive chart review of the electronic health record from within the Mayo Clinic system and outside records when available. Results: A total of 6,723 patients were included in the study. The 30-day and 90-day all-cause mortality rates were 0.09% and 0.22%, respectively. Among all 90-day deaths, majority of the deaths (73.3%) did not have a direct relationship with the procedure. Sudden death was the most common cause of early death (20%), followed by peri-procedural stroke (13%), respiratory failure (13%), atrioesophageal fistula (13%), infection (7%), heart failure (7%), and traumatic brain injury (7%). The 90-day mortality rate directly due to AF ablation procedural complications was 0.06%. Most of the early deaths (93.3%) occurred after discharge from index hospitalization, among which 64.3% were readmitted before their death, 14% died at home, and 7% were discharged on comfort care and died in hospice. The main reason for readmission leading to death was respiratory failure (33%). Conclusion: Atrial fibrillation ablation procedure has a 90-day mortality of 0.22% and the most common cause of early mortality was sudden death. The majority (73.3%) of early mortality was not directly associated with a procedural complication, and the mortality rate due to complications associated with the AF ablation procedure was 0.06%.

Background: Recognition of the causes of early mortality after ventricular tachycardia (VT) ablation in patients with reduced left ventricular ejection fraction is an essential step toward improving post-procedural outcomes. Objective: This study sought to determine the causes of early mortality (≤30-days) after VT ablation in patients with reduced left ventricular ejection fraction and to understand further the circumstances surrounding death after the procedure. Methods: We performed a retrospective analysis of all patients undergoing VT ablation in patients with reduced left ventricular ejection fraction from January 1, 2013, to November 10, 2021, at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a detailed chart review of the electronic health record within the Mayo Clinic system and outside records. Results: A total of 503 patients (mean age 63 ± 13 years, 11.2% female) with EF <50% were included in the study. The 30-day all-cause mortality rate was 5% (n=25), and the mortality rate due to a procedural complication was 0.4%. Among all 30-day deaths, recurrent VT was the most common primary cause of death (44%). This was followed by decompensated heart failure (28%), procedure-related death (8%), cerebrovascular accident (CVA) (4%), and infection (4%). Most patients (91%) who died from VT had the VT recurrence within three days of the ablation. 76% of patients with early mortality had delayed referral for VT ablation, and 72% opted for comfort care before death. Conclusions: The overall early mortality (≤30-days) rate after catheter ablation of VT in patients with reduced left ventricular ejection fraction was 5%, but the death rate directly due to a procedural complication was only 0.4%. The most common cause of death was recurrent VT, followed by heart failure. Further research into ablation strategies is vital to improving the safety, efficacy, and durability of VT ablation.

Background: Recognition of the infectious characteristics among the sepsis-related early mortality after transvenous lead removal (TLR) is an essential step to improving patient outcomes. Objective: This study sought to understand the infectious characteristic and circumstances among the sepsis-related early mortality after TLR. Methods: We performed a retrospective analysis of all patients undergoing TLR from January 1, 2001, to January 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Patient details were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system and outside records when available. Results: A total of 2,319 patients were included in the study. The overall 30-day sepsis-related mortality rate was 1.25% (n=29). Among the sepsis-related deaths, 24 patients (83%) had systemic cardiac implantable electronic device (CIED) infection, and 4 patients (14%) initially had isolated pocket infection. The average time from admission to TLR was 11 days. MSSA was the most common organism (n=8, 28%), and this was followed by MRSA (n=4, 14%) and Candida (n=3, 10%). Twenty of these patients (69%) had vegetation on the echocardiogram: vegetation on lead only in 9 patients, vegetation on both valve and lead in 8 patients, and vegetation on valve only in 3 patients. Among valvular vegetations, 5 patients had tricuspid valve vegetations, 3 patients had aortic valve vegetations, 2 patients had mitral valve vegetations, and 1 patient had both mitral and aortic valve vegetation. The average size of vegetation was 1.3±0.8 x 1.1±0.6 cm. Conclusions: The 30-day sepsis-related mortality rate was 1.25%. Among the sepsis-related early deaths, MSSA was the most common organism, and more than two-thirds (69%) of the patients had vegetations on cardiac imaging. This highlights the importance of further research to improve the infection outcome in TLR patients.

