Citations

Abstract Introduction Cardiopulmonary exercise testing (CPET) has an established role in the clinical evaluation of exercise intolerance and in the risk stratification of patients with heart failure. There is limited data assessing its prognostic utility in the evaluation of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The predisposition of patients with ARVC for ventricular arrhythmias and sudden cardiac death has led to recommendations for exercise restrictions and limits our understanding of how the impairment in oxygen extraction and cardiac output impact disease progression and outcomes in these patients. Purpose We examined the association between CPET indices and event free survival (time to mortality or cardiac transplantation) in patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Methods Patients with definite ARVC based on 2010 task force criteria and genetically positive were enrolled into our institutional ARVC registry. 43 patients underwent CPET and have been included in our analyses. Indications for testing included: Evaluation of exercise-induced palpitations/arrhythmias or syncope (37%), pharmacotherapy optimization (28%), heart failure evaluation (19%), and ARVC management decisions (16%). CPET data (peak oxygen consumption (pVO2), respiratory exchange ratio (RER), and ventilatory efficiency (VE/VCO2) were assessed in patients at time of initial evaluation. Median follow-up time was 4.9 years (IQR 9 years). Results 126 patients were studied (age 43.7+ 15 yrs; 41% women; LVEF 57+ 11%; 15% with LVEF <50%) and 43 underwent CPET evaluation. 41 patients (95%) performed at near maximal effort (RER >1) and no fatal events were reported during testing. During the follow up period, the outcome (death or cardiac transplantation) occurred in 31 patients. On Kaplan Meier analysis, pVO2 ≤14 mL/kg/min was associated with worse outcomes (unadjusted p<0.001). Peak oxygen consumption (pVO2) ≤14 mL/kg/min and ventilatory efficiency (VE/VCO2) >34 were associated with shorter event free survival (HR 5.58, p=0.002 and HR 5.56 p=0.005, respectively). After adjusting for age, sex, and right ventricular function, the association between peak oxygen consumption (pVO2) and event free survival remained significant (p=0.02). Conclusions In patients with ARVC, peak oxygen consumption (pVO2) was a prognostic indicator of worse outcomes. Our findings suggest a potential role for pVO2 in disease surveillance and early assessment for advanced heart failure therapies. Figure 1. KM plot pVO2 & event free survival Funding Acknowledgement Type of funding source: Other. Main funding source(s): Mayo Clinic

Abstract Background: Atezolizumab (atezo) and bevacizumab (bev) combination therapy has demonstrated robust clinical activity in patients with unresectable HCC who have not received prior systemic therapy (Lee et al., APPLE 2019; Cheng et al., ESMO Asia 2019). In this exploratory analysis, we aimed to identify tumor-based molecular biomarkers that may be associated with clinical response or resistance to atezo + bev. We also investigated how VEGF blockade with bev could potentiate PD-L1 checkpoint inhibition with atezo in pts with advanced HCC. Methods: Archival tumor tissues or fresh biopsies taken prior to treatment were collected from HCC pts enrolled in the Phase 1b trial GO30140 (NCT02715531). Arm A (n = 104) was a single-arm evaluation of atezo + bev; Arm F (n = 119) was a randomized arm comparing atezo + bev with atezo. Whole-exome sequencing was carried out on these tumor tissues to determine tumor mutation burden (TMB). Gene expression in tumors was profiled by RNAseq analysis. The association between biomarker expression and clinical response (responders [R] vs. non-responders [NR]) or PFS was assessed by t-tests or Cox regression models, respectively. All p-values are descriptive. Results: In Arm A, 90/104 pts were biomarker evaluable. TMB was not associated with response to atezo + bev or PFS. In contrast, analysis of baseline tumor gene expression showed that pre-existing immunity appeared to be associated with clinical response and longer PFS, which included high expression of CD274 (PD-L1) (R vs. NR, p < 2.1 × 10−5; PFS: HR = 0.42 [0.25-0.72]), and T effector signature (GZMB, PRF1, CXCL9) (R vs. NR, p < 0.0004; PFS: HR = 0.46 [0.27-0.78]). Gene expression related to Notch pathway activation (i.e. high expression of HES1) appeared to be associated with lack of response to atezo + bev (p < 0.039) and shorter PFS (HR = 2.1 [1.3-3.6]). In Arm F, 91/119 pts were biomarker evaluable. High expression of VEGF receptor 2 (VEGFR2; HR = 0.36 [0.16-0.81]), Treg (HR = 0.35 [0.15-0.82]), myeloid inflammation (HR = 0.43 [0.19-0.95]), and TREM1/MDSC signatures (HR = 0.43 [0.19-0.94]) was associated with longer PFS in patients treated with atezo + bev than in those treated with atezo alone. Analysis of 12 serial biopsy pairs confirmed reduced levels of VEGFR2 and Treg signatures after atezo + bev treatment. Conclusion: We identified candidate biomarkers for predicting response to atezo + bev in HCC. Furthermore, the findings in Arm F are consistent with previous preclinical studies supporting a multi-faceted role of VEGF/VEGFR signaling in promoting immune suppression in addition to angiogenesis. Overall, the data presented here further support the mechanistic hypotheses on how anti-VEGF may combine with immune checkpoint blockade to increase its clinical benefit. As these results are exploratory, future study is needed to confirm these findings in a larger population. Citation Format: Andrew X. Zhu, Yinghui Guan, Alexander R. Abbas, Hartmut Koeppen, Shan Lu, Chih-Hung Hsu, Kyung-Hun Lee, Michael S. Lee, Aiwu Ruth He, Amit Mahipal, Beiying Ding, Jessica Spahn, Wendy Verret, Baek-Yeol Ryoo, Yulei Wang. Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT044.

