Publications by authors named "James L Chen"

93 Publications

Stemless Total Shoulder Arthroplasty With Orthobiologic Augmentation.

Arthrosc Tech 2021 Feb 30;10(2):e531-e538. Epub 2021 Jan 30.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Total shoulder arthroplasty (TSA) has evolved over the years and is used for a variety of indications, with arthritis being the most common. Stemless TSA is a unique bone-preserving design that can eliminate rotational malalignment. Additionally, recent literature has found utility in the use of biological mesh and a platelet-rich plasma injection to improve healing. The purpose of this article is to outline the process of TSA using a stemless system and how to incorporate the use of amnion matrix and platelet-rich plasma into the surgical technique.
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http://dx.doi.org/10.1016/j.eats.2020.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917302PMC
February 2021

Mini-Open Achilles Repair With a Flat Braided Suture in a Low-Profile Configuration.

Arthrosc Tech 2021 Feb 16;10(2):e451-e455. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Achilles repair has evolved over the past 30 years, from large open procedures with high complication rates to shorter, less-invasive procedures with better outcomes. Percutaneous repair has comparable failure rates with open repairs, fewer complications, and faster recovery. However, percutaneous Achilles repairs risk sural nerve injury. A mini-open repair fuses the gap between percutaneous and open procedures, and this approach has the potential to mitigate nerve injury while maintaining the increased efficiency in procedure time and patient recovery. The purpose of this Technical Note and accompanying video is to outline the repair of the Achilles tendon using a mini open repair using a low-profile flat braided suture.
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http://dx.doi.org/10.1016/j.eats.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917089PMC
February 2021

Distal Clavicle Excision for Acromioclavicular Joint Osteoarthritis Using a Fluoroscopic Kirschner Wire Guide.

Arthrosc Tech 2021 Feb 16;10(2):e359-e365. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Pathology of the acromioclavicular joint is common and often resistant to conservative treatment, requiring distal clavicle excision for definitive relief. First described as an open technique by Mumford and Gurd in 1941, distal clavicle excision has evolved greatly, with arthroscopic techniques currently predominating. No significant difference has been found in patient satisfaction or rate of complication between the techniques in a recent meta-analysis. Indeed, open excisions are still performed at a high rate, owing to the difficulty in technique and visualization with arthroscopic methods. One major critique of arthroscopic distal clavicle excision is difficulty safeguarding against under- and overexcision of the distal clavicle due to the lack of depth perception and visual reference points of the arthroscopic perspective. This Technical Note and accompanying video describe an indirect subacromial arthroscopic distal clavicle excision using a fluoroscopic Kirschner wire guide placed at the proximal border prior to resection to serve as a visual and mechanical reference to overexcision.
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http://dx.doi.org/10.1016/j.eats.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917026PMC
February 2021

Combined Coracoclavicular and Acromioclavicular Joint Reconstruction with Allograft Using a Cerclage Tensioning System.

Arthrosc Tech 2021 Feb 16;10(2):e317-e323. Epub 2021 Jan 16.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Acromioclavicular joint separations are common shoulder injuries, yet standard treatment practices vary. Popular surgical techniques include reconstruction using allografts or neighboring ligaments as well as repair using screws and sutures. This Technical Note and accompanying video describe both an acromioclavicular and coracoclavicular joint reconstruction using an allograft to replace native acromioclavicular ligament along with an AC joint reduction using a Suture Cerclage System to precisely control reduction and restore anatomic alignment.
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http://dx.doi.org/10.1016/j.eats.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917031PMC
February 2021

Modern multimodality management of patients with caval leiomyosarcoma: New treatment paradigms and potential molecular insights.

J Surg Oncol 2021 Mar 2. Epub 2021 Mar 2.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio, USA.

Background And Objectives: Caval leiomyosarcomas (cLMS) are rare soft tissue sarcomas historically associated with high recurrence rates and poor prognosis. While radical resection remains the mainstay of therapy for cLMS, new systemic therapies have presented opportunities for multimodality treatment. We examined the clinical outcomes of patients with cLMS treated with modern, multimodality approaches, and compared their outcomes to those of patients with noncaval retroperitoneal LMS (ncLMS).

