Publications by authors named "Michael D Feldman"

136 Publications

Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 isolates from Pennsylvania.

bioRxiv 2021 Apr 21. Epub 2021 Apr 21.

Rapid whole genome sequencing of SARS-CoV-2 has presented the ability to detect new emerging variants of concern in near real time. Here we report the genome of a virus isolated in Pennsylvania in March 2021 that was identified as lineage B.1.1.7 (VOC-202012/01) that also harbors the E484K spike mutation, which has been shown to promote "escape" from neutralizing antibodies . We compare this sequence to the only 5 other B.1.1.7+E484K genomes from Pennsylvania, all of which were isolated in mid March. Beginning in February 2021, only a small number (n=60) of isolates with this profile have been detected in the US, and only a total of 253 have been reported globally (first in the UK in December 2020). Comparative genomics of all currently available high coverage B.1.1.7+E484K genomes (n=235) available on GISAID suggested the existence of 7 distinct groups or clonal complexes (CC; as defined by GNUVID) bearing the E484K mutation raising the possibility of 7 independent acquisitions of the E484K spike mutation in each background. Phylogenetic analysis suggested the presence of at least 3 distinct clades of B.1.1.7+E484K circulating in the US, with the Pennsylvanian isolates belonging to two distinct clades. Increased genomic surveillance will be crucial for detection of emerging variants of concern that can escape natural and vaccine induced immunity.
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http://dx.doi.org/10.1101/2021.04.21.440801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077577PMC
April 2021

The microbiome of HPV-positive tonsil squamous cell carcinoma and neck metastasis.

Oral Oncol 2021 Apr 23;117:105305. Epub 2021 Apr 23.

Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, United States.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) has now surpassed cervical cancer as the most common site of HPV-related cancer in the United States. HPV-positive OPSCCs behave differently from HPV-negative tumors and often present with early lymph node involvement. The bacterial microbiome of HPV-associated OPSCC may contribute to carcinogenesis, and certain bacteria may influence the spread of cancer from the primary site to regional lymphatics.

Objective: To determine the bacterial microbiome in patients with HPV-associated, early tonsil SCC and compare them to benign tonsil specimens.

Method: The microbiome of primary tumor specimens and lymph nodes was compared to benign tonsillectomy specimens with pan-pathogen microarray (PathoChip).

Results: A total of 114 patients were enrolled in the study. Patients with OPSCC had a microbiome that shifted towards more gram-negative. Numerous signatures of bacterial family and species were associated with the primary tumors and lymph nodes of cancer patients, including the urogenital pathogens Proteus mirabilis and Chlamydia trachomatis, Neisseria gonorrhoeae, Shigella dysenteriae, and Orientia tsutsugamushi.

Conclusion: Our results suggest that detection of urogenital pathogens is associated with lymph node metastasis for patients with HPV-positive OPSCCs. Additional studies are necessary to determine the effects of the OPSCC microbiome on disease progression and clinical outcomes.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105305DOI Listing
April 2021

Editorial Commentary: Suture Button-Anchor Fixation Is Preferable to Hook Plate Fixation for Acute Acromioclavicular Joint Dislocations: Form and Function Need to Be United.

Arthroscopy 2021 May;37(5):1424-1426

Both hook plate fixation and suture button-anchor fixation have been reported to yield good results in the treatment of acute acromioclavicular joint reconstruction. In addition to a mandatory secondary procedure, hook plate fixation clearly has an increased prevalence of post-traumatic acromioclavicular arthritis in the short term that is likely to progress in the long term. Conversely, suture button-anchor fixation-a minimally invasive technique that creates less soft-tissue disruption, does not require hardware removal, and does not violate the acromioclavicular joint-is more likely to promote primary healing of the coracoclavicular ligaments, reduce the risk of late displacement, and minimize the development of post-traumatic acromioclavicular arthritis. As stated by the noted architect Frank Lloyd Wright, it is not only about form (i.e., alignment), it is about function as well.
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http://dx.doi.org/10.1016/j.arthro.2021.01.051DOI Listing
May 2021

Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver.

JCI Insight 2021 Apr 8;6(7). Epub 2021 Apr 8.

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.
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http://dx.doi.org/10.1172/jci.insight.146883DOI Listing
April 2021

Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4.

