Publications by authors named "Paul Huang"

257 Publications

Effect of Prior Embolization on Outcomes After Stereotactic Radiosurgery for Pediatric Brain Arteriovenous Malformations: An International Multicenter Study.

Neurosurgery 2021 Sep;89(4):672-679

Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.

Background: Pediatric brain arteriovenous malformations (AVMs) are a significant cause of morbidity but the role of multimodal therapy in the treatment of these lesions is not well understood.

Objective: To compare the outcomes of stereotactic radiosurgery (SRS) with and without prior embolization for pediatric AVMs.

Methods: We retrospectively evaluated the International Radiosurgery Research Foundation pediatric AVM database. AVMs were categorized, based on use of pre-embolization (E + SRS) or lack thereof (SRS-only). Outcomes were compared in unadjusted and inverse probability weight (IPW)-adjusted models. Favorable outcome was defined as obliteration without post-SRS hemorrhage or permanent radiation-induced changes (RIC).

Results: The E + SRS and SRS-only cohorts comprised 91 and 448 patients, respectively. In unadjusted models, the SRS-only cohort had higher rates of obliteration (68.5% vs 43.3%,  < .001) and favorable outcome (61.2% vs 36.3%, P < .001) but a lower rate of symptomatic RIC (9.0% vs 16.7%, P = .031). The IPW-adjusted rates of every outcome were similar between the 2 cohorts. However, cumulative obliteration rates at 3, 5, 8, and 10 yr remained higher in the absence of prior embolization (46.3%, 64.6%, 72.6%, and 77.4% for SRS-only vs 24.4%, 37.2%, 44.1%, and 48.7% for E + SRS cohorts, respectively; SHR = 0.449 [0.238-0.846], P = .013).

Conclusion: Embolization appears to decrease cumulative obliteration rates after SRS for pediatric AVMs without affecting the risk of post-treatment hemorrhage or adverse radiation effects arguing against the routine use of pre-SRS embolization. While endovascular therapy can be considered for occlusion of high-risk angioarchitectural features prior to SRS, future studies are necessary to clarify its role.
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http://dx.doi.org/10.1093/neuros/nyab245DOI Listing
September 2021

The evolving management of epithelioid sarcoma.

Eur J Cancer Care (Engl) 2021 Jul 18. Epub 2021 Jul 18.

Sarcoma Unit, Royal Marsden Hospital, London, UK.

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http://dx.doi.org/10.1111/ecc.13489DOI Listing
July 2021

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas.

Cells 2021 Jun 17;10(6). Epub 2021 Jun 17.

The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.
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http://dx.doi.org/10.3390/cells10061533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235236PMC
June 2021

Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer.

Cells 2021 05 10;10(5). Epub 2021 May 10.

Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK.

Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer.
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http://dx.doi.org/10.3390/cells10051154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151052PMC
May 2021

Remodeling of the Posterior Cerebral Artery P1-Segment after Pipeline Flow Diverter Treatment of Posterior Communicating Artery Aneurysms.

Neurol Int 2021 May 7;13(2):195-201. Epub 2021 May 7.

Department of Radiology, Section of Interventional Neuroradiology, NYU Langone Medical Center, New York, NY 10016, USA.

Introduction: Flow diverters such as the pipeline embolization device (PED) cause hemodynamic changes of the treated vessel segment. In posterior communicating artery (PcomA), aneurysms' unique anatomic consideration have to be taken in account due to the connection between the anterior and posterior circulation. We hypothesize that in conjunction with PcomA remodeling, there will also be remodeling of the ipsilateral P1 segment of the posterior cerebral artery (PCA) after PED treatment for PcomA aneurysms.

Methods: We retrospectively collected radiological as well as clinical data of PcomA aneurysm patients treated with PED including PcomA and P1 vessel diameters before and after treatment as well as patient and aneurysm characteristics.

Results: Overall, 14 PcomA aneurysm patients were included for analysis and PED treatment was performed without complications in all patients. In 10 out of 14 patients (71%), a decrease in PcomA diameter was observed and there was a significant mean decrease of 0.78 mm in PcomA diameter on angiographic last follow-up (LFU) ( = 0.003). In the same patient population (10 out of 14 patients), there was meanwhile a significant mean increase of 0.43 mm in the ipsilateral P1 segment diameter observed ( = 0.015). These vessel remodeling effects were in direct correlation with aneurysm occlusion since all of these patients showed aneurysm occlusion at LFU while 29% showed only partial occlusion without vessel remodeling effects. A decrease in PcomA diameter was directly associated with aneurysm occlusion ( = 0.042). There were no neurologic complications on LFU.