Methods: A retrospective, single-institution review identified all patients diagnosed with primary retroperitoneal LMS from 2012 to 2018. Radiographic and pathologic review distinguished patients with cLMS and ncLMS. Standard clinicopathologic variables and response to chemotherapy (when applicable) were analyzed. Primary endpoints were overall (OS) and progression-free survival (PFS).

Results: Eleven patients with cLMS were identified. Median tumor size was 7.5 cm (IQR, 5.0-14.3 cm); all patients had Stage II/III disease. Seven patients received neoadjuvant chemotherapy. Nine cLMS patients underwent R0/R1 resection; two did not complete resection. Six patients received adjuvant systemic therapy. Twenty patients with ncLMS were treated during the same period. No statistical intergroup differences were noted in tumor size, pathologic grade, stage, or resection margin status. Patients with ncLMS were less likely to receive neoadjuvant (10% vs. 64%) and adjuvant chemotherapy (30% vs. 55%). Two-year OS (81% vs. 78%; p = NS) and PFS (55% vs. 46%; p = NS) were comparable between cLMS and ncLMS patients.

Conclusions: Multimodality treatment with systemic therapy and aggressive surgical resection may achieve equivalent survival outcomes for patients with cLMS versus similar ncLMS. We recommend that all patients with cLMS be evaluated for multidisciplinary treatment. Genomic and proteomic expression profiling may identify novel or targetable mutations.
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http://dx.doi.org/10.1002/jso.26442DOI Listing
March 2021

Compression induced hepatic injury: an unusual case of abnormal liver function tests.

Clin Res Hepatol Gastroenterol 2021 Feb 23:101655. Epub 2021 Feb 23.

Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State Wexner Medical Center, 410 West 10th Avenue, Columbus, OH 43210, United States. Electronic address:

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http://dx.doi.org/10.1016/j.clinre.2021.101655DOI Listing
February 2021

Identifying Opportunities and Challenges for Patients With Sarcoma as a Result of Comprehensive Genomic Profiling of Sarcoma Specimens.

JCO Precis Oncol 2020 18;4. Epub 2020 Mar 18.

The Ohio State University, Columbus, OH.

Purpose: Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP.

Methods: A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure.

Results: CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival.

Conclusion: To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.
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http://dx.doi.org/10.1200/PO.19.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446311PMC
March 2020

Prospective Decision Analysis Study of Clinical Genomic Testing in Metastatic Breast Cancer: Impact on Outcomes and Patient Perceptions.

JCO Precis Oncol 2019 18;3. Epub 2019 Nov 18.

The Ohio State University College of Medicine, Columbus, OH.

Purpose: To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC).

Patients And Methods: In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients' perceptions of genomic testing.

Results: In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with level I/II evidence for actionability. Among the 94 genomic text reports that were released, there was physician questionnaire data for 87 patients (response rate, 92.6%) and 31.0% of patients (27 of 87) had treatment change recommended by their physician. Of these, 37.0% (10 of 27) received the treatment supported by genomic testing. We did not detect a statistically significant difference in time-to-treatment failure (log-rank = .87) or overall survival ( = .71) among patients who had treatment change supported by genomic testing versus those who had no treatment change. For patients who completed surveys before and after genomic testing, there was a significant decrease in confidence of treatment success, specifically among patients who did not have treatment change supported by genomic testing (McNemar's test of agreement = .001).

Conclusion: In this prospective study, genomic profiling of tumors in patients with MBC frequently identified potential treatments and resulted in treatment change in a minority of patients. Patients whose therapy was not changed on the basis of genomic testing seemed to have a decrease in confidence of treatment success.
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http://dx.doi.org/10.1200/PO.19.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446448PMC
November 2019

Recommendations for patient similarity classes: results of the AMIA 2019 workshop on defining patient similarity.

J Am Med Inform Assoc 2020 11;27(11):1808-1812

The Ohio State University, Columbus, Ohio, USA.