Background: Preclinical studies and pilot patient studies have shown that chronic infarctions can be detected and characterized from cardiac magnetic resonance without gadolinium-based contrast agents using native-T1 maps at 3T. We aimed to investigate the diagnostic capacity of this approach for characterizing chronic myocardial infarctions (MIs) in a multi-center setting. Methods: Patients with a prior MI (n=105) were recruited at 3 different medical centers and were imaged with native-T1 mapping and late gadolinium enhancement (LGE) at 3T. Infarct location, size, and transmurality were determined from native-T1 maps and LGE. Sensitivity, specificity, receiver-operating characteristic metrics, and inter- and intraobserver variabilities were assessed relative to LGE. Results: Across all subjects, T1 of MI territory was 1621±110 ms, and remote territory was 1225±75 ms. Sensitivity, specificity, and area under curve for detecting MI location based on native-T1 mapping relative to LGE were 88%, 92%, and 0.93, respectively. Native-T1 maps were not different for measuring infarct size (native-T1 maps: 12.1±7.5%; LGE: 11.8±7.2%, P =0.82) and were in agreement with LGE ( R 2 =0.92, bias, 0.09±2.6%). Corresponding inter- and intraobserver assessments were also highly correlated (interobserver: R 2 =0.90, bias, 0.18±2.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%). Native T1 maps were not different for measuring MI transmurality (native-T1 maps: 49.1±15.8%; LGE: 47.2±19.0%, P =0.56) and showed agreement ( R 2 =0.71; bias, 1.32±10.2%). Corresponding inter- and intraobserver assessments were also in agreement (interobserver: R 2 =0.81, bias, 0.1±9.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%, respectively). While the overall accuracy for detecting MI with native-T1 maps at 3T was high, logistic regression analysis showed that MI location was a prominent confounder. Conclusions: Native-T1 mapping can be used to image chronic MI with high degree of accuracy, and as such, it is a viable alternative for scar imaging in patients with chronic MI who are contraindicated for LGE. Technical advancements may be needed to overcome the imaging confounders that currently limit native-T1 mapping from reaching equivalent detection levels as LGE.

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.

OBJECTIVELumbar decompression without arthrodesis remains a potential treatment option for cases of low-grade spondylolisthesis (i.e., Meyerding grade I). Minimally invasive surgery (MIS) techniques have recently been increasingly used because of their touted benefits including lower operating time, blood loss, and length of stay. Herein, the authors analyzed patients enrolled in a national surgical registry and compared the baseline characteristics and postoperative clinical and patient-reported outcomes (PROs) between patients undergoing open versus MIS lumbar decompression.METHODSThe authors queried the Quality Outcomes Database for patients with grade I lumbar degenerative spondylolisthesis undergoing a surgical intervention between July 2014 and June 2016. Among more than 200 participating sites, the 12 with the highest enrollment of patients into the lumbar spine module came together to initiate a focused project to assess the impact of fusion on PROs in patients undergoing surgery for grade I lumbar spondylolisthesis. For the current study, only patients in this cohort from the 12 highest-enrolling sites who underwent a decompression alone were evaluated and classified as open or MIS (tubular decompression). Outcomes of interest included PROs at 2 years; perioperative outcomes such as blood loss and complications; and postoperative outcomes such as length of stay, discharge disposition, and reoperations.RESULTSA total of 140 patients undergoing decompression were selected, of whom 71 (50.7%) underwent MIS and 69 (49.3%) underwent an open decompression. On univariate analysis, the authors observed no significant differences between the 2 groups in terms of PROs at 2-year follow-up, including back pain, leg pain, Oswestry Disability Index score, EQ-5D score, and patient satisfaction. On multivariable analysis, compared to MIS, open decompression was associated with higher satisfaction (OR 7.5, 95% CI 2.41–23.2, p = 0.0005). Patients undergoing MIS decompression had a significantly shorter length of stay compared to the open group (0.68 days [SD 1.18] vs 1.83 days [SD 1.618], p < 0.001).CONCLUSIONSIn this multiinstitutional prospective study, the authors found comparable PROs as well as clinical outcomes at 2 years between groups of patients undergoing open or MIS decompression for low-grade spondylolisthesis.