Conclusion: In the treatment of PcomA aneurysms with PED, the P1 segment of the PCA increases in diameter while the PcomA diameter decreases. Our results suggest that this remodeling effect is associated with aneurysm occlusion and decrease of PcomA is hemodynamically compensated for by an increase in the ipsilateral P1 diameter.
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http://dx.doi.org/10.3390/neurolint13020020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162531PMC
May 2021

Gastrointestinal leiomyosarcoma demonstrate a predilection for distant recurrence and poor response to systemic treatments.

Eur J Surg Oncol 2021 Oct 4;47(10):2595-2601. Epub 2021 May 4.

The Royal Marsden Hospital NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK. Electronic address:

Background: Primary leiomyosarcoma (LMS) of the gastrointestinal (GI) tract is rare. Limited literature exists regarding the clinical characteristics and outcome for patients with localised and metastatic disease.

Methods: A retrospective chart review was performed for patients greater than 18 years of age diagnosed with GI LMS at The Royal Marsden Hospital between 1 January 2000-1 May 2020. Descriptive statistics were performed. Patients were censored at data cut-off date of 27 June 2020.

Results: Forty-six patients with a median age at diagnosis of 54 years (range 25-85) were identified. Fifteen percent (n = 7) of patients previously received abdominal radiation for an unrelated cancer. All patients with localised disease (n = 36) had resection with oncological margins. For patients who underwent potentially curative surgery, median recurrence-free survival (mRFS) was 13 months (0.4-183 months), and half of these patients (n = 18) developed recurrent disease post resection (distant n = 16, local n = 2). Median overall survival (mOS) was 27 months for patients with distant recurrence. Twenty-one percent (n = 10) of patients presented with synchronous metastatic disease and their mOS was 19 months. Median progression-free survival (mPFS) for patients treated with conventional chemotherapy ranged from 2.0 to 8.0 months.

Conclusion: The risk of recurrence is significant, and recurrence-free survival was short even with complete oncologic resection. The relationship of prior abdominal radiotherapy to the development of GI LMS warrants further investigation. Outcomes with systemic therapy for metastatic disease were poor and there is a need for the development of more effective systemic therapies.
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http://dx.doi.org/10.1016/j.ejso.2021.04.043DOI Listing
October 2021

Next-generation sequencing for the management of sarcomas with no known driver mutations.

Curr Opin Oncol 2021 07;33(4):315-322

Sarcoma Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.

Purpose Of Review: Next-generation sequencing (NGS) has enabled fast, high-throughput nucleotide sequencing and has begun to be implemented into clinical practice for genomic-guided precision medicine in various cancer types. This review will discuss recent evidence that highlights opportunities for NGS to improve outcomes in sarcomas that have complex genomic profiles with no known driver mutations.

Recent Findings: Global genomic signatures detectable by NGS including tumour mutational burden and microsatellite instability have potential as biomarkers for response to immunotherapy in certain sarcoma subtypes including angiosarcomas. Identification of hallmarks associated with 'BRCAness' and homologous recombination repair defects in leiomyosarcomas and osteosarcomas may predict sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Lastly, the use of NGS for evaluating cancer predisposition in sarcomas may be useful for early detection, screening and surveillance.

Summary: Currently, the implementation of NGS for every sarcoma patient is not practical or useful. However, adopting NGS as a complementary approach in sarcomas with complex genomics and those with limited treatment options has the potential to deliver precision medicine to a subgroup of patients, with novel therapies such as immune checkpoint and PARP inhibitors. Moving forward, molecular tumour boards incorporating multidisciplinary teams of pathologists, oncologists and genomic specialists to interpret NGS data will complement existing tools in diagnosis and treatment decision making in sarcoma patients.
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http://dx.doi.org/10.1097/CCO.0000000000000741DOI Listing
July 2021

Proteomic profiling of soft tissue sarcomas with SWATH mass spectrometry.

J Proteomics 2021 06 22;241:104236. Epub 2021 Apr 22.

Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK. Electronic address:

Soft tissue sarcomas (STS) are a group of rare and heterogeneous cancers. While large-scale genomic and epigenomic profiling of STS have been undertaken, proteomic analysis has thus far been limited. Here we utilise sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for proteomic profiling of formalin fixed paraffin embedded (FFPE) specimens from a cohort of STS patients (n = 36) across four histological subtypes (leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma). We quantified 2951 proteins across all cases and show that there is a significant enrichment of gene sets associated with smooth muscle contraction in leiomyosarcoma, RNA splicing regulation in synovial sarcoma and leukocyte activation in undifferentiated pleomorphic sarcoma. We further identified a subgroup of STS cases that have a distinct expression profile in a panel of proteins, with worse survival outcomes when compared to the rest of the cohort. Our study highlights the value of comprehensive proteomic characterisation as a means to identify histotype-specific STS profiles that describe key biological pathways of clinical and therapeutic relevance; as well as for discovering new prognostic biomarkers in this group of rare and difficult-to-treat diseases.
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http://dx.doi.org/10.1016/j.jprot.2021.104236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135130PMC
June 2021

Pharmacotherapy for liposarcoma: current and emerging synthetic treatments.

