Jaffar M. Khan

Loss-of-function screen in rhabdomyosarcoma identifies CRKL-YES as a critical signal for tumor growth

To identify novel signaling pathways necessary for rhabdomyosarcoma (RMS) survival, we performed a loss-of-function screen using an inducible small hairpin RNA (shRNA) library in an alveolar and an embryonal RMS cell line. This screen identified CRKL expression as necessary for growth of alveolar RMS and embryonal RMS both in vitro and in vivo. We also found that CRKL was uniformly highly expressed in both RMS cell lines and tumor tissue. As CRKL is a member of the CRK adapter protein family that contains an SH2 and two SH3 domains and is involved in signal transduction from multiple tyrosine kinase receptors, we evaluated CRKL interaction with multiple tyrosine kinase receptor signaling pathways in RMS cells. While we saw no interaction of CRKL with IGFIR, MET or PI3KAKT/mTOR pathways, we determined that CRKL signaling was associated with SRC family kinase (SFK) signaling, specifically with YES kinase. Inhibition of SFK signaling with dasatinib or another SFK inhibitor, sarcatinib, suppressed RMS cell growth in vitro and in vivo. These data identify CRKL as a novel critical component of RMS growth. This study also demonstrates the use of functional screening to identify a potentially novel therapeutic target and treatment approach for these highly aggressive pediatric cancers.

Bedside Modification of Delivery System for Transcatheter Transseptal Mitral Replacement With POULEZ System and SAPIEN-3 Valve

Transcatheter mitral valve replacement (TMVR), using a balloon-expandable valve, recently received approval for degenerated surgical mitral prostheses. It is a relatively straightforward procedure because the prior surgical valve frame enforces coaxiality of the new transcatheter valve. By contrast

Predicting Left Ventricular Outflow Tract Obstruction Despite Anterior Mitral Leaflet Resection: The “Skirt NeoLVOT”

Transcatheter mitral valve replacement (TMVR) is a potential treatment for patients with severe mitral valve disease and high surgical risk ([Figures 1 to 6][1][⇓][1][⇓][2][⇓][3][⇓][4][⇓][5][⇓][6]). Pre-procedure computed tomography is mandatory to determine the risk of the following: 1

Transcatheter electrosurgery in bipolar or monopolar modes

Transcatheter electrosurgery has emerging value in a range of other new procedures that require traversing tissue (transcaval access, transcatheter Glenn Shunt) or slicing tissue (LAMPOON slicing of the mitral valve and BASILICA slicing of the aortic valve). This is the first report of bipolar radiofrequency wires used to cross lesions in humans, reported here in seven re‐entry CTO cases. The bipolar configuration may provide directionality to charge without need for wire alignment and advancement, but is theoretically disadvantageous for tissue “cutting” because of problems with charge concentration.

Transcatheter pledget-assisted suture tricuspid annuloplasty (PASTA) to create a double-orifice valve

Pledget‐assisted suture tricuspid valve annuloplasty (PASTA) is a novel technique using marketed equipment to deliver percutaneous trans‐annular sutures to create a double‐orifice tricuspid valve.

Adventures across the second dimension: Predicting left ventricular outflow tract obstruction following transcatheter mitral valve replacement