Mol Ther Oncolytics 2021 Mar 26;20:387-398. Epub 2021 Jan 26.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4) as a putative antigen target for CAR-based therapy of MTC. We show that GFRα4 is highly expressed in MTC, in parafollicular cells within the thyroid from which MTC originates, and in normal thymus. We isolated two single-chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by antibody phage display. CARs bearing the CD3ζ and the CD137 costimulatory domains were constructed using these GFRα4-specific scFvs. GFRα4-specific CAR Ts trigger antigen-dependent cytotoxicity and cytokine production , and they are able to eliminate tumors derived from the MTC TT cell line in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CAR T and support this antigen as a promising target for adoptive T cell immunotherapy and other antibody-based therapies for MTC.
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http://dx.doi.org/10.1016/j.omto.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879023PMC
March 2021

Editorial Commentary: Big Databases Are Not All Created Equal: Interpret Their Studies With Caution.

Arthroscopy 2021 01;37(1):290-291

"Big Data" studies are extremely important in orthopedic research, as randomized controlled trials with extremely large sample sizes are nearly impossible to perform. But, as always, the devil is in the details. Databases are only as good as the information that is put into them. And when evaluating these studies, let's not forget how to interpret them. Many factors-patient insurance status, age, socioeconomic status, ethnicity, and comorbidities; regional variations; hospital status (inpatient/outpatient); clerical errors, recording biases, and omission of relevant orthopedic outcome measures; temporal changes in billing codes; payer mix; population demographics and catchment area; and data collection methodology-mean that the results of a specific big data study may or may not be generalizable to other populations.
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http://dx.doi.org/10.1016/j.arthro.2020.11.009DOI Listing
January 2021

Editorial Commentary: Anterior Cruciate Ligament Hamstring Autografts Should Be Avoided in Patients Younger Than 25 Years Old: Autograft-Allograft Hybrids Remain Controversial.

Arthroscopy 2021 01;37(1):183-184

Some studies have reported no difference between autograft and hybrid anterior cruciate ligament reconstructions. However, other studies have shown a significantly greater revision rate. Consequently, surgeons are reluctant to perform hybrid reconstructions in younger patients with diminutive hamstring autografts and have turned to other autograft graft sources (e.g., quadriceps tendon, patellar tendon). Until we can perform high-quality prospective studies that can definitively answer this question, we should consider avoiding autograft hamstring reconstructions in patients younger than 25 years old so that we are not faced with the dilemma of implanting an undersized autograft or a hybrid graft, as both may be at increased risk for failure.
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http://dx.doi.org/10.1016/j.arthro.2020.10.002DOI Listing
January 2021

CT derived radiomic score for predicting the added benefit of adjuvant chemotherapy following surgery in stage I, II resectable non-small cell lung cancer: a retrospective multicohort study for outcome prediction.

Lancet Digit Health 2020 03 13;2(3):e116-e128. Epub 2020 Feb 13.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio, USA. Electronic address:

Background: Use of adjuvant chemotherapy in patients with early-stage lung cancer is controversial because no definite biomarker exists to identify patients who would receive added benefit from it. We aimed to develop and validate a quantitative radiomic risk score (QuRiS) and associated nomogram (QuRNom) for early-stage non-small cell lung cancer (NSCLC) that is prognostic of disease-free survival and predictive of the added benefit of adjuvant chemotherapy following surgery.

Methods: We did a retrospective multicohort study of individuals with early-stage NSCLC (stage I and II) who either received surgery alone or surgery plus adjuvant chemotherapy. We selected patients for whom we had available pre-treatment diagnostic CT scans and corresponding survival information. We used radiomic texture features derived from within and outside the primary lung nodule on chest CT scans of patients from the Cleveland Clinic Foundation (Cleveland, OH, USA; cohort D) to develop QuRiS. A least absolute shrinkage and selection operator-Cox regularisation model was used for data dimension reduction, feature selection, and QuRiS construction. QuRiS was independently validated on a cohort of patients from the University of Pennsylvania (Philadephia, PA, USA; cohort D) and a cohort of patients whose CT scans were derived from The Cancer Imaging Archive (cohort D). QuRNom was constructed by integrating QuRiS with tumour and node descriptors (according to the tumour, node, metastasis staging system) and lymphovascular invasion. The primary endpoint of the study was the assessment of the performance of QuRiS and QuRNom in predicting disease-free survival. The added benefit of adjuvant chemotherapy estimated using QuRiS and QuRNom was validated by comparing patients who received adjuvant chemotherapy versus patients who underwent surgery alone in cohorts D-D.

