tbuckley/cabot-search huggingface dataset:
Sentinel lymph node as a clue to the primary site of cancer of unknown primary.
Authors: Yilin Shao, Xin Liu, Silong Hu, Yingjian Zhang, Wentao Li, Xiaoyan Zhou, Huijuan Yang, Liangping Zhou, Qifeng WANG, Yifeng Hou, Yong Chen, Yan-Li Wang, Yaohui Wang, Zhong-Wu Lu, Zhiguo Luo, Xi-Chun Hu
Journal: Journal of Clinical Oncology (2018)

e24015 Background: Sentinel lymph node is the first stop of lymphatic spreading of cancer with known primary. The lymph node metastasis of cancer of known origin can follow similar rules. We assumed that figuring out the lymph node metastasis pattern of cancer of unknown primary site (CUP) may provide some clues to find the primary site of CUP. Methods: We retrospectively analyzed CUP patients admitted in Fudan University Shanghai Cancer Center between 2006 and 2017. The inclusion criteria were CUP patients who had lymph node metastasis identified by PET-CT or biopsy and primary tumor site identified and pathologically confirmed later. The relationship between lymph node metastasis pattern and primary site were assessed. Results: We had 303 cases of CUP patients admitted in Fudan University Shanghai Cancer Center from 2006 to 2017, and 258 cases had lymph node metastases. Of them, 46 cases had primary site identified: including 5 cases of nasopharyngeal cancer (NPC), 14 cases of head and neck cancer (except NPC), 8 cases of lung cancer, 4 cases of esophageal cancer, 2 cases of breast cancer, 5 cases of gastrointestinal cancer, and 1 case for each cancer of scrotum, anal tube, bladder, ovary, prostate, pancreas, cervix and kidney. Among these 46 cases, there were 17 cases with one-directional sentinel lymph node involved: 5 cases of nasopharyngeal cancer, 7 cases of other head and neck cancer, 2 cases of lung cancer, 2 cases of gastrointestinal cancer, and 1 case of ovarian cancer. 12 cases had two-directional lymph node metastases: 5 cases of lung cancer, 1 case of esophageal cancer, 2 cases of breast cancer, and 1 case of cancer of scrotum, anal 1 case of tube cancer, 1 case of bladder cancer, 1 case of cervix cancer. Overall, the percentage of finding the primary site of cancer by sentinel lymph node metastasis was 63% (29/46) in all pathological-confirmed primaries. Conclusions: Lymph node metastasis pattern may help approximately two thirds of CUP patients with nodal metastasis identifying their primary sites.
Real-world treatment patterns in patients with Hodgkin lymphoma (HL) treated with brentuximab vedotin (BV) in the US.
Authors: Changxia Shao, Xiting Cao, Wei Zhou, Monika Kumar Raut, Jinan Liu, Alejandro Daniel Ricart, Arun Balakumaran, Matthew J. Monberg
Journal: Journal of Clinical Oncology (2016)

e19019 Background: BV was associated with a 75% ORR in a single-arm trial of patients with relapsed HL. Yet real-world BV utilization data is limited. This study aimed to describe BV utilization, adverse event (AE) profile, and therapy post-BV among HL patients treated with BV in US. Methods: This was a retrospective database analysis of the Truven Health MarketScan Commercial and Medicare Database. Patients were included if they initiated BV treatment for HL between Jan 1, 2012 and Jun 30, 2014, were ≥ 18 yrs, and had ≥ 6 mos continuous enrollment before and after the 1st BV dose (index date). If two or more drugs started within 30 days, they were considered as 1 regimen. End of a therapy was defined when a new treatment was introduced or a treatment gap > 60 days or end of follow-up, whichever occurred first. Results: Among 219 patients initiated BV, 88 patients were observed with transplant (SCT), 50 patients underwent transplant before BV initiation. On average, patients were observed 2.7 yrs before and 1.1 yrs after index date. Median duration of treatment (DOT) for BV was 2.1 mos and time to next treatment (TTNT) was 4.8 mos. Over 50% of patients received therapy after BV. No dominant regimen was observed for 1L post-BV with median DOT of 1.4 mos. Conclusions: A significant percentage of patients experienced AEs associated with BV and received treatment after BV. DOT and TTNT were short for BV and 1L post-BV, suggesting short duration of response. Findings underscore the unmet medical need for rrHL patients. Total (N = 219) SCT (N = 88) * % % Age, yrs Median (Range) 46 (18-87) 40 (19-70) BV # BV cycles Mean (Sd) 5.5 (4.5) 5.1 (3.9) Median 4.0 4.0 DOT, Mos Mean (Sd) 3.0 (3.3) 2.6 (2.6) Median 2.1 2.1 TTNT, Mos Mean (Sd) 6.7 (5.7) 5.5 (5.6) Median 4.8 3.7 Top AEs Nausea 74.4 77.3 Anemia 41.6 35.2 Dyspnea 29.7 22.7 Neutropenia 27.4 28.4 Fatigue 25.6 25.0 Pyrexia 24.7 26.1 Pneumonia 23.7 22.7 Peripheral neuropathy 21.5 21.6 First line (1L) post-BV Therapy by modality Systemic therapy (ST) only 32.4 33.0 Radiation (RT) only 12.3 11.4 SCT /+ST/+RT 11.0 27.3 ST+RT 2.7 3.4 No therapy / Other 41.5 25.0 DOT for 1L ST post-BV, Mos Mean (Sd) 2.4 (3.2) 2.1 (2.6) Median 1.4 1.6 *SCT occurred outside the observation period was not captured
