Multicenter evaluation of left ventricular assist device implantation with or without ECMO bridge in cardiogenic shock.

BACKGROUND: The efficacy of extracorporeal membrane oxygenation (ECMO) as a bridge to left ventricular assist device (LVAD) remains unclear, and recipients of the more contemporary HeartMate 3 (HM3) LVAD are not well represented in previous studies. We therefore undertook a multicenter, retrospective study of this population. METHODS AND RESULTS: INTERMACS 1 LVAD recipients from five U.S. centers were included. In-hospital and one-year outcomes were recorded. The primary outcome was the overall mortality hazard comparing ECMO versus non-ECMO patients by propensity-weighted survival analysis. Secondary outcomes included survival by LVAD type, as well as postoperative and one-year outcomes. One hundred and twenty-seven patients were included; 24 received ECMO as a bridge to LVAD. Mortality was higher in patients bridged with ECMO in the primary analysis (HR 3.22 [95%CI 1.06-9.77], p = 0.039). Right ventricular assist device was more common in the ECMO group (ECMO: 54.2% vs non-ECMO: 11.7%, p < 0.001). Ischemic stroke was higher at one year in the ECMO group (ECMO: 25.0% vs non-ECMO: 4.9%, p = 0.006). Among the study cohort, one-year mortality was lower in HM3 than in HeartMate II (HMII) or HeartWare HVAD (10.5% vs 46.9% vs 31.6%, respectively; p < 0.001) recipients. Pump thrombosis at one year was lower in HM3 than in HMII or HVAD (1.8% vs 16.1% vs 16.2%, respectively; p = 0.026) recipients. CONCLUSIONS: Higher mortality was observed with ECMO as a bridge to LVAD, likely due to higher acuity illness, yet acceptable one-year survival was seen compared with historical rates. The receipt of the HM3 was associated with improved survival compared with older generation devices.

Immune checkpoint inhibitors and pericardial disease: a systematic review.

INTRODUCTION: Despite the growing use of immune checkpoint inhibitors (ICI) in cancer treatment, data regarding ICI-associated pericardial disease are primarily derived from case reports and case series. ICI related pericardial disease can be difficult to diagnose and is associated with significant morbidity. We conducted a systematic review to further characterize the epidemiology, clinical presentation, and outcomes of this patient population. METHODS: A search of four databases resulted in 31 studies meeting inclusion criteria. Patients > 18 years old who presented with ICI mediated pericardial disease were included. Intervention was medical + surgical therapy and outcomes were development of cardiac tamponade, morbidity, and mortality. RESULTS: Thirty- eight patients across 31 cases were included. Patients were majority male (72%) with a median age of 63. Common symptoms included dyspnea (59%) and chest pain (32%), with 41% presenting with cardiac tamponade. Lung cancer (81%) was the most prevalent, and nivolumab (61%) and pembrolizumab (34%) were the most used ICIs. Pericardiocentesis was performed in 68% of patients, and 92% experienced symptom improvement upon ICI cessation. Overall mortality was 16%. DISCUSSION: This study provides the most comprehensive analysis of ICI-mediated pericardial disease to date. Patients affected were most commonly male with lung cancer treated with either Nivolumab or Pembrolizumab. Diagnosis may be challenging in the setting of occult presentation with normal EKG and physical exam as well as delayed onset from therapy initiation. ICI-associated pericardial disease demonstrates high morbidity and mortality, as evidenced by a majority of patients requiring pericardiocentesis.

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.