Findings: We included: 329 patients in cohort D (73 [22%] had surgery plus adjuvant chemotherapy and 256 (78%) had surgery alone); 114 patients in cohort D (33 [29%] had surgery plus adjuvant chemotherapy and 81 (71%) had surgery alone); and 82 patients in cohort D (24 [29%] had surgery plus adjuvant chemotherapy and 58 (71%) had surgery alone). QuRiS comprised three intratumoral and 10 peritumoral CT-radiomic features and was found to be significantly associated with disease-free survival (ie, prognostic validation of QuRiS; hazard ratio for predicted high-risk vs predicted low-risk groups 1·56, 95% CI 1·08-2·23, p=0·016 for cohort D; 2·66, 1·24-5·68, p=0·011 for cohort D; and 2·67, 1·39-5·11, p=0·0029 for cohort D). To validate the predictive performance of QuRiS, patients were partitioned into three risk groups (high, intermediate, and low risk) on the basis of their corresponding QuRiS. Patients in the high-risk group were observed to have significantly longer survival with adjuvant chemotherapy than patients who underwent surgery alone (0·27, 0·08-0·95, p=0·042, for cohort D; 0·08, 0·01-0·42, p=0·0029, for cohorts D and D combined). As concerns QuRNom, the nomogram-estimated survival benefit was predictive of the actual efficacy of adjuvant chemotherapy (0·25, 0·12-0·55, p<0·0001, for cohort D; 0·13, <0·01-0·99, p=0·0019 for cohort D).

Interpretation: QuRiS and QuRNom were validated as being prognostic of disease-free survival and predictive of the added benefit of adjuvant chemotherapy, especially in clinically defined low-risk groups. Since QuRiS is based on routine chest CT imaging, with additional multisite independent validation it could potentially be employed for decision management in non-invasive treatment of resectable lung cancer.

Funding: National Cancer Institute of the US National Institutes of Health, National Center for Research Resources, US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, Department of Defence, National Institute of Diabetes and Digestive and Kidney Diseases, Wallace H Coulter Foundation, Case Western Reserve University, and Dana Foundation.
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http://dx.doi.org/10.1016/S2589-7500(20)30002-9DOI Listing
March 2020

Editorial Commentary: Perfecting Practice: Can We Train Residents to Be Proficient Arthroscopists Before Actually Treating Patients?

Arthroscopy 2020 11;36(11):2873-2874

Although a spaced retraining schedule improved resident arthroscopic task completion time and camera path length on a virtual simulator, it did not improve the degree of cartilage injury. To quote former Green Bay Packer Head Coach Vince Lombardi: "Practice does not make perfect. Only perfect practice makes perfect."
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http://dx.doi.org/10.1016/j.arthro.2020.08.025DOI Listing
November 2020

Editorial Commentary: Arthroscopic Ankle Arthrodesis Requires Intraoperative Deformity Correction: Size of the Deformity Is Not the Primary Determinant of Outcome.

Arthroscopy 2020 10;36(10):2748-2749

Traditional teaching has told us that arthroscopic ankle arthrodesis is reserved for those patients with severe osteoarthrosis but minimal deformity. However, it is not the size of the deformity that matters; rather, it is the ability to correct the deformity intraoperatively that leads to satisfactory results. Preoperative identification of those patients with significant deformity that can be corrected with an arthroscopic approach would allow for improved selection and likely lead to better patient-reported outcomes and fewer complications.
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http://dx.doi.org/10.1016/j.arthro.2020.07.036DOI Listing
October 2020

Towards Population-Based Histologic Stain Normalization of Glioblastoma.

Brainlesion 2020 19;11992:44-56. Epub 2020 May 19.

Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, PA, USA.

Glioblastoma ( ) is the most aggressive type of primary malignant adult brain tumor, with very heterogeneous radio-graphic, histologic, and molecular profiles. A growing body of advanced computational analyses are conducted towards further understanding the biology and variation in glioblastoma. To address the intrinsic heterogeneity among different computational studies, reference standards have been established to facilitate both radiographic and molecular analyses, e.g., anatomical atlas for image registration and housekeeping genes, respectively. However, there is an apparent lack of reference standards in the domain of digital pathology, where each independent study uses an arbitrarily chosen slide from their evaluation dataset for normalization purposes. In this study, we introduce a novel stain normalization approach based on a composite reference slide comprised of information from a large population of anatomically annotated hematoxylin and eosin ( ) whole-slide images from the Ivy Glioblastoma Atlas Project ( ). Two board-certified neuropathologists manually reviewed and selected annotations in 509 slides, according to the World Health Organization definitions. We computed summary statistics from each of these approved annotations and weighted them based on their percent contribution to overall slide ( ), to form a global histogram and stain vectors. Quantitative evaluation of pre- and post-normalization stain density statistics for each annotated region with PCOS > 0.05% yielded a significant (largest = 0.001, two-sided Wilcoxon rank sum test) reduction of its intensity variation for both & . Subject to further large-scale evaluation, our findings support the proposed approach as a potentially robust population-based reference for stain normalization.
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http://dx.doi.org/10.1007/978-3-030-46640-4_5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394499PMC
May 2020

Social Media Engagement at Academic Conferences: Report of the Association of Pathology Chairs 2018 and 2019 Annual Meeting Social Media Committee.