P01.046 Complete radiological response under treatment with Tumor Treating Fields following subtotal resection in a series of three Glioblastoma patients
Authors: A Kessler, T Linsenmann, T Westermaier, W Wolber, C Hagemann, R Ernestus, M Löhr
Journal: Neuro-Oncology (2018)

After subtotal resection (STR), residual contrast-enhancing glioblastoma multiforme (GBM) rarely undergo complete regression following radiochemotherapy and adjuvant chemotherapy. Moreover, in comparison to gross total resection (GTR) overall survival (OS) and progression-free survival (PFS) is significantly decreased in GBM patients with STR. GBM therapy following resection consists of radio- and chemotherapy with Temozolomide (TMZ). In addition Tumor Treating Fields (TTFields), low intensity (1–3 V/cm), intermediate frequency (100–300 kHz) alternating electric fields, are applied during adjuvant chemotherapy. The addition of TTFields led to a significant increase in PFS, OS and long-term survival in the EF-14 phase III trial. Here, we report three patients with subtotally resected GBMs localized in eloquent areas. These patients received TTFields (200 kHz) in addition to TMZ after surgery and radiochemotherapy. All patients showed complete radiological response (CR) under TTFields therapy. A 54-year-old woman with primary IDH1/2-wildtype and O6-methylguanine-DNA methyltransferase promoter methylated GBM (IDH1/2 WT, MGMT+) received combined radiochemotherapy after STR. TTFields therapy was initiated in parallel to 6 cycles of adjuvant TMZ. CR was observed after 5 months of TTFields treatment and remained stable for 7 months before new tumor growth was detected. A 46-year-old woman with a primary GBM, IDH1/2 WT, MGMT+, sustained nuclear ATRX expression (ATRX+) received combined radiochemotherapy followed by 6 cycles of TMZ after STR. TTFields were initiated simultaneously to the first cycle of adjuvant TMZ and continued for 6 months. CR was seen after 4 months of TTFields treatment, for 16 month up to date no recurrent tumor growth occurred. A 44-year-old man developed a secondary GBM (IDH1 WT, MGMT+) while receiving radiochemotherapy according to the Stupp-protocol due to an anaplastic astrocytoma WHO°III (cycle 4 of TMZ). Concomitant to additional 6 cycles of TMZ, TTFields therapy was initiated 4 months after STR and was continued for 37 months. After 35 months of ongoing TTFields treatment as monotherapy CR is still stable. We report on three GBM patients with newly diagnosed and recurrent GBM who underwent STR, radiochemotherapy and were subsequently treated with temozolomide and TTFields at our institution. The reported patients showed complete radiological responses under TTFields treatment.
Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy.
Authors: Jae Hong Park, Isabelle Riviere, Xiuyan Wang, Brigitte Senechal, Yongzeng Wang, Elena Mead, Bianca Santomasso, Elizabeth Halton, Claudia Diamonte, Yvette Bernal, Daniel Li, Michel Sadelain, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2017)

7008 Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-ALL. However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL (NCT01044069) with a focus to identify those patients who optimally benefit from 19-28z CAR T cell therapy with durable long-term survival and reduced toxicities. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR following conditioning chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion; patients with &lt; 5% blasts were classified as minimal residual disease (MRD) cohort vs. patients ≥5% blasts as morphologic disease cohort. Response assessment occurred at 4 weeks. Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p = 0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 – 36.2) (p = 0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p = 0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p = 0.0326 and p = 0.0001, respectively). Conclusions: Despite comparable initial CR rates regardless of pre-treatment disease burden, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Clinical trial information: NCT01044069.
Do cyclin e levels correlate with recurrence in meningioma? Results from an observational study.
