Citations

Introduction: As the US population ages and indications for cardiac device implantation expand, there is a concomitant increase in patients undergoing lead removal/extraction (LR/E).. We sought to examine trends in outcomes and complications associated with LR/E. Methods: We conducted a retrospective analysis using data from a large U.S. commercial insurance database (privately insured and Medicare Advantage patients) identifying all patients undergoing LR/E between 2004 and 2013 with at least one year continuous medical plan enrollment prior to LR/E (to identify baseline comorbidities). Using ICD9 codes and CPT codes, major complications (hemorrhage requiring transfusion, vascular injury, pericardial complications, respiratory complications, cerebrovascular complications, and requirement for cardiac surgery) associated with LR/E and 30-day readmission rates were evaluated. Results: Among 42,878 patients who underwent LR/E (median age of 62 ( 54, 72) years, 70% male); approximately 1 in 40 experienced a major adverse event (2.4%) during the study period. Respiratory complications were the most common complication and 311 patients required cardiac surgery. 30-day readmission occurred in 11.1% of the total population. The most common reasons for readmission were heart failure exacerbation (18.7%) and device related complications (13.2%). Conclusion: The observed complication rates after LE/R in clinical practice are similar to those seen in recent clinical trials and have been relatively stable over the past 10 years.

Introduction: Patients with congenital heart disease (CHD) frequently require implantable cardiac devices. Device infection or malfunction may necessitate lead extraction. Extraction may be challenging due to long lead dwell times, anatomic abnormalities, and prior cardiac surgery. Little is known about extraction outcomes in the CHD population. Methods and Results: This retrospective study included 41 CHD patients and 82 age and gender matched controls that underwent lead extractions at two centers between 2001-2014. Only patients with leads older than 12 months were included. There were 79 leads in CHD patients and 150 in controls. Patients with CHD had a mean age of 39±17 years at extraction and on average their leads had been implanted for 81±84 months, this was not significantly different from the control group. Eighty eight percent of CHD patients had 1 or more cardiac surgeries as compared to only 22% of controls (p<0.001). The number of abandoned leads was also significantly different with 16 abandoned leads in the CHD group and 3 in controls (p<0.001). There was no statistically significant difference in extraction techniques between the groups. Complete extraction was achieved in 94% of patients in both groups. There were no CHD group complications. Control group complications included 3 SVC lacerations requiring sternotomy (one was fatal), and 1 ventricular perforations with tamponade requiring sternotomy. None of these patients had a history of cardiac surgery. The average age of leads in patients with a complication was 15.3 years which was older than the mean lead age seen in the CHD and control populations which was 6.75 and 4.6 years respectively. Conclusions: Lead extraction can be safely performed in patients with CHD. Despite anatomic abnormalities and previous cardiac surgery, the outcome of lead extraction in patients with CHD is comparable to controls. Prior cardiac surgery may lower the risk for extraction complications.

Introduction Multi-detector computed tomography (MDCT) is commonly used to identify pulmonary vein and left atrial anatomy prior to catheter ablation for atrial fibrillation (CAAF). Additionally, transesophageal echocardiography (TEE) is utilized to exclude left atrial/left atrial appendage thrombus (ICT). Whether MDCT alone can be used to exclude thrombus obviating the need for TEE is unknown. Methods All Pts referred for CAAF at Mayo Clinic between March 2004 and October 2006 were included. Clinical data (including CHADS score), 64 slice MDCT (non-ECG gated), TEE and intra-cardiac echocardiograph (ICE) were all performed and recorded. Image data was reviewed independently and blinded. The left atrial appendage (LAA) was defined as fully opacified or underfilled. An underfilled LAA was further interrogated using a region of interest over the filling defect and mean attenuation in Hounsfield Units (HU) were recorded. Results In total 400 Pts (mean age 56 ± 10 yrs; 76% male; EF 56 ± 10 % ) were included. 362 had no ICT by TEE nor filling defect by MDCT. 38 patients had an underfilled LAA in whom ICT was confirmed by TEE in 7. Sensitivity and specificity of MDCT for ICT was 100% and 92% respectively with a NPV of 100%. In 19 Pts with underfilled LAA’s, a mean LAA emptying velocity was found to be significantly reduced at 26 cm/s (6 – 61 cm/s). Those with a thrombus had a mean attenuation value below 70 HU. CHADS2 score was higher (2.0 versus 1.0) in Pts with LAA filling defect versus those without LAA filling defect. All Pts with confirmed thrombus were taking Warfarin. ICT was not seen in any Pts aged <52 yrs with CHADS score ≤1. Conclusions Sensitivity and specificity of MDCT for detection of LAA thrombus is high. LAA filling defects on MDCT correlate with low emptying velocities by TEE and low attenuation value in HU. These data would suggest that in the absence of MDCT filling defect, no further imaging is required. TEE should be utilized prior to CAAF to investigate MDCT filling defects. Multidetector Computed Tomography for the Detection of LAA Thrombus