Future Oncol 2021 Jul 21;17(20):2659-2670. Epub 2021 Apr 21.

The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.

Liposarcomas are rare tumors arising from adipocytic tissue and accounting for approximately 15-20% of all soft tissue sarcomas. Liposarcoma can be further classified into histopathological subtypes with variable chemosensitivity according to subtype. Decisions regarding management should be made on an individual basis, but surgery for localized disease and systemic chemotherapy remain the mainstay of treatment. Currently, only doxorubicin and trabectedin have robust Phase III data to support their use in the management of advanced liposarcoma. However, in the subgroup analysis of a Phase III trial comparing eribulin with dacarbazine, there was a greater than 7-month improvement in median overall survival in those treated with eribulin. There are also promising results from emerging studies in novel and targeted agents for the treatment of liposarcoma.
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http://dx.doi.org/10.2217/fon-2020-1092DOI Listing
July 2021

Clinical management and outcomes of primary ovarian leiomyosarcoma - Experience from a sarcoma specialist unit.

Gynecol Oncol Rep 2021 May 2;36:100737. Epub 2021 Mar 2.

Sarcoma Unit, The Royal Marsden Hospital, 203 Fulham Rd, London SW3 6JJ, UK.

Ovarian sarcomas account for 1% of all ovarian malignancies and amongst these, primary ovarian leiomyosarcoma is the rarest subtype. Primary ovarian leiomyosarcoma has a very poor prognosis, with less than 20% of patients being alive at 5 years. Only a few cases have been published in the literature and there is very limited knowledge on the clinical behaviour and optimal management of these tumours. We have performed a retrospective analysis of a prospectively maintained database to identify all primary ovarian leiomyosarcoma diagnosed and treated at the Royal Marsden NHS Foundation Trust between 1998 and 2020. Sixteen patients were identified from our database and fifteen were eligible for the analysis. Twelve patients presented with localized disease and underwent initial surgery and three patients had metastatic disease at presentation. Recurrence-free survival post-surgery was 16 months. Eight patients received first-line chemotherapy and four patients received second-line chemotherapy. Two patients had indolent metastatic disease and benefited from local therapies only. The median overall survival in the metastatic setting in our cohort was 51 months, which is consistent with previously published cases. Primary ovarian leiomyosarcoma is an extremely rare malignancy with a poor prognosis. This study is the largest case series of primary ovarian leiomyosarcoma published to date, providing clinically important information regarding survival and metastatic rate as well as treatment outcomes in the metastatic setting.
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http://dx.doi.org/10.1016/j.gore.2021.100737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941038PMC
May 2021

Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer.

Pharmgenomics Pers Med 2021 9;14:301-317. Epub 2021 Mar 9.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Insertion mutations in exon 20 (Ex20ins) of the epidermal growth factor receptor () gene are the largest class of mutations in non-small cell lung cancer (NSCLC) for which there are currently no approved targeted therapies. NSCLC patients with these mutations do not respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. A number of early phase clinical trials are currently underway to evaluate the efficacy of a new generation of TKIs that are capable of binding to and blocking Ex20ins. Although these agents have shown some clinical activity, patient responses have been restricted by dose-limiting toxicity or rapid acquisition of resistance after a short response. Here we review the current understanding of the mechanisms of resistance to these compounds, which include on-target secondary mutations, compensatory bypass pathway activation and acquisition of an EMT phenotype. Taking lessons from conventional EGFR inhibitor therapy in NSCLC, we also consider other potential sources of resistance including the presence of drug-tolerant persister cells. We will discuss therapeutic strategies which have the potential to overcome different forms of drug resistance. We conclude by evaluating recent technological developments in drug discovery such as PROTACs as a means to better tackle TKI resistance in NSCLC harbouring Ex20ins mutations.
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http://dx.doi.org/10.2147/PGPM.S242045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955704PMC
March 2021

Assessing the quality of online information on glaucoma procedures.

Can J Ophthalmol 2021 Mar 13. Epub 2021 Mar 13.