Background: Recognition of the causes of early mortality after transvenous lead removal (TLR) is an essential step for the development of quality improvement programs. Objective: This study sought to determine the causes of early mortality after TLR and to further understand the circumstances surrounding death after TLR. Methods: We performed a retrospective analysis of all patients undergoing TLR from January 1, 2001, to January 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a detailed chart review of the electronic health record from within the Mayo Clinic system and outside records when available. The causes of death were further characterized based on whether it was related to the TLR procedure. Results: A total of 2,319 patients were included in the study. The overall 30-day all-cause mortality rate was 3%. Among all 30-day deaths, infection was the most common primary cause of death (42%). This was followed by decompensated heart failure (17%), procedure-related death (10%), sudden cardiac arrest (7%), and respiratory failure (6%). The 30-day mortality rate directly due to complications associated with the TLR procedure was 0.3% due to vascular tear and cardiac perforation. A third of deaths (33%) occurred after discharge from index hospitalization, among which 43% were readmitted before their death, 35% died at home or a nursing facility, and 22% were discharged on comfort care and died in hospice. The main reasons for readmission prior to death were sepsis and decompensated heart failure. Conclusions: The majority (90%) of 30-day mortality after TLR was not due to complications associated with TLR procedures. The primary causes were infection and decompensated heart failure. This highlights the importance of further research to reduce postoperative mortality from these factors, including deaths after hospital discharge.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

Abstract Background: Recently, it was described that macrophages and tumor cells can fuse to form tumor macrophage fusion cells (TMFs) which are detectable within primary tumors and patient’s (pts) circulation. However, there are multiple pathways and subsequent subtypes of TMFs, with limited data on the various TMF types, commonality in blood, and clinical relevance. Here we evaluated n=120 metastatic breast cancer (mBC) blood samples for CTCs & TMFs. We describe numerous types of TMFs with vastly different fusion phenotypes, including partial (i.e. some membrane interaction & both cells retaining their original phenotypes), homodimeric (i.e. both cells with fused membranes & sharing cytoplasm), cannibalistic (i.e. CTC within a CD14+ macrophage & cells retaining their individual phenotypes), binucleated (i.e. both cells completely merge & becoming one cell with dual expression phenotypes), and hyperploidy (i.e. multiple cells merge to form a large polyploid cell). As CTCs & TMFs are isolated in conjunction from a single blood sample, we evaluated both CTCs & all TMF subtypes to determine their prognostic and predictive values for aggressiveness of disease. Methods: We categorized and enumerated the 5 forms of TMFs from a prospective pilot study using n=120 mBC pts that were starting new lines of treatment. Whole peripheral blood (7.5mL) was procured, filtered and stained using cytokeratin & CD45/CD14 to identify CTCs & TMFs. We compared the presence of the various types of TMFs & CTCs to pt’s progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs), analyzed by censored univariate analysis based on RECIST v1.1 over 24 months. Results: CTCs were found in 39% (n=47/120), with partial fusion TMFs in 26% (n=31/120), homodimeric 2% (n=2/120), cannibalistic 0% (n=0/120), binucleated 2% (n=2/120), hyperploidy 93% (n=113/120). Presence of CTCs alone, binucleated, or hyperploidy TMFs were not prognostic for PFS (p=0.0988, p=0.4120, & p=0.7615 respectively), or OS (p=0.2015, p=0.0845, p=0.1121 respectively). However, TMFs with partial or homodimeric fusion were prognostic for worse PFS (HR=2.2, p=0.0063 and HR=6.0, p=0.0305, respectively) and for worse OS (HR=2.8, p=0.0037 and HR=8.8, p=0.0271, respectively). Furthermore, combining pts with any TMFs into one group, minus hyperploidy, was highly significant for worse PFS (HR=2.9, 95%CI 1.7-5.0, p=0.0002) and worse OS (HR=3.8, 95%CI 2.0-7.5, p=0.0002), though certain subtypes of hyperploidy were also indicative of worse outcomes. Conclusion: The study of TMFs is relativity limited and their existence is new in oncology. Here we detected and described TMFs in the blood of mBC pts while demonstrating an association with poor clinical outcomes. These data suggest TMF involvement in the pathogenic cascade of cancer and further understanding of their biology may be important in the study of tumorigenesis. Citation Format: Daniel L. Adams, R. Katherine Alpaugh, Rena G. Lapidus, Saranya Chumsri, Carolina Reduzzi, Kirby P. Gardner, Cha-Mei Tang, Giuseppe Del Priore, William V. Williams, Massimo Cristofanilli. Tumor macrophage fusion cells detected in the circulation of metastatic breast cancer patients is prognostic for rapid progression and death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2310.