Background : Lipid lowering therapy reduces mortality in patients with both ischemic and nonischemic cardiomyopathies and recently has been shown to decrease ICD shocks. Radiofrequency ablation (RFA) of recurrent VT in patients with an ICD also reduces shocks following intervention. It is unclear if statin therapy after VT RFA will further impact ICD shock rates. Methods : All patients from 1993–2005 who underwent a RFA procedure for recurrent VT at the Mayo Clinic with an ICD were included. Patient records were extracted for medical and procedural details and all ICD interrogations were reviewed for VT recurrence and therapies. Results: 63 patients (age 62±15 years) were followed over 3.9±3.6 years. Comorbid diseases included: coronary artery disease 37(58%, 34 prior myocardial infarction), ARVD/C 6(10%), nonischemic dilated cardiomyopathy 7(11%), moderate-severe valve disease 14(22%), hypertension 34(54%), and hyperlipidemia 35(56%). Ejection fraction was <0.35 in 34(56%). VT was induced in all patients (LV 55 (LVOT 1), RV 8 (RVOT 3) with multiple inducible VTs in 21(33%). VT was noninducible after RFA in 39(62%) patients. Dismissal medications included: statins 19(30%), beta blockers 40(66%), ACE/ARB 37(61%), diuretics 34(55%), and digoxin 23(37%). 5-year overall survival was 63%(95% CI 55–71). Age, diabetes, and renal insufficiency were associated with increased post ablation mortality, with no medication improving survival. 5-year survival free of ICD shocks was 31%(95% CI 24–38). Only statin therapy at discharge was associated with a decreased risk of ICD shocks [5(26%) versus 26(59%), p=0.020]. 7 additional patients received statins during follow-up, but not at discharge, of these 5(71%) had shocks. Conclusion : Statin use at discharge in patients with an ICD undergoing RFA for refractory VT significantly reduced recurrent ventricular arrhythmias and ICD shocks. Although the mechanism underlying the effects of statins on arrhythmic recurrence early after RFA requires further study, these data support aggressive therapy of the underlying substrate responsible for the VT.

Determining whether retrograde ventriculoatrial (VA) conduction is through the AV node (AVN) or an accessory pathway (AP) is critical for successful ablation of supraventricular tachycardia (SVT). With introduction of ventricular extrastimuli (VEST), retrograde right bundle branch block (retro RBBB) may occur and result in abrupt VH interval prolongation. We hypothesized when retrograde conduction is via an AP, VA interval change is less than VH interval change, whereas with retrograde AVN conduction, VA interval change is equal to or greater than VH interval change. We retrospectively reviewed the electrophysiology (EP) studies of patients undergoing ablation for AVNRT (n=55) or AVRT (n=50). The intracardiac electrograms were reviewed for induction of retro RBBB and change in VH and VA intervals during VEST. Parahisian pacing, decremental pacing, arrhythmia diagnosis and ablation outcomes were reviewed. All results were found to be reproducible between two independent observers with inter and intra observer reliability scores of 1.00 for identification of retro RBBB and greater than 0.85 for measurement of VH and VA intervals. Of 105 patients, 84 (80%) had evidence of induced retro RBBB during VEST. The average VH interval increase with induction of retro RBBB was 53.7 ms for patients with retrograde AP conduction and 54.4 ms for patients with AVN conduction (p=ns). The average VA interval increase with induction of retro RBBB was 13.6 ms with AP conduction and 70.1 ms with AVN conduction (P < 0.001). All patients with a greater VH than VA interval change had a final diagnosis of AVRT and those with a VH change less than VA change had AVNRT, yielding sensitivity and specificity of 100%. Using a cutoff of 50 ms for change in VA interval with onset of retro RBBB to diagnose AVNRT accurately identified AVNRT in 100% and AVRT in 95%. Induction of retro RBBB during VEST is common during EP studies for SVT. The relative change in the VH and VA intervals during retro RBBB accurately differentiates retrograde AVN from retrograde AP conduction with strong predictive accuracy. The use of retro RBBB based intervals is a useful technique facilitating the diagnosis of SVT in the EP laboratory, even in the absence of inducible tachycardia.