Cumming School of Medicine, University of Calgary, Calgary, Alberta.

Objective: To investigate the quality of information related to glaucoma procedures found online using 2 different assessment tools.

Design: Cross-sectional survey of 100 web sites found via Google search engine.

Methods: The terms "peripheral iridotomy" and "trabeculectomy" along with synonymous keywords were inputted into Google's search engine. The first 50 functional websites for each term were assessed by 2 independent raters using the DISCERN instrument as well as a quality assessment tool by the Journal of the American Medical Association (JAMA). Statistical analysis included an evaluation of intra-rater reproducibility and interclass correlation between the 2 scales.

Main Outcome Measures: (i) Quality of web site content based on DISCERN and JAMA scores, (ii) quality of web site based on categorization of web site (iii), intra-rater reproducibility of each scale, and (iv) interclass correlation between the 2 rating scales.

Results: Only 22% of the web sites for peripheral iridotomy and 34% of the web sites for trabeculectomy met all the criteria for JAMA's quality assessment. The mean DISCERN scores for peripheral iridotomy and trabeculectomy were 44 and 43.7, respectively, indicating poor quality. For the DISCERN scale, level of agreement between raters for each question ranged from κ = 0.550 (95% confidence interval [CI] 0.700-1.026) to κ = 0.884 (95% CI 0.751-1.017). For the JAMA 4 scale, level of agreement for each question ranged from κ = 0.874 (95% CI 0.734-1.01) to κ = 1.00.

Conclusion: Our study indicates that information found online for two common ophthalmic procedures is of variable and poor quality. Thus, patients may be receiving misinformation online and better measures need to be implemented to avoid the dissemination of low-quality health information.
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http://dx.doi.org/10.1016/j.jcjo.2021.02.010DOI Listing
March 2021

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas.

NPJ Precis Oncol 2021 Mar 5;5(1):17. Epub 2021 Mar 5.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Soft tissue sarcomas (STS) are rare and heterogeneous tumours comprising over 80 different histological subtypes. Treatment options remain limited in advanced STS with high rates of recurrence following resection of localised disease. Prognostication in clinical practice relies predominantly on histological grading systems as well as sarcoma nomograms. Rapid developments in gene expression profiling technologies presented opportunities for applications in sarcoma. Molecular profiling of sarcomas has improved our understanding of the cancer biology of these rare cancers and identified potential novel therapeutic targets. In particular, transcriptomic signatures could play a role in risk classification in sarcoma to aid prognostication. Unlike other solid and haematological malignancies, transcriptomic signatures have not yet reached routine clinical use in sarcomas. Herein, we evaluate early developments in gene expression profiling in sarcomas that laid the foundations for transcriptomic signature development. We discuss the development and clinical evaluation of key transcriptomic biomarker signatures in sarcomas, including Complexity INdex in SARComas (CINSARC), Genomic Grade Index, and hypoxia-associated signatures. Prospective validation of these transcriptomic signatures is required, and prospective trials are in progress to evaluate reliability for clinical application. We anticipate that integration of these gene expression signatures alongside existing prognosticators and other Omics methodologies, including proteomics and DNA methylation analysis, could improve the identification of 'high-risk' patients who would benefit from more aggressive or selective treatment strategies. Moving forward, the incorporation of these transcriptomic prognostication signatures in clinical practice will undoubtedly advance precision medicine in the routine clinical management of sarcoma patients.
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http://dx.doi.org/10.1038/s41698-021-00157-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935908PMC
March 2021

Unmet Medical Needs and Future Perspectives for Leiomyosarcoma Patients-A Position Paper from the National LeioMyoSarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN).

Cancers (Basel) 2021 Feb 20;13(4). Epub 2021 Feb 20.

Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.

As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, making the treatment of this patient group challenging. Therefore, in a joint effort together with patient networks and organizations, namely Sarcoma Patients EuroNet (SPAEN), the international network of sarcoma patients organizations, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we aim to summarize state-of-the-art treatments for leiomyosarcoma patients in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This position paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the NLMSF and SPAEN.
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http://dx.doi.org/10.3390/cancers13040886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924026PMC
February 2021

Endothelial Nitric Oxide Synthase Knockdown in Human Stem Cells Impacts Mitochondrial Biogenesis and Adipogenesis: Live-Cell Real-Time Fluorescence Imaging.

J Clin Med 2021 Feb 7;10(4). Epub 2021 Feb 7.

Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.