Defining patient-to-patient similarity is essential for the development of precision medicine in clinical care and research. Conceptually, the identification of similar patient cohorts appears straightforward; however, universally accepted definitions remain elusive. Simultaneously, an explosion of vendors and published algorithms have emerged and all provide varied levels of functionality in identifying patient similarity categories. To provide clarity and a common framework for patient similarity, a workshop at the American Medical Informatics Association 2019 Annual Meeting was convened. This workshop included invited discussants from academics, the biotechnology industry, the FDA, and private practice oncology groups. Drawing from a broad range of backgrounds, workshop participants were able to coalesce around 4 major patient similarity classes: (1) feature, (2) outcome, (3) exposure, and (4) mixed-class. This perspective expands into these 4 subtypes more critically and offers the medical informatics community a means of communicating their work on this important topic.
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http://dx.doi.org/10.1093/jamia/ocaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671612PMC
November 2020

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.

Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.
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http://dx.doi.org/10.3390/cancers12082157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463633PMC
August 2020

Activity of PD1 inhibitor therapy in advanced sarcoma: a single-center retrospective analysis.

BMC Cancer 2020 Jun 5;20(1):527. Epub 2020 Jun 5.

The Ohio State University Comprehensive Cancer Center, The Ohio State University, 410 W 12th Avenue, Columbus, OH, 43210, USA.

Background: Sarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear.

Methods: Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study.

Results: Partial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS.

Conclusions: This study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.
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http://dx.doi.org/10.1186/s12885-020-07021-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275332PMC
June 2020

Metastatic breast cancer patient perceptions of somatic tumor genomic testing.

BMC Cancer 2020 May 6;20(1):389. Epub 2020 May 6.

The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.

Background: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing.

Methods: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement.

Results: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04).

Conclusions: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention.

Clinical Trial Information: NCT01987726, registered November 13, 2013.
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http://dx.doi.org/10.1186/s12885-020-06905-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201768PMC
May 2020

Tibial Plateau With Arthroscopic Reduction-Internal Fixation.

Arthrosc Tech 2020 Feb 8;9(2):e213-e216. Epub 2020 Jan 8.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Arthroscopic-assisted internal fixation is an ideal technique for visualizing chondral reduction during tibial open reduction-internal fixation. Typically, open reduction-internal fixation is performed using radiographic and Fluoroscan imaging (Hologic, Bedford, MA) for reduction of subchondral bone. However, reduction without visualization does not ensure chondral surface reduction. This Technical Note and supplemental video describe an arthroscopic-assisted technique involving the tibial plateau that gives complete visualization as tamping occurs to restore the cartilage surface of the subchondral bone and elevate the fracture.
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http://dx.doi.org/10.1016/j.eats.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029054PMC
February 2020

Transtibial Pull-Out Repair of Converted Radial Tear Adjacent to Medial Meniscus Root.

Arthrosc Tech 2020 Jan 31;9(1):e171-e176. Epub 2019 Dec 31.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Radial tears increase tibiofemoral contact pressure and disrupt the ability of the meniscus to withstand hoop stress, leading to earlier-onset osteoarthritis. Repair of radial tears is problematic because they have a lower healing rate and lack a single gold standard technique. However, when a radial tear is proximal to the root, there is an opportunity to convert it into a root tear. This is ideal because root tears fixed through a transtibial tunnel technique have improved clinical outcomes and reduced rates of osteoarthritis. This Technical Note and accompanying video describe a method for repairing a radial tear near the meniscus root by converting a radial tear to a root tear followed by a pull-out root repair through a transtibial tunnel. This method restores the meniscus root, allowing it to withstand hoop stress. Our technique uses a disposable root repair kit that includes a FlipCutter, a Knee Scorpion Suture Passer, a 4.75-mm SwiveLock anchor tap, a SutureLasso, a PassPort Cannula, 0 FiberLink sutures, and TigerLink sutures.
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http://dx.doi.org/10.1016/j.eats.2019.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993483PMC
January 2020

Inside-Out Bucket-Handle Meniscus Repair With a Single-Handed Self-Advancing Zone-Specific Meniscus Repair Device.