OBJECTIVE Return to work (RTW) and satisfaction are important outcome measures after surgery for degenerative spine disease. The authors queried the prospective Quality Outcomes Database (QOD) to determine if RTW correlated with patient satisfaction. METHODS The QOD was queried for patients undergoing surgery for degenerative lumbar spondylolisthesis. The primary outcome of interest was correlation between RTW and patient satisfaction, as measured by the North American Spine Society patient satisfaction index (NASS). Secondarily, data on satisfied patients were analyzed to see what patient factors correlated with RTW. RESULTS Of 608 total patients in the QOD spondylolisthesis data set, there were 292 patients for whom data were available on both satisfaction and RTW status. Of these, 249 (85.3%) were satisfied with surgery (NASS score 1–2), and 224 (76.7%) did RTW after surgery. Of the 68 patients who did not RTW after surgery, 49 (72.1%) were still satisfied with surgery. Of the 224 patients who did RTW, 24 (10.7%) were unsatisfied with surgery (NASS score 3–4). There were significantly more people who had an NASS score of 1 in the RTW group than in the non-RTW group (71.4% vs 42.6%, p < 0.05). Failure to RTW was associated with lower level of education, worse baseline back pain (measured with a numeric rating scale), and worse baseline disability (measured with the Oswestry Disability Index [ODI]). CONCLUSIONS There are a substantial number of patients who are satisfied with surgery even though they did not RTW. Patients who were satisfied with surgery and did not RTW typically had worse preoperative back pain and ODI and typically did not have a college education. While RTW remains an important measure after surgery, physicians should be mindful that patients who do not RTW may still be satisfied with their outcome.

Abstract BACKGROUND The factors driving the best outcomes following minimally invasive surgery (MIS) for grade 1 degenerative lumbar spondylolisthesis are not clearly elucidated. OBJECTIVE To investigate the factors that drive the best 24-mo patient-reported outcomes (PRO) following MIS surgery for grade 1 degenerative lumbar spondylolisthesis. METHODS A total of 259 patients from the Quality Outcomes Database lumbar spondylolisthesis module underwent single-level surgery for degenerative grade 1 lumbar spondylolisthesis with MIS techniques (188 fusions, 72.6%). Twenty-four-month follow-up PROs were collected and included the Oswestry disability index (ODI) change (ie, 24-mo minus baseline value), numeric rating scale (NRS) back pain change, NRS leg pain change, EuroQoL-5D (EQ-5D) questionnaire change, and North American Spine Society (NASS) satisfaction questionnaire. Multivariable models were constructed to identify predictors of PRO change. RESULTS The mean age was 64.2 ± 11.5 yr and consisted of 148 (57.1%) women and 111 (42.9%) men. In multivariable analyses, employment was associated with superior postoperative ODI change (β-7.8; 95% CI [−12.9 to −2.6]; P = .003), NRS back pain change (β −1.2; 95% CI [−2.1 to −0.4]; P = .004), EQ-5D change (β 0.1; 95% CI [0.01-0.1]; P = .03), and NASS satisfaction (OR = 3.7; 95% CI [1.7-8.3]; P < .001). Increasing age was associated with superior NRS leg pain change (β −0.1; 95% CI [−0.1 to −0.01]; P = .03) and NASS satisfaction (OR = 1.05; 95% CI [1.01-1.09]; P = .02). Fusion surgeries were associated with superior ODI change (β −6.7; 95% CI [−12.7 to −0.7]; P = .03), NRS back pain change (β −1.1; 95% CI [−2.1 to −0.2]; P = .02), and NASS satisfaction (OR = 3.6; 95% CI [1.6-8.3]; P = .002). CONCLUSION Preoperative employment and surgeries, including a fusion, were predictors of superior outcomes across the domains of disease-specific disability, back pain, leg pain, quality of life, and patient satisfaction. Increasing age was predictive of superior outcomes for leg pain improvement and satisfaction.