Acad Pathol 2020 Jan-Dec;7:2374289520934019. Epub 2020 Jul 17.

Association of Pathology Chairs, Wilmington, DE, USA.

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields.
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http://dx.doi.org/10.1177/2374289520934019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370333PMC
July 2020

Automated gleason grading on prostate biopsy slides by statistical representations of homology profile.

Comput Methods Programs Biomed 2020 Oct 26;194:105528. Epub 2020 May 26.

School of Automation, Nanjing University of Information Science & Technology, Nanjing 210044, China; Jiangsu Key Laboratory of Big Data Analysis Technique and CICAEET, Nanjing University of Information Science and Technology, Nanjing 210044, China. Electronic address:

Background And Objective: Gleason grading system is currently the clinical gold standard for determining prostate cancer aggressiveness. Prostate cancer is typically classified into one of 5 different categories with 1 representing the most indolent disease and 5 reflecting the most aggressive disease. Grades 3 and 4 are the most common and difficult patterns to be discriminated in clinical practice. Even though the degree of gland differentiation is the strongest determinant of Gleason grade, manual grading is subjective and is hampered by substantial inter-reader disagreement, especially with regard to intermediate grade groups.

Methods: To capture the topological characteristics and the degree of connectivity between nuclei around the gland, the concept of Homology Profile (HP) for prostate cancer grading is presented in this paper. HP is an algebraic tool, whereby, certain algebraic invariants are computed based on the structure of a topological space. We utilized the Statistical Representation of Homology Profile (SRHP) features to quantify the extent of glandular differentiation. The quantitative characteristics which represent the image patch are fed into a supervised classifier model for discrimination of grade patterns 3 and 4.

Results: On the basis of the novel homology profile, we evaluated 43 digitized images of prostate biopsy slides annotated for regions corresponding to Grades 3 and 4. The quantitative patch-level evaluation results showed that our approach achieved an Area Under Curve (AUC) of 0.96 and an accuracy of 0.89 in terms of discriminating Grade 3 and 4 patches. Our approach was found to be superior to comparative methods including handcrafted cellular features, Stacked Sparse Autoencoder (SSAE) algorithm and end-to-end supervised learning method (DLGg). Also, slide-level quantitative and qualitative evaluation results reflect the ability of our approach in discriminating Gleason Grade 3 from 4 patterns on H&E tissue images.

Conclusions: We presented a novel Statistical Representation of Homology Profile (SRHP) approach for automated Gleason grading on prostate biopsy slides. The most discriminating topological descriptions of cancerous regions for grade 3 and 4 in prostate cancer were identified. Moreover, these characteristics of homology profile are interpretable, visually meaningful and highly consistent with the rubric employed by pathologists for the task of Gleason grading.
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http://dx.doi.org/10.1016/j.cmpb.2020.105528DOI Listing
October 2020

Editorial Commentary: Should We Consider Early Retirement for Adolescent Pitchers and Catchers With Osteochonditis Dissecans of the Capitellum?

Arthroscopy 2020 05;36(5):1281-1282

Repetitive throwing in the adolescent athlete often leads to long-term problems. Strict pitch counts and limitation of pitches (e.g., curve balls) that place extreme stress on the immature elbow must be monitored closely. And until our outcomes for osteochondritis dissecans of the capitellum in adolescent baseball players improve, it may be wise to counsel those pitchers and catchers who are symptomatic to consider switching to another position or sport.
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http://dx.doi.org/10.1016/j.arthro.2020.02.029DOI Listing
May 2020

In Situ Immune Profiling of Heart Transplant Biopsies Improves Diagnostic Accuracy and Rejection Risk Stratification.

JACC Basic Transl Sci 2020 Apr 1;5(4):328-340. Epub 2020 Apr 1.

Cardiovascular Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.

Recognizing that guideline-directed histologic grading of endomyocardial biopsy tissue samples for rejection surveillance has limited diagnostic accuracy, quantitative, in situ characterization was performed of several important immune cell types in a retrospective cohort of clinical endomyocardial tissue samples. Differences between cases were identified and were grouped by histologic grade versus clinical rejection trajectory, with significantly increased programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cells suppressed in clinically evident rejections, especially cases with marked clinical-histologic discordance. Programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cell proportions are also significantly higher in "never-rejection" when compared with "future-rejection." These findings suggest that in situ immune modulators regulate the severity of cardiac allograft rejection.
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http://dx.doi.org/10.1016/j.jacbts.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188920PMC
April 2020

Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study.