Authors: Guilherme Lepski, Breno Jose Alencar Pires Barbosa, Pedro Augustto de Santana Junior, Sueli Mieko Oba Shinjo, Paulo Henrique Pires de Aguiar, Isac de Castro, Manoel Jacobsen Teixeira, Suely Kazue Nagahashi Marie
Journal: Journal of Clinical Oncology (2016)

e23123 Background: Cell cycle checkpoints are critical for controlling cell proliferation. Tumors like colon, breast and gastric carcinomas appear to deregulate cyclin expression, especially cyclin E, which plays a major role in the G1-S transition of the cell cycle. Although meningiomas are usually benign tumors, 10-15% of patients will present an unfavorable course, with recurrence before 10 years, despite aggressive surgery. There is currently no consensus regarding the potential prognostic value of genes such as cyclin E in meningiomas. Methods: Between 2000 and 2007, we assigned 83 consecutive patients harboring suspected intracranial meningiomas at our institution to the present study. After histopathological confirmation, frozen tumor samples were used for RNA extraction, followed by reverse transcription. We used quantitative real-time PCR and Imuno-histochemistry to assess the relative expression levels of the genes Cyclin E, SKP2 and p27. In order to calculate relative gene expression, we compared the threshold cycles (Cts) of Cyclin E to those of housekeeping genes. We normalized reactions using the median expression of CCNE in benign meningiomas (grade I) and used the chi-square test and Kaplan-Meyer functions to analyze the data. Results were considered significant at p < 0.05. Results: Twenty-five cases were excluded due to lack of follow-up or unavailable tumor samples. Of the remaining 58 cases, 17 (29%) were men and 41 (71%) were women with a median age at diagnosis of 53 years (range 22 – 80). Of these, 19,6% were atypical. Recurrence was observed in 18 cases (33%), after a median follow-up of 66 months. Cyclin E levels higher than 53 x 10-5 were associated with a 62.5% increased probability of recurrence (p = 0.0017). Neither SKP2 nor p27 expression levels predicted recurrence in our sample. Conclusions: In accordance with the oncologic literature for other tumors, the present study suggests that Cyclin E is a potential molecular marker for meningioma recurrence. Overexpression of Cyclin E was associated with higher rates of recurrence, a finding of major relevance in the context of molecular neuro-oncology.
<i>ERBB2</i> mutation profiling with next-generation sequencing (NGS) in solid tumors.
Authors: Fei Ma, Min Zhang, Quchang Ouyang, Jun Zhao, Xiaorong Dong, Xinghao Ai, Bo Zhu, Lingjun Zhu, Wenjing Hu, Gen Lin, Xiaotong Zhang, Yanhong Gu, Qiang Liu, Qiong Zhao, Tiejun Yin, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e24264 Background: ERBB2 (HER2) is a member of the human epidermal growth factor receptor family. HER2 amplification or over-expression has been shown to play an important role in the development and treatment of breast cancer and gastric cancer. Recently HER2 mutations have been found in non-small-cell lung cancer (NSCLC). However, mutation profiling of HER2 and its therapeutic potential in other solid tumors have not been clearly demonstrated. Methods: We retrospectively reviewed gene test results of 6000 solid tumor samples in our institute. Tumor biopsy, ctDNA or pleural effusion samples were analyzed using hybridization capture-based NGS ER-seq method, which enables simultaneously assess single-nucleotide variants(SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) viriation at least 59 genes (range 59-1021 genes). Results: One hundred and forty seven cases with HER2 alterations were identified, including 53 breast cancer (BC), 62 lung cancer (LC), 10 colorectal cancer (CRC), 10 gastric cancer (GC), 6 hepatobiliary cancer (HBC), 4 cervical cancer (CC) and 2 urothelial cancer (UC) patients. HER2 amplification occurred in 41 BC, 11 LC, 7 CRC, 6 GC, 2 HBC and 2 CC. HER2 mutation occurred in 9 BC, 48 LC, 3 CRC, 2 GC, 4 HBC, 1 CC and 2 UC. Concurrent HER2 amplification and mutation were identified in 3 BC, 3 LC, 2 GC and 1 CC. There were 80 HER2 mutations of 14 types as listed in the table. Interestingly, the HER2 S310F mutation occurred in multiple tumors, while the G778_P780dup mutation and Y772_A775dup almost exclusively. Conclusions: HER2 amplification, mutations and coexist of them occurred in multiple solid tumors. Some of HER2 mutations were tumor-specific, indicating researches of anti-HER2 therapies may consider cancer types as well. HER2 mutation BC LC CRC GC HBC CC UC S310F 1 7 0 3 2 2 1 V659E/D 0 4 1 0 0 0 0 L755_T759del 1 0 0 0 0 0 0 L755P/S 2 1 0 1 0 0 1 I767M 0 1 0 0 0 0 0 D769N/Y 4 1 1 0 0 0 0 Y772_A775dup 1 22 0 0 0 0 0 A775_G776insSVMA 0 2 0 0 0 0 0 G776delinsAVGC/LV/VC 1 6 0 0 0 0 0 G776V 0 0 1 0 0 0 0 V777L 2 0 0 0 0 0 0 G778_P780dup 0 6 0 0 0 0 0 V842I 0 1 1 0 2 0 0 R869H 0 1 0 0 0 0 0 ALL 12 52 4 4 4 2 2
Phase 1 study of AG-881, an inhibitor of mutant IDH1/IDH2, in patients with advanced IDH-mutant solid tumors, including glioma.