Left ventricular outflow tract (LVOT) obstruction is a common and fatal complication of transcatheter mitral valve replacement (TMVR) [1]. Predicting LVOT obstruction is important in selecting patients for TMVR, and for adjunctive procedures to prevent LVOT obstruction such as transcatheter laceration of the anterior mitral leaflet (LAMPOON) [2], trans-coronary alcohol septal ablation [3], and surgical mitral resection. The neoLVOT is the smallest cross-sectional area circumscribed by the transcatheter heart valve and the left ventricular septum, and contributes to postprocedure LVOT gradient. The neoLVOT can be predicted on multi-slice cardiac CT imaging by simulating a virtual transcatheter heart valve and measuring the projected minimal cross-sectional area [4]. The concept of predicted neoLVOT has not been validated in a sizeable patient cohort, a cut-off has not been established, and the tools for measurement have not been standardized. Therefore, the paper from Wang et al. [5], attempting to validate CT-predicted neoLVOT against post-TMVR LVOT pressure gradients, is important and timely. The paper describes 38 patients who underwent TMVR over four years, including 17 valve-in-valve, 12 valve-in-ring and 9 valve-inMAC cases. There were five catastrophic cases of LVOT obstruction, all in the valve-in-MAC arm. There were two cases with LVOT gradients marginally over 10 mmHg and therefore likely inconsequential, one each in valve-in-MAC and valve-in-valve. This work provides initial validation of one method of predicting neoLVOT from CT using semiautomated computer segmentation software. The authors found impressive correlation between predicted neoLVOT and postprocedure neoLVOT. A neoLVOT cut-off of 189 mm was sensitive and specific for a LVOT catheter gradient greater than 10 mmHg. There are some limitations worth noting. There were no patients with LVOT gradients between 15 mmHg and 70 mmHg, so the imputed threshold of 189 mm may not be accurate. The paper is unclear about what was the planned implantation depth, which is important because more ventricular implantation may cause smaller neoLVOT. More important, had they used a pressure threshold of 30 mmHg, a gradient considered important in hypertrophic cardiomyopathy, the resulting neoLVOT threshold would probably have been different. The report does not describe the relation between actual postprocedure neoLVOT and LVOT gradient. There was no correction for body mass or LV function. That said, the resulting threshold is close the “expert consensus” threshold (<200 mm) used to identify candidates at high risk of LVOT obstruction to participate in the LAMPOON study (NCT03015194), which will be reported in the second half of 2018. Readers should be aware of other limitations of computer-model based predictions of LVOT obstruction. Positioning the transcatheter heart valve, both virtually on CT and actually in the catheter laboratory, is variable. Depth of implantation and canting of the valve may be difficult to control during implantation, especially via the trans-septal approach and in small ventricles. A slightly more ventricular implant, with flaring, and canting toward the septum will result in a smaller neoLVOT. These assessments have been based on two-dimensional CT analysis of a single end-systolic phase. The next step would be 3dimensional neoLVOT volume assessment, because the neoLVOT is a complex geometric structure. Flow is maximal in early systole but neoLVOT is typically measured in end-systole when cross-sectional area is

Guidewire electrosurgery-assisted trans-septal puncture

Electrifying a coronary guidewire may be a simple escalation strategy when trans‐septal needle puncture is unsuccessful.

Summary of the 2018 Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) for transcatheter aortic valve replacement

Medicare coverage for transcatheter aortic valve replacement (TAVR) in the United States (US) is governed by the 2012 National Coverage Determination (NCD 20.32), which enshrined minimum numbers of TAVR, surgical aortic valve replacement, and percutaneous coronary intervention that centers must perform to begin or maintain TAVR programs. In July 2018, the Centers for Medicare and Medicaid Services (CMS) convened a meeting of the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) to review the evidence for setting minimum procedure volume requirements and to evaluate the impact of such requirements on access to care. In this paper, we summarize the MEDCAC panel deliberations, the evidence presented to the panel, and how the panel members voted. CMS is expected to publish a draft decision in March 2019 that may reshape the TAVR landscape in the US for years to come.

Unnatural milieu: Thrombus after transcatheter mitral valve replacement

What the article teaches Transcatheter heart valve thrombosis in the mitral position causes increased valve gradients, valve dysfunction, and symptoms, and may be associated with lack of therapeutic anticoagulation. How it will impact practice Anticoagulation with a vitamin K antagonist should be considered in all patients undergoing transcatheter mitral valve replacement. What new research/study would help answer the question posed Efficacy, optimal duration, and safety of anticoagulation therapy, balancing reduced thrombosis against increased bleeding risk, needs to be assessed in larger cohort studies and prospective trials.

TCT-642 Intentional Laceration of the Anterior Mitral valve leaflet to Prevent left ventricular Outflow tract ObstructioN (LAMPOON) during transcatheter mitral valve implantation: preclinical findings

Left ventricular outflow tract (LVOT) obstruction is a life-threatening complication of transcatheter mitral valve implantation (TMVR), caused by septal displacement of the anterior mitral leaflet. We propose a novel transcatheter transection of the anterior mitral leaflet. In vivo procedures in