Background: Data regarding ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation following MVS is limited.) CA can be challenging given perivalvular substrate in the setting of mitral annuloplasty or prosthetic valves. Objective: To investigate the characteristics, safety, and outcomes of radiofrequency catheter ablation (CA) in patients with prior mitral valve surgery (MVS) and ventricular arrhythmias (VA). Methods: We identified consecutive patients with prior MVS who underwent CA for VT or PVC between January 2013- December 2018. We investigated the mechanism of arrhythmia, ablation approach, peri-operative complications, and outcomes. Results: In our cohort of 31 patients (77% men, mean age 62.3±10.8 years, left ventricular ejection fraction 39.2±13.9%) with prior MVS underwent CA (16 VT; 15 PVC). Access to the left ventricle was via transseptal approach in 17 patients, and a retrograde aortic approach was used in 13 patients. A combined transseptal and retrograde aortic approach was used in one patient, and a percutaneous epicardial approach was combined with trans-septal approach in 1patient. Heterogenous scar regions were present in 94% of VT patients and scar-related reentry was the dominant mechanism of VT. Clinical VA substrates involved the peri-mitral area in 6 patients with VT and 5 patients with PVC ablation. No procedure-related complications were reported. The overall recurrence-free rate at 1-year was 72.2%; 67% in the VT group and 78% in the PVC group. No arrhythmia-related death was documented on long-term follow-up. Conclusion: CA of VAs can be performed safely and effectively in patients with MVS

Abstract Background: CCR5 is a motility chemokine receptor implicated in tumor progression, whose activation and endocytosis may identify highly aggressive breast cancer (BC) subtypes likely to spread via the circulatory system. We first studied the activation and endocytosis of CCR5 in response to its ligand CCL5 (RANTES) in the model BC cell line MDA-MB231. We then screened two types of circulating tumor-associated cells (TACs) with known negative clinical outcomes, 1) circulating tumor cells (CTCs) and 2) cancer-associated macrophage-like (CAMLs) cells, to evaluate CCR5 upregulation in relation to disease progression in metastatic breast cancer (mBC). Methods: MB231 cells were used to visualize CCR5 activation within the cell's surface and intracellular space using an anti-CCR5 antibody after stimulation with RANTES. MB231 cells were stained with LAMP-1A to verify co-localization of CCR5 and RANTES to endosomes. Anonymized peripheral blood samples from (n=54) mBC patients were obtained in accordance with local IRB regulations and with informed consent. TACs were isolated using a low-flow CellSieve Microfiltration system and stained for Cytokeratin, CD45, and CCR5. CCR5 expression signal and localization were evaluated on all TACs via fluorescence microscopy. Results: CCR5 in MB231 cells appeared as ~1μm clusters known as “CCR5 pools”, which can be found on the cell's surface, within the cytoplasm, and in the nuclear space. CCR5 pools were upregulated in the presence of RANTES, which appears to relate to endocytosis and nuclear translocation. Within the TACs of mBCs, we found similar patterns of CCR5 pooling with 70% of patients (n=38) having CCR5+ CAMLs and 41% (n=22) having CCR5+ CTCs. It was found that higher numbers of CCR5 pools (≥10pools/cell) were correlated to a 2-fold increase in both CTCs and CAMLs in circulation. In the analysis of outcome data, it was determined that patients having ≥10 CCR5 pools on their CAMLs was a highly significant predictor of worse progression free survival (PFS) and overall survival (OS) (PFS HR=4.8, CI 95% 1.9-11.6, p=0.0015) and (OS HR=3.6, CI 95% 1.3-10.0, p=0.0331). In CTCs ≥10 pools/cell was not a significant predictor for worse PFS and OS. However, ≥5 CCR5 pools/cell significantly predicted for worse PFS but not OS (PFS HR=2.9, CI 95% 1.2-7.4, p=0.0418 and OS HR=3.3, CI 95% 1.1-9.3, p= 0.0539). Conclusion: We observed the activation and endocytosis of CCR5 pools using RANTES in MD-MB231 cell lines, and then demonstrated that this upregulated motility pathway appears to be conserved in migratory cells in mBC patients. Further, this upregulation of CCR5 appears to correlate with worse clinical outcomes, which may provide an explanation for how tumor-associated cells move into circulation and acquire metastatic potential. Citation Format: Ashvathi Raghavakaimal, Massimo Cristofanilli, Cha-Mei Tang, R. K. Alpaugh, Kirby P. Gardener, Saranya Chumsri, Daniel L. Adams. CCR5 upregulation in two subtypes of tumor associated circulating cells predict worse prognosis in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 589.