We carried out live-cell real-time fluorescence imaging to follow the effects of genetic (siRNA) knockdown (KD) of endothelial nitric oxide synthase (eNOS) on mitochondrial biogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). We report here that eNOS KD in hMSCs blocks mitochondrial biogenesis and adipogenesis. The transfer of mitochondria from normal hMSCs to eNOS-deficient hMSCs restores adipogenesis. Furthermore, cell-free mitochondria purified from normal hMSCs also restores adipogenesis in eNOS-deficient cells. Thus, eNOS and NO signaling are essential for mitochondrial biogenesis, and mitochondrial activity is indispensable for adipogenesis in hMSC differentiation. We mapped the path and identified the mechanisms of mitochondrial transfer. We captured real-time images of differentiated mature adipocytes in mitosis and replication. These results reveal that human stem cell-differentiated fat cells are capable of replication. This new finding offers novel insights into our understanding of fat cell expansion and the development of obesity. Real-time imaging in live cells allows synchronized investigation of mitochondrial biogenesis and adipogenesis in stem cell differentiation without reducing living cells to nonliving samples for functional analysis. Live-cell real-time imaging can thus be a faithful and immediate tool for molecular diagnostic medicine. Furthermore, our results suggest that mitochondrial remodeling can be a useful approach in treating adiposity, diabetes, and abnormalities in energy metabolism and vascular signaling.
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http://dx.doi.org/10.3390/jcm10040631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914526PMC
February 2021

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Cancer Res 2021 02 28;81(4):847-859. Epub 2021 Jan 28.

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, England, United Kingdom.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model -like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611219PMC
February 2021

Future Directions in the Treatment of Osteosarcoma.

Cells 2021 01 15;10(1). Epub 2021 Jan 15.

Sarcoma Unit, Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK.

Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd-3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy.
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http://dx.doi.org/10.3390/cells10010172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829872PMC
January 2021

Efficacy of Gemcitabine-based Chemotherapy in Clear Cell Sarcoma of Soft Tissue.

Anticancer Res 2020 Dec;40(12):7003-7007

Sarcoma Unit, The Royal Marsden Hospital, London, U.K.

Background/aim: Clear cell sarcoma (CCS) is an aggressive sarcoma subtype, resistant to conventional anthracycline-based chemotherapy and radiation. The diagnosis is often challenging due to similarities with malignant melanoma.

Patients And Methods: We aimed to analyse the activity of gemcitabine-based chemotherapy in a cohort of patients with CCS treated at the Royal Marsden Hospital.

Results: Five patients with metastatic CCS received gemcitabine as first- or second-line systemic therapy. The median time-to-progression was 10 weeks. The median number of cycles of gemcitabine-based therapy was 3 (range=2-7 cycles). Median overall survival in our cohort was 66 months from the initial diagnosis but in the metastatic setting, the overall survival was reduced to 28 months.

Conclusion: Gemcitabine-based therapy has modest activity in CCS. There remains a significant unmet medical need for novel, effective therapies for this disease.
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http://dx.doi.org/10.21873/anticanres.14725DOI Listing
December 2020

Optimal Clinical Management and the Molecular Biology of Angiosarcomas.

Cancers (Basel) 2020 Nov 10;12(11). Epub 2020 Nov 10.

Division of Molecular Pathology, The Institute of Cancer Research, London SW3 6JB, UK.

Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis. Most angiosarcomas occur without obvious risk factors but secondary angiosarcoma could arise after radiotherapy or chronic lymphedema. Surgery remains the standard treatment for localized angiosarcoma but neoadjuvant systemic treatment may improve the curability. For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options. Anti-angiogenic agents have a substantial role but the failure of a randomized phase 3 trial of pazopanib with or without an anti-endoglin antibody brings a challenge to future trials in angiosarcomas. Immune checkpoint inhibitors as single agents or in combination with oncolytic virus may play an important role but the optimal duration remains to be investigated. We also report the current understanding of the molecular pathways involved in angiosarcoma pathogenesis including MYC amplification, activation of angiogenic pathways and different molecular alterations that are associated with angiosarcomas of different aetiology. The success of the patient-partnered Angiosarcoma Project (ASCProject) has provided not only detailed insights into the molecular features of angiosarcomas of different origins but also offers a template for future fruitful collaborations between patients, physicians, and researchers. Lastly, we provide our perspective of future developments in optimizing the clinical management of angiosarcomas.
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http://dx.doi.org/10.3390/cancers12113321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696056PMC
November 2020

Sirolimus for patients with progressive epithelioid hemangioendothelioma.

Cancer 2021 02 27;127(4):504-506. Epub 2020 Oct 27.

Sarcoma Unit, The Royal Marsden Hospital National Health Service Trust, London, United Kingdom.