Arthrosc Tech 2020 Jan 24;9(1):e117-e121. Epub 2019 Dec 24.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Meniscus tears are among the most common knee injuries in the general population and often are treated arthroscopically with a meniscus repair. Of the various meniscus repair techniques available, the inside-out meniscus tear is considered the gold standard due to its versatility and good clinical outcomes. The purpose of this Technical Note and accompanying video is to describe an inside-out bucket-handle meniscus repair using a single handed, self-advancing meniscus repair device with an interchangeable zone-specific multicannula system to decrease the technical difficulty and operative time of the repair.
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http://dx.doi.org/10.1016/j.eats.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993263PMC
January 2020

Arthroscopic Harvesting of Autologous Bone Graft for Use as a Mesenchymal Stem Cell Carrier in Anterior Cruciate Ligament Reconstruction.

Arthrosc Tech 2020 Jan 18;9(1):e45-e50. Epub 2019 Dec 18.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Anterior cruciate ligament (ACL) tears are detrimental to knee stability and normal function. Although the standard of treatment is an ACL reconstruction, technical improvements are sought to enhance clinical outcomes due to the appreciable failure rate. The use of autologous biologic substances as carriers of stem cells are desirable because of their multipotent properties. Traditionally, the collection of autologous bone grafts is through an open incision of the iliac crest, which causes substantial morbidity to the patient. This Technical Note describes an arthroscopic, minimally invasive collection method of autologous tibial and femoral bone graft to use in backfilling the tunnels during an ACL reconstruction to improve graft incorporation and clinical outcomes.
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http://dx.doi.org/10.1016/j.eats.2019.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993187PMC
January 2020

Acromioclavicular Joint Repair Using a Suture Cerclage Tensioning System.

Arthrosc Tech 2019 Dec 25;8(12):e1555-e1560. Epub 2019 Nov 25.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Injuries to the acromioclavicular (AC) joint are common among adults in their twenties and account for 8% of all joint dislocations. Although there are numerous operative approaches to treating AC joint separations, a gold standard does not exist because of lack of conclusive evidence supporting the use of 1 standard technique. In this Technical Note and accompanying video, we describe an anatomic AC joint repair using a suture cerclage tensioning system to accurately control the reduction and improve the precision and outcomes of the repair.
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http://dx.doi.org/10.1016/j.eats.2019.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928360PMC
December 2019

Stem Cell-Infused Anterior Cruciate Ligament Reconstruction.

Arthrosc Tech 2019 Nov 11;8(11):e1313-e1317. Epub 2019 Oct 11.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Anterior cruciate ligament (ACL) tears are unfortunate but common injuries in the athletic population. The standard of care for ACL tears is a surgical intervention to reconstruct the ACL to restore knee functionality as well as quality of life. In recent years, bone marrow aspirate concentrate (BMAC) has seen increasing use in various orthopaedic settings. This increase can be attributed to the potential beneficial qualities that mesenchymal stem cells, progenitor cells, and growth factors, all of which are present in BMAC, can provide. In this technical note and accompanying video, we describe an anatomic allograft ACL reconstruction infused with BMAC to utilize BMAC's potential benefits.
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http://dx.doi.org/10.1016/j.eats.2019.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926314PMC
November 2019

Prospective Evaluation of the Concordance of Commercial Circulating Tumor DNA Alterations with Tumor-Based Sequencing across Multiple Soft Tissue Sarcoma Subtypes.

Cancers (Basel) 2019 Nov 21;11(12). Epub 2019 Nov 21.

Division of Medical Oncology, The Ohio State University, Columbus, OH 43210, USA.