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab and MEK inhibitor, binimetinib. Here we evaluated potential biomarkers in peripheral blood to predict response. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in phase I, and Simon’s two-stage Optimal design was used in phase II. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test and Cox regression model were used for analysis. Results: A total of 22 patients were enrolled, with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30), and CBR was 66.67% (95% CI: 29.93-92.51). There was no response observed in all 5 patients with liver metastases. Baseline mean CTC count was 1.3 cells, and CAML count was 8.9 cells/7.5 mL. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle were significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Baseline PD-L1 expression, early reduction in CAML count, size, and PD-L1 expression were significantly associated with subsequent responses, providing potential noninvasive biomarkers to predict response to this combination. Future larger clinical trials are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Daniel L. Adams, Kathleen S. Tenner, Cha-Mei Tang, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-aspitia, Edith A. Perez, Keith L. Knutson. Peripheral blood biomarkers in Phase II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5454.

3054 Background: Tumor Macrophage Fusion Cells (TMFCs) are hybrids fusions of tumor cells and macrophage/immune cells that have recently been documented in advanced solid tumors, such as metastatic Breast Cancer (mBC). Further, TMFCs are found in the blood of patients (pts) as a CD45+/CD14+ binucleated subtype of standard circulating tumor cells (CTCs), which are Cytokeratin+ (CK+) & CD45 negative, but distinct from highly hyperploidy cells known as cancer associated macrophage-like cells. However, no study has explored the clinical meaning of TMFCs in blood. To better elucidate the clinical meaning of TMFCs, we prospectively pooled 137 mBC pt samples prior to induction of new therapy, ie baseline (BL), and after therapy induction (FU). Both TMFCs or standard CTCs were identified and enumerated to analyze their prognostic value for progression-free survival (PFS) and overall survival (OS). Methods: In this prospective study, we collected 7.5 mL blood samples from n=137 mBC pts enrolled in prospective trials from multiple institutions before starting new treatment lines for newly progressive mBC. If possible, an optional FU sample was collected (n=73) after BL (median=4.9 weeks). TMFCs & CTCs were isolated using a CellSieve microfilter and differentiated by staining for CK, CD45, CD14, and DAPI. Cox proportional regression hazard ratios (HRs) with 95% Confidence Intervals (CI) for PFS & OS by univariate & multivariate analyses were based on RECIST v1.1, determined by local institutional pathologist over 24 months (M). Results: TMFCs were detected in 26.3% (n=36/137) at BL and associated with significantly worse PFS (HR=3.3, CI 1.9-5.7, p<0.001) & OS (HR=2.7, CI 1.4-5.1, p=0.005). TMFCs were also detected in 27.4% (n=20/73) at FU (n=73) and prognostic for PFS (HR=5.2, CI 2.3-11.9, p<0.001) & OS (HR=5.1, 1.8-14.2, p=0.004). Further, pts with increases in TMFCs between BL and FU had worse PFS (HR=4.3, CI 1.9-10.1, p=0.001) & OS (HR=4.5, CI 1.6-12.7, p=0.011). In contrast, pts with CTCs were found in 39.4% (n=54/137) at BL, which were prognostic for worse PFS (HR=2.0, CI 1.3-3.2, p=0.005) and not prognostic for OS (HR=1.7, CI 0.9-3.0, p=0.103). At FU, pts with CTCs were found in 38.4% (n=28/73), which were prognostic for worse PFS (HR=3.6, CI 1.8-7.3, p=0.001) & OS (HR=3.2, CI 1.3-8.0, p=0.021). Overall at BL, pts without CTCs or TMFCs had a 5.7 M mPFS & >24M mOS, CTCs alone had a 5.0 M mPFS & 20.3 M mOS, TMFCs had 2.0 M mPFS & 5.8 M mOS. At FU, pts without CTCs or TMFCs had a 5.8 M mPFS & 14.5 M mOS, CTCs alone had a 3.3 M mPFS & 14.6 M mOS, while TMFCs pts had a 1.7 M mPFS & 4.8 M mOS. Conclusions: TMFCs appear to represent a CTC subgroup with additional prognostic value to standard CTCs, that may correlate with significantly faster PFS and OS versus pts with CTCs alone, or without CTCs. Subtyping treatment regimens is ongoing to determine if the TMFC populations are responsive to specific therapy types in these mBC pts.