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http://dx.doi.org/10.1002/cncr.33246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894141PMC
February 2021

Benefit of hospital admission for detecting serious adverse events among emergency department patients with syncope: a propensity-score-matched analysis of a multicentre prospective cohort.

CMAJ 2020 Oct;192(41):E1198-E1205

John A. Burns School of Medicine (Krishnan), University of Hawai'i at Mānoa, Honolulu, Hawaii; Ottawa Hospital Research Institute (Krishnan, Mukarram, Ghaedi, Nemnom, Calder, Thiruganasambandamoorthy), The Ottawa Hospital, Ottawa, Ont.; Departments of Emergency Medicine (Sivilotti) and Biomedical and Molecular Sciences (Sivilotti), Queen's University, Kingston, Ont.; Department of Family Medicine and Emergency Medicine (Le Sage, Mercier), Laval University-Centre hospitalier universitaire de Québec - Université Laval Research Centre, Québec, Que.; Division of Emergency Medicine (Yan), Western University, London, Ont.; Department of Emergency Medicine (Huang), University of British Columbia, Vancouver, BC; Department of Emergency Medicine (Hegdekar), University of Manitoba, Winnipeg, Man.; Department of Emergency Medicine (Calder, Thiruganasambandamoorthy) and School of Epidemiology and Public Health (Wells, Thiruganasambandamoorthy), University of Ottawa, Ottawa, Ont.; Departments of Emergency Medicine (McRae) and Community Health Sciences (McRae), University of Calgary, Calgary, Alta.; Department of Emergency Medicine (Rowe) and School of Public Health (Rowe), University of Alberta, Edmonton, Alta.

Background: The benefit of hospital admission after emergency department evaluation for syncope is unclear. We sought to determine the association between hospital admission and detection of serious adverse events, and whether this varied according to the Canadian Syncope Risk Score (CSRS).

Methods: We conducted a secondary analysis of a multicentre prospective cohort of patients assessed in the emergency department for syncope. We compared patients admitted to hospital and discharged patients, using propensity scores to match 1:1 for risk of a serious adverse event. The primary outcome was detection of a serious adverse event in hospital for admitted patients or within 30 days after emergency department disposition for discharged patients.

Results: We included 8183 patients, of whom 743 (9.1%) were admitted; 658/743 (88.6%) were matched. Admitted patients had higher odds of detection of a serious adverse event (odds ratio [OR] 5.0, 95% confidence interval [CI] 3.3-7.4), nonfatal arrhythmia (OR 5.1, 95% CI 2.9-8.8) and nonarrhythmic serious adverse event (OR 6.3, 95% CI 2.9-13.5). There were no significant differences between the 2 groups in death (OR 1.0, 95% CI 0.4-2.7) or detection of ventricular arrhythmia (OR 2.0, 95% CI 0.7-6.0). Differences between admitted and discharged patients in detection of serious adverse events were greater for those with a CSRS indicating medium to high risk ( = 0.04).

Interpretation: Patients with syncope were more likely to have serious adverse events identified within 30 days if they were admitted to hospital rather than discharged from the emergency department. However, the benefit of hospital admission is low for patients at low risk of a serious adverse event.
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http://dx.doi.org/10.1503/cmaj.191637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588246PMC
October 2020

Data-independent acquisition mass spectrometry (DIA-MS) for proteomic applications in oncology.

Mol Omics 2021 02 9;17(1):29-42. Epub 2020 Oct 9.

Division of Molecular Pathology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

Data-independent acquisition mass spectrometry (DIA-MS) is a next generation proteomic methodology that generates permanent digital proteome maps offering highly reproducible retrospective analysis of cellular and tissue specimens. The adoption of this technology has ushered a new wave of oncology studies across a wide range of applications including its use in molecular classification, oncogenic pathway analysis, drug and biomarker discovery and unravelling mechanisms of therapy response and resistance. In this review, we provide an overview of the experimental workflows commonly used in DIA-MS, including its current strengths and limitations versus conventional data-dependent acquisition mass spectrometry (DDA-MS). We further summarise a number of key studies to illustrate the power of this technology when applied to different facets of oncology. Finally we offer a perspective of the latest innovations in DIA-MS technology and machine learning-based algorithms necessary for driving the development of high-throughput, in-depth and reproducible proteomic assays that are compatible with clinical diagnostic workflows, which will ultimately enable the delivery of precision cancer medicine to achieve optimal patient outcomes.
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http://dx.doi.org/10.1039/d0mo00072hDOI Listing
February 2021

Large Subcortical Intracerebral Hemorrhage Because of Reversible Cerebral Vasoconstriction Syndrome: A Case Study.