Soft tissue sarcomas (STS) are diverse tumors with heterogenous alterations. Platforms to detect circulating tumor DNA (ctDNA) have rapidly increased in popularity as they may avoid invasive biopsy morbidity. However, ctDNA profiling concordance with standard solid tumor comprehensive genomic profiling (CGP) is poorly characterized. Here, we report the outcomes of a single-institution experience comparing mutational results from commercial ctDNA and solid tumor CGP in advanced STS subjects. We identified STS subjects who had undergone solid tumor based CGP in four distinct cohorts: Dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), and gastrointestinal stromal tumor (GIST). Subjects with radiographically measurable tumor were profiled using a commercial ctDNA CGP panel. Overlapping genes/exons on both biopsy panels were analyzed. Twenty-four subjects completed both ctDNA and solid tumor CGP. ctDNA was detected in 18/24 subjects. Subject level concordance rates in all overlapping genes were: LMS = 4/6; UPS = 2/6; DDLPS = 1/6; GIST = 0/6. Copy number alterations were notably poorly concordant. For subjects with short variant alterations and detectable tumor fractions, concordance with solid tumor CGP was 76% (13/17). LMS subjects had the highest median tumor fraction and concordance. No correlation was seen between tumor fraction or radiographic tumor volume largely driven by low estimated tumor fraction. A limitation of the study is that only targeted sequencing was performed. However, given the poor concordance in commonly altered genes, ctDNA panels in sarcoma cannot be broadly applied. Further, more extensive studies will need to be performed.
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http://dx.doi.org/10.3390/cancers11121829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966562PMC
November 2019

Inhibition of histone deacetylase 2 reduces MDM2 expression and reduces tumor growth in dedifferentiated liposarcoma.

Oncotarget 2019 Oct 1;10(55):5671-5679. Epub 2019 Oct 1.

Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.

Dedifferentiated liposarcoma (DDLPS) is a highly morbid mesenchymal tumor characterized and driven by genomic amplification of the gene. Direct inhibition of MDM2 has shown promise pre-clinically, but has yet to be validated in clinical trials. Early studies have demonstrated that pan-histone deacetylase (HDAC) inhibition may have anti-MDM2 effects. Here we present , , and mouse xenograft studies that suggest that specifically targeting HDAC2 reduces MDM2 expression and has anti-tumor affects in DDLPS. Two independent datasets, The Cancer Genome Atlas (TCGA; = 58) and the Memorial Sloan-Kettering Cancer Center Dataset (MSKCC; = 63), were used to identify the co-expression between class I and , and their clinical impact. 2 was highly co-expressed with (TCGA: Spearman's coefficient = 0.29, = 0.03; MSKCC: Spearman's coefficient = 0.57, < 0.001). As both a continuous and dichotomous predictor, elevated expression was associated with worsened disease-free survival in the TCGA (Continuous: Hazard-ratio (HR) 1.7; 95% Confidence Interval (95%CI) 0.97-2.9; = 0.06; Dichotomous: HR 7.1, 95%CI 2.5-19.8, < 0.001) and distant recurrence-free survival in the MSKCC (Continuous: HR 2.2; 95%CI 1.1-4.8; = 0.04; Dichotomous: HR 2.8, 95%CI 1.2-6.4, = 0.02). , treatment of DDLPS cell lines with the HDAC inhibitors MI-192 (HDAC2/3 inhibitor) or romidepsin (HDAC1/2 inhibitor) reduced expression and induced apoptosis. In a murine DDLPS xenograft model, romidepsin reduced tumor growth and lowered tumor MDM2 expression. RNA-sequencing of romidepsin treated mouse tumors demonstrated markers of TP53 reactivation. Taken together, our data supports the hypothesis that targeting HDAC2 may represent a potential strategy to modulate MDM2 expression in DDLPS.
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http://dx.doi.org/10.18632/oncotarget.27144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779286PMC
October 2019

Common Secondary Genomic Variants Associated With Advanced Epithelioid Hemangioendothelioma.

JAMA Netw Open 2019 10 2;2(10):e1912416. Epub 2019 Oct 2.

Department of Biomedical Informatics, The Ohio State University, Columbus.

Importance: Epithelioid hemangioendothelioma (EHE) is a rare, malignant vascular sarcoma characterized in most cases by a WWTR1-CAMTA1 fusion. The clinical course of EHE exhibits a dual nature. The condition is often indolent but can rapidly grow and metastasize unpredictably. No biomarkers to date are available to predict this phenotype. The hypothesis of this study was that better defining the genomic landscape of EHE using next-generation sequencing could offer additional therapies and insight into clinical outcomes.