e14548 Background: Micronuclei (MN) are small, excised DNA fragments resulting from biological DNA repair mechanisms in response to internal chromosomal instability, such as those caused by genotoxic events (i.e. chemotherapy and radiation), and whose formation in tumor stromal cells in blood circulation is prognostic for worse clinical outcomes (Fenech 2020). Further, mutagenic events occurring during the formation of MN are associated with the development of cancer neoantigens, which are a major element in the programmed cell death ligand (PD-L1) pathway that influences response to immunotherapies. We hypothesized that MN can be detected in metastatic breast cancer (mBC) patients (pts) within circulating stromal cells (CStCs) that prognosticates for clinical outcomes and may associate with PD-L1 cell expression. Methods: We initiated a prospective pilot study using a compiled set of n=124 mBC samples, from multiple institutions, enrolled prior to starting new lines of treatment for progressive mBC. We enumerated MN formation found in CStCs from whole peripheral blood (7.5mL), filtered for CStCs, then stained for PD-L1 and DAPI. DAPI was used to identify MN, defined by small (<3 µm) DAPI+ circular formations within the cytoplasm, separate from primary nuclei. In conjunction, all cells were stained with PD-L1 with expression normalized to background and evaluated against MN by T-test analysis. MN presence was compared to all available clinical variables, including induction of PD-L1 immunotherapy. Pts’ progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were analyzed by censored univariate and multivariate analyses based on RECIST v1.1 over 24 months. Results: MN were identified in 56% (n=70/124) of CStCs and their presence was significantly prognostic for worse PFS (HR=2.4, CI= 1.53-3.76, p<0.001) & OS (HR= 1.89 CI=1.07-3.34, p=0.039) over 24 months. Overall, mPFS of pts with MN was 2.8 months and without MN was 12.1 months. The mOS of pts with MN was 12.7 months and without MN was 20.8 months. Additionally, MN positive CStCs had a significantly higher PD-L1 expression than MN negative CStCs (p<0.001), with 67% of MN positive pts (n=46/66) having high PD-L1 expression while 30% of MN positive pts (n=20/66) having low PD-L1. Further, evaluation of PD-L1 in CStCs showed a linear relationship (R=0.9806) between MN number and PD-L1 in cells, with 0 MN average=0.016, 1 MN=0.200, 2 MN=0.318, and ≥3 MN=0.400. Conclusions: These initial findings suggest that MN are detected in pts with advanced mBC and may identify pts with faster progression and worse survival outcomes. Further, the number of MN in CStCs appears to correlate with higher PD-L1 expression within cells. Follow up clinical information and subtyping studies are ongoing to also evaluate of the effect of MN positive CStCs on PD-L1 immunotherapies in these pts.