Authors: Ingo K. Mellinghoff, Marta Penas-Prado, Katherine B. Peters, Timothy Francis Cloughesy, Howard A. Burris, Elizabeth A. Maher, Filip Janku, Gregory Michael Cote, Macarena Ines De La Fuente, Jennifer Clarke, Lori Steelman, Kha Le, Yanwei Zhang, Alison Sonderfan, Diana Hummel, Steven Schoenfeld, Katharine Yen, Shuchi Sumant Pandya, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2018)

2002 Background: Isocitrate dehydrogenase 1 and 2 mutations (mIDH1/2) occur in solid tumors including glioma, and result in production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting tumorigenesis. AG-881 is an oral, potent, brain-penetrant inhibitor of mIDH1/2 that reduces 2-HG by up to 98% in glioma models. Methods: Patients (pts) with recurrent/progressive mIDH1/2 glioma (G) and non-glioma (NG) solid tumors were eligible to receive AG-881 daily in continuous 28-day cycles. Dose escalation cohorts for G and NG solid tumors enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Blood and tumor samples were evaluated for pharmacokinetics (PK)/pharmacodynamics (PD). Dose-limiting toxicity (DLT) was defined as a Grade (Gr) ≥3 AG-881-related event in Cycle 1 or by sponsor designation. Results: As of 1Dec2017, 93 pts had received AG-881 (G: 52; NG: 41) and 20 remain on AG-881 (G: 19, NG: 1). Demographics: M/F = 40/53; median age = 51; median no. prior systemic therapies = 3 (range 1–7). Seven initial dose levels were tested: 25mg QD (n = 10); 50mg QD (n = 12); 100mg QD (n = 21); 200mg QD (n = 22); 200mg BID (n = 5); 300mg QD (n = 5) and 400mg QD (n = 6). To further assess safety and PK in the G cohort, a 10mg dose level was tested (n = 6) and 6 additional pts enrolled in the 50mg cohort. PK showed less than dose-proportional plasma exposure with a mean effective half-life of 71±54 hrs. Common adverse events (AEs) across all pts regardless of attribution: fatigue (38.7%), nausea (35.5%), ALT/AST increase (34.4% each). Elevated ALT/AST AEs were dose-dependent (n = 0 at 10mg, n = 7 at ≤50mg, n = 10 at 100mg, n = 20 at > 100mg). Five G pts experienced DLTs at 100mg and above: Gr ≥2 ALT/AST which resolved to Gr ≤1 with dose modification (n = 4) or discontinuation (n = 1). The MTD or RP2D were not reached by BLRM with EWOC. Conclusions: AG-881 was associated with a favorable safety profile at doses < 100mg in pts with glioma and non-glioma solid tumors. No ALT/AST AEs Gr > 2 were observed at 10mg and 50mg. These doses are being explored in an ongoing perioperative glioma study. Updated safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT02481154.
A systematic literature review of the clinical prognosis of HR+/HER2- advanced or metastatic breast cancer with and without PIK3CA mutation.