Objective: To characterize secondary EHE genomic alterations and their association with clinical outcomes.

Design, Setting, And Participants: Multicenter, cross-sectional, retrospective study of next-generation sequencing results collected from participants diagnosed with EHE. Data were abstracted between May 1, 2013, and May 31, 2019. This analysis was conducted from January through June 2019. Summary genomic data were provided by commercial genomic testing companies.

Main Outcomes And Measures: Presence or absence of secondary pathogenic genomic variants and their association with disease stage and clinical features.

Results: A total of 49 participants with EHE were assessed for the presence or absence of secondary genomic variants. Of these, 32 (65.3%) were female; the mean (SD) age at diagnosis was 49.9 (18.3) years (range, 11-81 years). In all, 46 participants (93.9%) had confirmed WWTR1-CAMTA1 fusion; 26 participants (57.1%) exhibited a pathogenic genomic variant secondary to the WWTR1-CAMTA1 fusion; and 9 participants (18.4%) exhibited potentially targetable genomic variants. Commonly altered genes included CDKN2A/B, RB1, APC, and FANCA. Participants older than 45 years at diagnosis had an increased prevalence of secondary genomic variants that was not statistically significant (65.6% vs 38.5%; difference, 27.1%; 95% CI, -3.5% to 58.0%; P = .16) and were more likely to have a clinically targetable variant (28.1% vs 0%; difference, 28.1%; 95% CI, 11.2%-40.2%; P = .03). In 14 participants with clinical data available, those with stage III/IV EHE were more likely to exhibit a secondary pathogenic genomic variant (80% vs 0%; difference, 80%; 95% CI, 55.2%-100%; P = .006). Participants with stage III/IV EHE were diagnosed at an older age (mean [SD] age, 54.6 [14.1] years vs 31.7 [16.0] years; P = .05) and had elevated WWTR1-CAMTA1 fusion expression that was not statistically significant (mean [SD] expression, 677 [706] copies vs 231 [213] copies; P = .20).

Conclusions And Relevance: Although EHE exhibits few secondary genomic variants, presence of key secondary variants may be prognostic for aggressive EHE. Further research is needed to confirm this finding and determine whether more intensive upfront treatment is necessary for these patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.12416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777396PMC
October 2019

A 360° Labral Repair Using Two Portals and a Percutaneous Cannula.

Arthrosc Tech 2019 Jul 17;8(7):e763-e767. Epub 2019 Jul 17.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Pan-labral tears are relatively uncommon, but they present significant challenges to arthroscopists. The difficulty lies in the need to access the glenoid rim circumferentially for proper anchor placement. Traditionally, this requires that multiple portals and percutaneous access be established as needed. Additionally, proper preoperative planning is needed to accurately reduce the labrum. In this Technical Note, we demonstrate a technique that accomplishes circumferential access and a well-planned approach with 2 portals and a percutaneous cannula.
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http://dx.doi.org/10.1016/j.eats.2019.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714521PMC
July 2019

Arthroscopic Double-Pulley Remplissage Using a 2-Portal Technique for Hill-Sachs Lesions in Recurrent Anterior Shoulder Instability.

Arthrosc Tech 2019 Jun 6;8(6):e527-e533. Epub 2019 May 6.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Hill-Sachs lesions of the humeral head are associated with recurrent anterior shoulder instability. Arthroscopic double-pulley remplissage has emerged as the leading alternative to the open Latarjet procedure to address recurrent shoulder instability with comparable recurrence rates and favorable complication rates. This Technical Note describes our adaptation of the double-pulley remplissage technique by using 2 portals, with the anterior portal used as the viewing portal and suture passage through the posterior portal. This technique eliminates the need for a lateral percutaneous portal, consequently minimizing operative time and postoperative morbidity. Furthermore, using the anterior portal as the viewing portal allows for direct visualization of the reduction of the infraspinatus into the Hill-Sachs defect. The drawback of this technique is that there is no view of the subacromial space during knot tying.
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http://dx.doi.org/10.1016/j.eats.2019.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620479PMC
June 2019

Effect of Acid-Suppressive Strategies on Pazopanib Efficacy in Patients With Soft-Tissue Sarcoma.