Stroke 2020 11 1;51(11):e305-e309. Epub 2020 Sep 1.

Department of Neurology (A.A., S.K.R.), New York University School of Medicine.

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http://dx.doi.org/10.1161/STROKEAHA.120.029363DOI Listing
November 2020

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation.

Circ Genom Precis Med 2020 10 21;13(5):387-395. Epub 2020 Aug 21.

DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.

Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.

Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (, , , , , , , ). The top variants at known sarcomere genes () were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, and ) were associated with longer PWD but lower AF risk.

Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
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http://dx.doi.org/10.1161/CIRCGEN.119.002874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578098PMC
October 2020

Impact of COVID-19 pandemic on STEMI care: An expanded analysis from the United States.

Catheter Cardiovasc Interv 2021 08 7;98(2):217-222. Epub 2020 Aug 7.

The Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio.

Objective: To evaluate the impact of COVID-19 pandemic migitation measures on of ST-elevation myocardial infarction (STEMI) care.

Background: We previously reported a 38% decline in cardiac catheterization activations during the early phase of the COVID-19 pandemic mitigation measures. This study extends our early observations using a larger sample of STEMI programs representative of different US regions with the inclusion of more contemporary data.

Methods: Data from 18 hospitals or healthcare systems in the US from January 2019 to April 2020 were collecting including number activations for STEMI, the number of activations leading to angiography and primary percutaneous coronary intervention (PPCI), and average door to balloon (D2B) times. Two periods, January 2019-February 2020 and March-April 2020, were defined to represent periods before (BC) and after (AC) initiation of pandemic mitigation measures, respectively. A generalized estimating equations approach was used to estimate the change in response variables at AC from BC.

Results: Compared to BC, the AC period was characterized by a marked reduction in the number of activations for STEMI (29%, 95% CI:18-38, p < .001), number of activations leading to angiography (34%, 95% CI: 12-50, p = .005) and number of activations leading to PPCI (20%, 95% CI: 11-27, p < .001). A decline in STEMI activations drove the reductions in angiography and PPCI volumes. Relative to BC, the D2B times in the AC period increased on average by 20%, 95%CI (-0.2 to 44, p = .05).

Conclusions: The COVID-19 Pandemic has adversely affected many aspects of STEMI care, including timely access to the cardiac catheterization laboratory for PPCI.
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http://dx.doi.org/10.1002/ccd.29154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436427PMC
August 2021

Early obliteration of pediatric brain arteriovenous malformations after stereotactic radiosurgery: an international multicenter study.

J Neurosurg Pediatr 2020 Jun 26:1-8. Epub 2020 Jun 26.

1Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia.

Objective: Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.

Methods: The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.

Results: The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.

Conclusions: Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.
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http://dx.doi.org/10.3171/2020.4.PEDS19738DOI Listing
June 2020

Effects of different types of sensory signals on reaching performance in persons with chronic schizophrenia.

PLoS One 2020 24;15(6):e0234976. Epub 2020 Jun 24.

Department of Occupational Therapy, Chung Shan Medical University, Taichung, Taiwan.

Previous studies have reported movement abnormalities in persons with schizophrenia. This study aimed to examine the differences between persons with chronic schizophrenia and healthy control participants in reaching movement and the effects of sensory signals on reaching performance in persons with chronic schizophrenia. A counter-balanced repeated-measures design was employed. Twenty persons with schizophrenia and 20 age- and gender-matched control participants were recruited in this study. Reaching performance was measured in three types of sensory signal conditions (visual, auditory, and no signal), i.e., two externally triggered and one self-initiated movement were assessed in reaction time/inter-response interval, movement time, peak velocity, percentage of time in which peak velocity occurred, and movement units. The results revealed significant main effects of group in reaction time/inter-response interval (p = 0.003), movement time (p < 0.001), peak velocity (p < 0.001), and movement units (p < 0.001). The persons with chronic schizophrenia demonstrated slower response to signals and in self-initiated movement, increased movement time, and less forceful and less smooth movement compared to healthy control participants when performing the reaching task. The interaction effect between group and signal in reaction time/inter-response interval was also significant (p < 0.001). The inter-response interval for self-initiated reaching was the shortest in healthy controls. Conversely, the inter-response interval for self-initiated reaching was the longest in persons with schizophrenia. The main effect of the signal on movement time was significant (p < 0.001). The movement time of reaching was longer in response to the auditory signal than in response to visual or self-initiated. The differences in percentages of time in which peak velocity occurred between persons with schizophrenia and healthy controls (p > 0.01) and across the three conditions (p > 0.01) were non-significant. Neither duration of illness nor antipsychotic dosage was significantly associated with reaching performance (all p > 0.01). In conclusion, these findings indicate that reaching movement in persons with chronic schizophrenia is slower, less forceful, and less coordinated compared to healthy control participants. In addition, persons with chronic schizophrenia also had shorter inter-response interval for self-initiated movement and shorter movement time in auditory signal condition, independent of duration of illness and antipsychotic dosage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314021PMC
September 2020

Tropomyosin receptor kinase inhibitors in the management of sarcomas.