Abstract Background: Prostate cancers (PC) are intrinsically complex, with few prognostic biomarkers that differentiate aggressive and indolent disease. Cancer associated macrophage like cells (CAMLs) have shown to be significant independent prognostic indicators for poor survival in tumors if engorged to ≥50μm. However, no group has examined CAMLs' in PC. In this prospective pilot study, we analyzed PSA & ≥50μm CAML presence in (n=51) Stage I-III & (n=41) metastatic PC (mPC) prior to the start of new treatments to examine CAMLs' on outcomes. We found that ≥50μm CAML presence significantly predicted worse patient survival in mPC. These preliminary results suggest that CAMLs may serve as a cheap, non-invasive prognostic biomarker that predicts for worse outcomes in both local & mPC prior to new therapies. Methods: We prospectively recruited (n=92) PC patients in this pilot study to examine CAML's prognostic significance in non-metastatic (stages I-III) and mPC. Of (n=92) total patients, 15% (n=14/92) were stage I, 32% (n=29/92) stage II, 9% (n=8/92) stage III, and 45% (n=41/92) Stage IV. Prior to the induction of new therapy or first line therapy for newly diagnosed patients, 7.5mL peripheral baseline (BL) blood was collected. Blood was filtered via CellSieveTM microfiltration, which excludes cells by size ≥7μm. In parallel, changes in PSA was monitored to compare prognostic significance against ≥50μm CAMLs. Wilcoxon univariate analysis was used to analyze ≥50μm CAMLs and PSA in progression free survival (PFS) and overall survival (OS). Results: CAML's were identified in 78.9% (n=71/90) of available BL samples, with two samples failing from clotting. Stage I-III patients had an average of ~3 CAMLs/7.5mL blood, whereas mPCs contained ~6 CAMLs/7.5mL. Average CAML size increased linearly with advancing stage of disease with stage I patients averaging 23μm, stage II 33μm, stage III 65μm, and stage IV 78μm. Of available BL samples, 41% (n=38/90) patients with ≥50μm CAMLs significantly predicted for worse PFS (HR=10.0, p&lt;0.001, 95%CI=0.07-0.31) and OS (HR=34.2, p&lt;0.001, 95%CI=0.03-0.21). Further, ≥50μm CAMLs significantly predicted for poorer survival in mPC with PFS (HR=9.4, p=0.028, 95%CI=0.18-0.84) and OS (HR=5.1, p=0.003, 95%CI=0.07-0.53), but only non-significantly trended in non-metastatic disease. Initial analysis of PSA found that high PSA at BL was a significant predictor for worse outcomes in patients, while changes in PSA was not a predictor. Conclusions: CAMLs have shown potential as a predictive non-invasive blood based biomarker across multiple solid malignancies, and here we compared this biomarker in PC. While preliminary, these data suggests that engorged CAML presence prior to the start of new treatment may be a statistically significant predictor of survival in both the local and metastatic setting, and a larger validation cohort should be established. Citation Format: Daniel J. Gironda, Raymond Bergan, R K. Alpaugh, Daniel C. Danila, Tuan L. Chuang, Brenda Y. Hurtado, Thai Ho, Cha-Mei Tang, Daniel L. Adams. Cancer associated macrophage like cells predict aggressive disease in local and metastatic prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 357.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P &lt; .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P &lt; .001). Long-term relapse was lower with FM (HR = 0.65, P &lt; .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in PIK3CA E542K, E545K, or H1047R were detected in 41.7% of tumors. PIK3CA mutation detected in the patient’s circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. PIK3CA mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of PIK3CA mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women’s cancer.