Clin Transl Sci 2019 09 2;12(5):529-533. Epub 2019 Jul 2.

Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.

Pazopanib (PAZ), a tyrosine kinase inhibitor used in the treatment of soft tissue sarcoma (STS), should not be administered with acid-suppressive medications (ASMs) due to decreased drug solubility. Common practice for patients requiring ASM with PAZ is to separate administration by 12 hours; however, there is little real-world evidence describing clinical outcomes using this strategy. The aim of this study was to determine whether concomitant ASM impacted efficacy and adverse event rates in patients with STS receiving PAZ. Medical records were retrospectively reviewed for patients with STS who received PAZ from June 2011 to July 2017. Patients were stratified into two groups, PAZ with or without ASM (PAZ + ASM or PAZ only). The primary objective was to determine whether progression-free survival (PFS) differed between groups. Secondary objectives were to determine overall survival (OS) and occurrence of grade 3/4 toxicities. Ninety-one patients were included in the study, 42 patients in the PAZ + ASM group and 49 in the PAZ only group. Median PFS was significantly shorter in the PAZ + ASM group than the PAZ only group (5.3 vs. 6.7 months). The PAZ + ASM group also had a 74% higher relative risk of progression or death than the PAZ only group, but there was no difference in OS. Regarding adverse events, the PAZ + ASM group trended toward lower levels of grade 3/4 hypertension (19% vs. 37%). These results suggest that ASM should be avoided in patients with STS receiving PAZ. Larger studies are needed to further elucidate the impact of ASM use with PAZ in clinical practice.
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http://dx.doi.org/10.1111/cts.12648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742936PMC
September 2019

Double-Bundle Medial Patellofemoral Ligament Reconstruction With Allograft.

Arthrosc Tech 2019 May 26;8(5):e513-e520. Epub 2019 Apr 26.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Medial patellofemoral ligament (MPFL) reconstruction is the treatment of choice for recurrent patellofemoral instability. Although attention to MPFL reconstruction in the orthopaedic literature has increased dramatically in recent years, there is no clear consensus on surgical technique, graft option, or method of fixation. Nevertheless, most studies have shown improved pain scores and low rates of recurrent dislocation in patients after surgery. Despite the early success of MPFL reconstruction, complications may occur more frequently than previously appreciated and include patellar fracture, postoperative instability, and loss of flexion. This article describes our technique for double-bundle MPFL reconstruction with an allograft while highlighting certain aspects of the procedure that are critical for achieving favorable outcomes. The main advantages of the technique include strong patellar fixation with suture anchors and anatomic graft placement at the origin and insertion of the native MPFL. In our experience, this method of reconstruction has been safe, reproducible, and effective in the treatment of patients with patellar instability.
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http://dx.doi.org/10.1016/j.eats.2019.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552203PMC
May 2019

The Impact of Big Data Research on Practice, Policy, and Cancer Care.

Am Soc Clin Oncol Educ Book 2019 Jan 17;39:e167-e175. Epub 2019 May 17.

6 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH.

The concept of "big data" research-the aggregation and analysis of biologic, clinical, administrative, and other data sources to drive new advances in biomedical knowledge-has been embraced by the cancer research enterprise. Although much of the conversation has concentrated on the amalgamation of basic biologic data (e.g., genomics, metabolomics, tumor tissue), new opportunities to extend potential contributions of big data to clinical practice and policy abound. This article examines these opportunities through discussion of three major data sources: aggregated clinical trial data, administrative data (including insurance claims data), and data from electronic health records. We will discuss the benefits of data use to answer key oncology practice and policy research questions, along with limitations inherent in these complex data sources. Finally, the article will discuss overarching themes across data types and offer next steps for the research, practice, and policy communities. The use of multiple sources of big data has the promise of improving knowledge and providing more accurate data for clinicians and policy decision makers. In the future, optimization of machine learning may allow for current limitations of big data analyses to be attenuated, thereby resulting in improved patient care and outcomes.
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http://dx.doi.org/10.1200/EDBK_238057DOI Listing
January 2019

Degree of Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma.