Curr Opin Oncol 2020 07;32(4):307-313

Department of Medical Oncology, Sarcoma Unit, The Royal Marsden Hospital.

Purpose Of Review: Genetic aberrations resulting in tropomyosin receptor kinase (TRK) fusion proteins can drive oncogenesis and are postulated to occur in up to 1% of solid tumours. However, TRK fusions in adult sarcomas are rare and there is a significant challenge in identifying patients with sarcomas harbouring TRK fusions in the clinical setting. Despite a recent European Society of Medical Oncology consensus article regarding screening of tumours for TRK fusions, economical and practical limitations present a barrier to widespread screening of sarcomas.

Recent Findings: Larotrectinib and entrectinib are pan-TRK inhibitors which have both received FDA approval for the management of solid tumours harbouring NTRK fusions. Initial results of a number of clinical trials have demonstrated promising efficacy and safety data, including dramatic and durable responses in patients with sarcomas. As such, TRK inhibitors represent a promising treatment option in a small cohort of adult sarcoma patients, where currently treatment options are limited. The emergence of acquired resistance is a concern associated with TRK inhibitor therapy and a number of second-generation agents targeting TRK kinase mutations driving acquired resistance have entered early-phase clinical trials.

Summary: With the growing appreciation of the implications of TRK fusions, this review will summarize the emerging clinical trial data of TRK inhibitors in sarcomas. Although in their infancy, clinical trial results are encouraging, and as further results and analyses are released, we will have a greater understanding of their impact on clinical practice and the management of patients with sarcomas.
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http://dx.doi.org/10.1097/CCO.0000000000000650DOI Listing
July 2020

Differential Use and Impact of Bleeding Avoidance Strategies on Percutaneous Coronary Intervention-Related Bleeding Stratified by Predicted Risk.

Circ Cardiovasc Interv 2020 06 12;13(6):e008702. Epub 2020 Jun 12.

Duke Clinical Research Institute, Durham, NC (S.V.R.).

Background: Procedural anticoagulation with bivalirudin (BIV), trans-radial intervention (TRI), and use of a vascular closure device (VCD) are thought to mitigate percutaneous coronary intervention (PCI)-related bleeding. We compared the impact of these bleeding avoidance strategies (BAS) for PCIs stratified by bleeding risk.

Methods: We performed a retrospective cohort analysis of PCIs from 18 facilities within one health care system from 2009Q3 to 2017Q4. Bleeding risk was assessed per the National Cardiovascular Data Registry CathPCI bleeding model, with procedures stratified into 6 categories (first, second, third quartiles, 75th-90th, 90th-97.5th, and top 2.5th percentiles). Regression models were used to assess the impact of BAS on bleeding outcome.

Results: Of 74 953 PCIs, 9.4% used no BAS, 12.0% used BIV alone, 20.8% used TRI alone, 26.8% used VCD alone, 5.4% used TRI+BIV, and 25.6% used VCD+BIV. The crude bleeding rate was 4.4% overall. Only 2 comparisons showed significant trends across all risk strata: VCD+BIV versus no BAS, odds ratio (95% CI) range: first quartile, 0.36 (0.18-0.72) to top 2.5th percentile, 0.50 (0.32-0.78); TRI versus no BAS, odds ratio (95% CI) range: first quartile, 0.15 (0.06-0.38) to top 2.5th percentile, 0.49 (0.28-0.86). TRI had lower odds of bleeding compared with BIV for all risk strata except the top 2.5th percentile. Addition of BIV to TRI did not change the odds of bleeding for any risk strata. Factors potentially limiting use of TRI (renal failure, shock, cardiac arrest, and mechanical circulatory support) were present in ≤10% of procedures below the 90th percentile.

Conclusions: Among individual BAS, only TRI had consistently lower odds of bleeding across all risk strata. Factors potentially limiting TRI were found infrequently in procedures below the 90th percentile of bleeding risk. For transfemoral PCI, VCD+BIV had lower odds of bleeding compared with no BAS across all risk strata.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008702DOI Listing
June 2020
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