ABSTRACT BACKGROUND It remains unclear if minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is comparable to traditional, open TLIF because of the limitations of the prior small-sample-size, single-center studies reporting comparative effectiveness. OBJECTIVE To compare MI-TLIF to traditional, open TLIF for grade 1 degenerative lumbar spondylolisthesis in the largest study to date by sample size. METHODS We utilized the prospective Quality Outcomes Database registry and queried patients with grade 1 degenerative lumbar spondylolisthesis who underwent single-segment surgery with MI- or open TLIF methods. Outcomes were compared 24 mo postoperatively. RESULTS A total of 297 patients were included: 72 (24.2%) MI-TLIF and 225 (75.8%) open TLIF. MI-TLIF surgeries had lower mean body mass indexes (29.5 ± 5.1 vs 31.3 ± 7.0, P = .0497) and more worker's compensation cases (11.1% vs 1.3%, P < .001) but were otherwise similar. MI-TLIF had less blood loss (108.8 ± 85.6 vs 299.6 ± 242.2 mL, P < .001), longer operations (228.2 ± 111.5 vs 189.6 ± 66.5 min, P < .001), and a higher return-to-work (RTW) rate (100% vs 80%, P = .02). Both cohorts improved significantly from baseline for 24-mo Oswestry Disability Index (ODI), Numeric Rating Scale back pain (NRS-BP), NRS leg pain (NRS-LP), and Euro-Qol-5 dimension (EQ-5D) ( P > .001). In multivariable adjusted analyses, MI-TLIF was associated with lower ODI (β = −4.7; 95% CI = −9.3 to −0.04; P = .048), higher EQ-5D (β = 0.06; 95% CI = 0.01-0.11; P = .02), and higher satisfaction (odds ratio for North American Spine Society [NASS] 1/2 = 3.9; 95% CI = 1.4-14.3; P = .02). Though trends favoring MI-TLIF were evident for NRS-BP ( P = .06), NRS-LP ( P = .07), and reoperation rate ( P = .13), these results did not reach statistical significance. CONCLUSION For single-level grade 1 degenerative lumbar spondylolisthesis, MI-TLIF was associated with less disability, higher quality of life, and higher patient satisfaction compared with traditional, open TLIF. MI-TLIF was associated with higher rates of RTW, less blood loss, but longer operative times. Though we utilized multivariable adjusted analyses, these findings may be susceptible to selection bias.

OBJECTIVELoss to follow-up has been shown to bias outcomes assessment among studies utilizing clinical registries. Here, the authors analyzed patients enrolled in a national surgical registry and compared the baseline characteristics of patients captured with those lost to follow-up at 2 years.METHODSThe authors queried the Quality Outcomes Database for patients with grade I lumbar degenerative spondylolisthesis undergoing a surgical intervention between July 2014 and June 2016. Only those patients enrolled in a multisite study investigating the impact of fusion on clinical and patient-reported outcomes (PROs) among patients with grade I spondylolisthesis were evaluated.RESULTSOf the 608 patients enrolled in the study undergoing 1- or 2-level decompression (23.0%, n = 140) or 1-level fusion (77.0%, n = 468), 14.5% (n = 88) were lost to follow-up at 2 years. Patients who were lost to follow-up were more likely to be younger (59.6 ± 13.5 vs 62.6 ± 11.7 years, p = 0.031), be employed (unemployment rate: 53.3% [n = 277] for successful follow-up vs 40.9% [n = 36] for those lost to follow-up, p = 0.017), have anxiety (26.1% [n = 23] vs 16.3% [n = 85], p = 0.026), have higher back pain scores (7.4 ± 2.9 vs 6.6 ± 2.8, p = 0.010), have higher leg pain scores (7.4 ± 2.5 vs 6.4 ± 2.9, p = 0.003), have higher Oswestry Disability Index scores (50.8 ± 18.7 vs 46 ± 16.8, p = 0.018), and have lower EQ-5D scores (0.481 ± 0.2 vs 0.547 ± 0.2, p = 0.012) at baseline.CONCLUSIONSTo execute future, high-quality studies, it is important to identify patients undergoing surgery for spondylolisthesis who might be lost to follow-up. In a large, prospective registry, the authors found that those lost to follow-up were more likely to be younger, be employed, have anxiety disorder, and have worse PRO scores.