Oncologist 2019 07 24;24(7):989-996. Epub 2019 Apr 24.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

Background: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 () is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of amplification, not simply the presence of amplification, may be biologically important to the actions of DDLPS.

Patients And Methods: The distribution of amplification in DDLPS was assessed using data from a commercial sequencing laboratory ( = 642) and The Cancer Genome Atlas ( = 57). Data from two retrospective clinical trials ( = 15, = 16) and one prospective clinical trial ( = 25) were used to test 's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines.

Results: Genomic amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated was associated with shortened time to recurrence as measured by genomic amplification ( = .003) and mRNA expression ( = .04). In patients requiring systemic therapy, higher amplification was associated with reduced overall survival ( = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity.

Conclusion: amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of as a predictive biomarker in DDLPS is warranted.

Implications For Practice: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 () is currently used for diagnosis, the clinical relevance of amplification has yet to be fully assessed. This study found that amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that amplification may be a useful biomarker in DDLPS.
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http://dx.doi.org/10.1634/theoncologist.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656442PMC
July 2019

Osteochondral Allograft Transplantation of the Medial Femoral Condyle With Orthobiologic Augmentation and Graft-Recipient Microfracture Preparation.

Arthrosc Tech 2019 Mar 25;8(3):e321-e329. Epub 2019 Feb 25.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Osteochondritis dissecans (OCD) has been recognized for over 100 years yet still poses treatment challenges owing to both the avascular nature of articular cartilage and the inability to generate hyaline cartilage. The knee is most commonly involved, and without repair, patients have chronic knee pain, loose bodies, and early-onset osteoarthritis. There are a number of surgical techniques for repairing OCD, some of which are still being refined. Currently, common procedures used to treat OCD lesions include microfracture, autologous chondrocyte implantation, osteochondral autograft transplantation, and osteochondral allograft transplantation. In this Technical Note, we describe osteochondral allograft transplantation with the addition of platelet-rich plasma and graft-recipient microfracture. We believe the micropores augment the osteoconductive and osteoinductive properties of the allograft and aid in the incorporation of the allograft plug by improving angiogenesis, enhancing clot formation in the allograft, and providing a homogeneous environment for remodeling.
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http://dx.doi.org/10.1016/j.eats.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475622PMC
March 2019

Arthroscopic-Assisted Osteochondral Allograft Transplantation for Posterolateral Lesions of the Talus Without Fibular Osteotomy.

Arthrosc Tech 2019 Mar 18;8(3):e311-e316. Epub 2019 Feb 18.

Advanced Orthopaedics and Sports Medicine, San Francisco, California, U.S.A.

Osteochondral lesions of the talus are chondral defects often caused by acute trauma to the ankle such as sprains and fractures. If operative treatment is necessary, microfracture, cartilage replacement, and autologous chondrocyte implantation can be used. We describe a single-step osteochondral allograft transfer to access the posterolateral talar dome that avoids the need for a fibular osteotomy and therefore eliminates morbidity while reducing operative time.
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http://dx.doi.org/10.1016/j.eats.2018.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475624PMC
March 2019

Functional Loss Defines a Targetable Subset in Leiomyosarcoma.

Oncologist 2019 07 12;24(7):973-979. Epub 2018 Dec 12.

Division of Bioinformatics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio, USA

Background: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS).

Materials And Methods: DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition.

Results: In an unselected STS study population, alterations were identified in 15 (1%) patients, and homozygous loss was detected in 9 (<1%). However, subset analysis revealed that these alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with loss.

Conclusion: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS.

Implications For Practice: Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for alterations and may benefit from treatment targeted to these alterations.
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http://dx.doi.org/10.1634/theoncologist.2018-0448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656468PMC
July 2019