Authors: Elizabeth J Anderson, Lea Mollon, Joni L Dean, Alejandra Aguilar, Lisa E. Davis, Terri L Warholak, Ayal Aaron Aizer, Emma Platt, Aditya Bardia, Derek Tang
Journal: Journal of Clinical Oncology (2018)

e13037 Background: The predictive and prognostic value of PIK3CA mutation in HR+/HER2–metastatic breast cancer (mBC) is not known. This study aimed to assess clinical prognosis for patients with HR+/HER2–mBC with or without PIK3CA mutation. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers. English-language articles published 01/1993 to 12/2017 with patients with HR+/HER2– mBC treated with monotherapy or combination therapy and reporting efficacy and safety were included. Studies were summarized by PIK3CA mutation status, clinical outcomes, and mechanism of action (PI3Ki-based therapies vs. non-PI3Ki targeted therapies vs. endocrine monotherapies). Results: Of 558 full-text articles reviewed, 12 met inclusion criteria, encompassing 20 distinct study arms. Eight arms combined PI3Ki with antiestrogens (fulvestrant, n = 5; letrozole, n = 2; tamoxifen, n = 1); six arms investigated an endocrine monotherapy (fulvestrant, n = 4, letrozole, n = 1, exemestane, n = 1); four arms investigated a non-PI3Ki targeted therapy (mTOR inhibitors, n = 2, ribociclib, n = 1, palbociclib, n = 1). Across ten non-PI3Ki- based study arms that reported median PFS, nine arms showed a numerically lower median PFS in the PIK3CA mutant subgroup relative to the non-mutant subgroup (non-PI3Ki targeted therapies, 4/4; endocrine monotherapies 5/6). All four PI3Ki-based arms that reported median PFS demonstrated a numerical benefit of median PFS in PIK3CA mutant vs. non-mutant patients. Findings from other available outcomes were generally consistent. Conclusions: PIK3CA mutation may exhibit both prognostic and predictive value in HR+/HER2- mBC. PIK3CA mutant cohorts may be associated with worse clinical prognosis vs. wild-type when treated with non-PI3Ki- based therapies. However, PI3Ki-based therapy may yield oncologic benefit for such patients. As this study is qualitative in nature, future investigation using a quantitative approach is warranted.
Efficacy by consolidation administration site: Subgroup analysis of a phase III study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).
Authors: Jonathan E. Kolitz, Stephen Anthony Strickland, Jorge E. Cortes, Donna Hogge, Jeffrey E. Lancet, Stuart L. Goldberg, Karen C Chung, Robert Ryan, Michael Chiarella, Arthur Chin Louie, Robert K. Stuart, Bruno C. Medeiros
Journal: Journal of Clinical Oncology (2017)

7036 Background: The CPX-351 liposomal formulation delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D) preferentially to leukemia cells. CPX-351 has demonstrated significantly improved overall survival (OS) versus 7+3 in a randomized, open-label, phase III study in patients (pts) aged 60-75 years with newly diagnosed, high-risk AML. In contrast to 7+3, which includes C continuous infusion, CPX-351 is administered as a 90-minute infusion and has the potential to be given in the outpatient setting. The current analysis of the phase III trial assessed the setting of consolidation therapy. Methods: Pts were randomized 1:1 to 1-2 induction cycles of CPX-351 or 7+3; pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles (CPX-351: 65 u/m 2 [C 65 mg/m 2 + D 28.6 mg/m 2 ] on Days 1 and 3; 7+3: C 100 mg/m 2 /day x 5 days + D 60 mg/m 2 on Days 1 and 2). Site of administration was not protocol defined. Results: Few pts received induction as outpatient therapy (CPX-351 n = 3/153 and 7+3 n = 1/151 in each cycle). 49/153 CPX-351 pts and 32/151 7+3 pts received consolidation, with a substantial proportion of pts receiving CPX-351 as outpatients (consolidation 1: 51%; consolidation 2: 61%). CPX-351 consolidation was associated with substantial improvement in median OS versus 7+3 irrespective of inpatient/outpatient status (Table). Median OS was not diminished with CPX-351 administration in the outpatient versus inpatient setting (consolidation 1: 25.43 and 14.72, respectively; consolidation 2: 26.32 and not reached). Conclusions: Some pts can successfully receive CPX-351 consolidation as outpatients without diminished efficacy, potentially reducing hospitalizations associated with treatment administration. Clinical trial information: NCT01696084. [Table: see text]
TCT-273 Italian Multicenter Registry of Bare Metal Stent Use in Modern Percutaneous Coronary Intervention Era: a multicenter observational study.
Authors: Francesco Giannini, Matteo Pagnesi, Gianluca Campo, None michael donahue, Luca Angelo Ferri, Carlo Briguori, Giulio Stefanini, Raffaele Scardala, Gennaro Sardella, Salvatore De Rosa, Filippo Figini, Alberto Monello, Luigi Emilio Pastormerlo, Luca Testa, Annamaria Nicolino, Alfonso Ielasi, Alessandro Durante, Angelo Leone, Giovanni Ciccarelli, None martina briani, Bernhard Reimers, None claudio rapetto, Andrea Ceccacci, Ciro Indolfi, Imad Sheiban, Cataldo Palmieri, Francesco Bedogni, Maurizio Tespili, Azeem Latib, Antonio Colombo
Journal: Journal of the American College of Cardiology (2018)