Citations

Background: Left bundle branch area pacing (LBBAP) has rapidly emerged as a promising modality of physiologic pacing and has demonstrated excellent lead stability. In this retrospective study, we evaluate whether this pacing modality can allow concomitant atrioventricular node (AVN) ablation and same-day dismissal. Methods: Twenty-four consecutive patients (female 63%, male 37%) with an average age of 78 ± 5 years were admitted for pacemaker (75%)/defibrillator (25%) implantations and concomitant AVN ablation. Device implantation with LBBAP was performed first, followed by concomitant AVN ablation through left axillary vein access to allow for quicker post-procedure ambulation. The patients were discharged on the same day after satisfactory post-ambulation device checks. Results: LBBAP was successful in 22 patients (92% in total, 20 patients had an LBBP and two patients had a likely LBBP), followed by AVN ablation from left axillary vein access (21/24, 88%). All patients had successful post-op chest x-rays, post-ambulation device checks, and were discharged on the same day. After a mean follow up of three months, no major complications occurred, such as LBBA lead dislodgement requiring a lead revision. The LBBA lead pacing parameters immediately after implantation vs. three-month follow up were a capture threshold of 0.8 ± 0.3 V@0.4 ms vs. 0.6 ± 0.3 V@0.4 ms, sensing 9.9 ± 3.9 mV vs. 10.4 ± 4.1 mV, and impedance of 710 ± 216 ohm vs. 544 ± 110 ohm. The QRS duration before and after AVN ablation was 117 ± 32 ms vs. 123 ± 14 ms. Mean LVEF before and three months after the implantation was 44 ± 14% vs. 46 ± 12%. Conclusion: LBBA pacing not only offers physiologic pacing, but also allows for a concomitant AVN ablation approach from the left axillary vein and safe same-day hospital dismissal.

Abstract Background Physiologic pacing through left bundle branch area pacing (LBBAP) has recently been shown to be a very promising alternative for cardiac resynchronization therapy (CRT) and to avoid pacing induced cardiomyopathy. However, it is not clear whether the position of LABBP lead may affect the clinical outcomes. Case Report We here report a case of likely LBBAP induced worsening heart failure and cardiomyopathy reversed by re‐positioning of the pacing lead towards a more annular position. A 70‐year‐old male with a previous history of non‐ischemic dilated cardiomyopathy (ejection fraction 40%) who developed intermittent complete heart block and required permanent ventricular pacing. LBBAP was performed with the lead positioned to a position relatively far away from the tricuspid annulus (3.7 cm), due to difficulty in fixating the lead deep into the septum at a more annular position. One month post procedure, the patient's heart failure symptoms worsened, and his EF decreased to 31% despite good heart failure management. He underwent CRT upgrade with successful revision of the originally implanted LBBAP lead to a more annular position, using a deflectable delivery sheath. This resulted in further narrowing of the paced QRS duration from 135 to 106 ms. Two months post procedure, his heart failure symptoms improved by one functional class, and EF improved to 41% by echocardiogram. Conclusions LBBAP may be harmful when the lead is placed too far away from the annulus and may cause paced induced cardiomyopathy.

AbstractBackgroundConventional cardiac resynchronization therapy (CRT) involves implantation of a coronary sinus pacing lead through a delivery sheath, which typically requires a large venous access through a safe sheath of 9 French or greater in size. In patients who have very limited access due to scar tissue from previous implants or critical venous stenosis/closure, such large caliber access may not be available.Methods and ResultsWe report a case of CRT procedure in an 84‐year‐old male with a previous history of ischemic dilated cardiomyopathy (ejection fraction 40%) who was dependent on right ventricular pacing with worsening heart failure symptoms. The patient was incidentally discovered to have chronic total closure (CTO) of the left subclavian vein during the procedure. Although the CTO was crossed by a wire and dilated, the venous access was limited to a 7 French sheath which rendered conventional CRT through coronary sinus lead implant impossible. However, using the left bundle branch area pacing (LBBAP) technique which requires a smaller venous access, we were able to successfully achieve CRT. Postprocedure, the patient's paced QRS duration narrowed from 198 to 130 ms. His heart failure symptoms improved, and ejection fraction increased to 45% one‐month after the procedure.ConclusionsIn patients with vascular access limited to a small caliber sheath not suitable for conventional CRT, LBBAP may help achieve procedural success and improve clinical outcome.

AbstractBackgroundThe feasibility of remote perioperative telemonitoring of patient‐generated physiologic health data and patient‐reported outcomes in a high risk complex general and urologic oncology surgery population is evaluated.MethodsComplex general surgical/urologic oncology patients wore a pedometer, completed ePROs (electronic patient‐reported outcome surveys) and record their vitals (weight, pulse, pulse oximetry, blood pressure, and temperature) via a telehealth app platform. Feasibility (% adherence) was assessed as the primary outcome measure.ResultsTwenty‐one patients with a median age 58 (32−82) years were included. The readmission rate was 33% and the incidence of ≥Grade 3a morbidity was 24%. Adherence to vital sign and ePRO measurements was 95% before surgery, 91% at discharge, and 82%, 68%, and 64% at postdischarge d2, 7, 14, and 30, respectively. There was significant worsening of mobility, self‐care and usual daily activity at postdischarge d2 compared to preoperative baseline (p < 0.05). Median daily preoperative steps taken by patients with <Grade 3a versus ≥Grade 3a postoperative morbidity was 6062 versus 4166 (p < 0.05). Of those interviewed, 87% (13/15) viewed vital sign devices as helpful in recovery.ConclusionsTelemonitoring is feasible in a general surgical and urologic oncology setting. Future studies will ascertain optimal patient selection, duration, and extent of perioperative monitoring.

Background: A patient with ischemic cardiomyopathy and left bundle branch block (LBBB) who did not respond to standard bi-ventricular pacing underwent attempted left bundle area (LBA) pacing to achieve better cardiac resynchronization (CRT). Methods: LBA pacing failed to correct the LBBB or narrow the QRS. However, simultaneous pacing through the coronary sinus (CS) and LBA pacing leads resulted in marked shortening of the QRS Results: The patient’s EF improved from 30% to 45% two months post procedure and heart failure symptoms improved by one functional class. Conclusions: Simultaneous LBA and CS pacing may improve clinical outcomes compared to either alone.

Abstract Our goal is to identify novel targeted therapies for Ewing sarcoma (ES). ES is a devastating malignancy that predominantly affects children and young adults. It is the second most common cancer of the bone, yet in contrast to many other malignancies, survival rates have not improved for decades. For patients with localized disease, no biomarkers exist to predict recurrence or response to chemotherapy. For those with metastatic disease, chemotherapy is largely ineffective, and 5-year survival rates have stagnated at approximately 20%. Thus, there is an urgent need to identify biomarkers that can predict recurrence and response to therapy, as well as identify novel targeted therapies to combat this lethal disease. USP6 is the key etiologic agent in several benign bone and soft tissue tumors (BSTTs), where its chromosomal translocation results in overexpression. USP6 encodes a deubiquitylating enzyme, and our prior studies identified the tyrosine kinase Jak1 as an essential substrate of USP6 during BSTT development. Jak1 levels are dramatically elevated in USP6-overexpressing cells, leading to phosphorylation and activation of STAT transcription factors. We recently discovered that USP6 is also highly expressed in multiple sarcomas, including ES. Since Jak1-STATs play a central in mediating response to interferon (IFN), we hypothesized that USP6 might cause dysregulated IFN signaling in ES. Microarray and RNA-sequencing analysis revealed that USP6 by itself induced an IFN-response gene signature, both in immortalized, patient-derived ES cells and in primary human ES tumors. USP6+ ES cells were found to be exquisitely sensitive to exogenous IFN compared to USP6- ES cells, with both prolonged and heightened STAT1 and STAT3 activation observed. Furthermore, IFN selectively induced apoptosis of USP6+ but not USP6- ES cells. Gene expression analysis confirmed that in USP6+ ES cells, IFN synergistically induced expression of numerous IFN-stimulated genes (ISGs), including the pro-apoptotic ligand TRAIL. CRISPR-mediated depletion of TRAIL completely abrogated IFN-induced death of USP6+ ES cells. In sum, these results identify USP6 as a potential novel biomarker that may predict sensitivity of ES to targeted IFN therapy. This abstract is also being presented as Poster B11. Citation Format: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou. Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR08.

AimsBiphenotypic sinonasal sarcoma (SNS) is a locally aggressive tumour that occurs in the sinonasal region. PAX3–MAML3 has recently been identified as a recurrent fusion gene event in this entity; however, a subset of tumours harbour alternative PAX3 rearrangement without the involvement of MAML3. In this study we sought to characterize the molecular profile of a large series of cases, with a special emphasis on tumours with alternative fusions.Methods and resultsForty‐four examples of SNS were screened by fluorescence in‐situ hybridization and reverse transcription polymerase chain reaction to better characterize its molecular profile and identify potential novel fusion genes. Twenty‐four were positive for PAX3–MAML3 (55%), 15 showed rearrangements of PAX3 without MAML3 involvement (34%), one showed rearrangement of MAML3 without PAX3 involvement, and four were negative for the involvement of either gene (9%). Among 15 cases with PAX3 involvement only, three were found to harbour PAX3–FOXO1. Two of these cases arose in the nasal cavities of female patients (aged 31 and 47 years), and one showed bilateral involvement of the nasal cavities of a 35‐year‐old male. A fourth case involved the skull base of a 47‐year‐old male, and was positive for PAX3–NCOA1. Patients with fusion‐negative tumours were slightly older.ConclusionMore than half of the SNSs in this series were positive for PAX3–MAML3. However, a subset of tumours may harbour alternative PAX3 fusion genes or show no involvement of PAX3. Except for a possible weak association between age and molecular profile, the overall morphological and immunophenotypic features of all cases seem to be similar. Because of the rarity of these tumours, the impact of the molecular profile on the clinical course of these tumours remains to be determined.

Abstract Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a critical effector pathway for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC) and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP6′s relevant substrates has been obscure. Here we report that the Jak1–STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1–STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression. Cancer Res; 76(18); 5337–47. ©2016 AACR.

Nodular fasciitis (NF) is a clonal self‐limited neoplastic proliferation characterized by rearrangements of the USP6 locus in most examples. To our knowledge well‐documented malignant behavior has never been previously observed in NF. In this report we present an unusual case of NF with classical histologic features that showed a protracted clinical course characterized by multiple recurrences and eventual metastatic behavior over a period of 10 years. Molecular analyses revealed the presence and amplification of the novel PPPR6‐USP6 gene fusion, which resulted in USP6 mRNA transcriptional upregulation. These findings further support the oncogenic role of the USP6 protease in mesenchymal neoplasia and expand the biologic potential of NF. © 2016 Wiley Periodicals, Inc.

Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage‐essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt‐domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal‐derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX‐responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI‐responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. J. Cell. Physiol. 229: 2049–2056, 2014. © 2014 Wiley Periodicals, Inc.