J Clin Oncol 2020 06 10;38(16):1814-1823. Epub 2020 Apr 10.

Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY.

Purpose: Single-agent PD-1 blockade exhibits limited efficacy in epithelial ovarian cancer (EOC). We evaluated ipilimumab plus nivolumab compared with nivolumab alone in women with persistent or recurrent EOC.

Methods: Eligibility criteria included measurable disease, 1-3 prior regimens, and platinum-free interval (PFI) < 12 months. Participants were randomly allocated to intravenous nivolumab (every 2 weeks) or induction with nivolumab plus ipilimumab for 4 doses (every 3 weeks), followed by every-2-week maintenance nivolumab for a maximum of 42 doses. The primary null hypothesis was equal probability of objective response within 6 months of random allocation in each arm.

Results: One hundred patients were allocated to receive either nivolumab (n = 49), or nivolumab plus ipilimumab (n = 51), with PFI of < 6 months in 62%. Six (12.2%) responses occurred within 6 months in the nivolumab group and 16 (31.4%) in the nivolumab plus ipilimumab group (odds ratio, 3.28; 85% CI, 1.54 to infinity; = .034). The median progression-free survival (PFS) was 2 and 3.9 months in the nivolumab and nivolumab plus ipilimumab groups, respectively, with a PFI-stratified hazard ratio of 0.53 (95% CI, 0.34 to 0.82); the respective hazard ratio for death was 0.79 (95% CI, 0.44 to 1.42). Grade ≥ 3 related adverse events occurred in 33% of patients in the nivolumab group and 49% in the combination group, with no treatment-related deaths. PD-L1 expression was not significantly associated with response in either treatment group.

Conclusion: Compared with nivolumab alone, the combination of nivolumab and ipilimumab in EOC resulted in superior response rate and longer, albeit limited, PFS, with toxicity of the combination regimen comparable to prior reports. Additional combination studies to enhance durability of the dual regimen are warranted.
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http://dx.doi.org/10.1200/JCO.19.02059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255977PMC
June 2020

Editorial Commentary: Taking the Time to Teach the Next Generation of Orthopaedic Sports Medicine Physicians.

Arthroscopy 2020 03;36(3):842-843

Most everything in life has a cost, and for the academic orthopaedic sports medicine physician, it is time. But if it is to improve the skill set of the next generation of arthroscopic or sports medicine surgeons (who someday may perform surgery on me!), then I believe it is worth it.
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http://dx.doi.org/10.1016/j.arthro.2019.11.107DOI Listing
March 2020

Stable and discriminating radiomic predictor of recurrence in early stage non-small cell lung cancer: Multi-site study.

Lung Cancer 2020 04 26;142:90-97. Epub 2020 Feb 26.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA. Electronic address:

Objectives: To evaluate whether combining stability and discriminability criteria in building radiomic classifiers will improve the prognosis of cancer recurrence in early stage non-small cell lung cancer on non-contrast computer tomography (CT).

Materials And Methods: CT scans of 610 patients with early stage (IA, IB, IIA) NSCLC from four independent cohorts were evaluated. A total of 350 patients from Cleveland Clinic Foundation and University of Pennsylvania were divided into two equal sets for training (D) and validation set (D). 80 patients from The Cancer Genome Atlas Lung Adenocarcinoma and Squamous Cell Carcinoma and 195 patients from The Cancer Imaging Archive, were used as independent second (D) and third (D) validation sets. A linear discriminant analysis (LDA) classifier was built based on the most stable and discriminate features. In addition, a radiomic risk score (RRS) was generated by using least absolute shrinkage and selection operator, Cox regression model to predict time to progression (TTP) following surgery.

Results: A feature selection strategy focusing on both feature discriminability and stability resulted in the classifier having a higher discriminability on validation datasets compared to the discriminability alone criteria in discriminating cancer recurrence (D, AUC of 0.75 vs. 0.65; D, 0.74 vs. 0.62; D, 0.76 vs. 0.63). The RRS generated by most stable-discriminating features was significantly associated with TTP compared to discriminating alone criteria (HR = 1.66, C-index of 0.72 vs. HR = 1.04, C-index of 0.62).

Conclusion: Accounting for both stability and discriminability yielded a more generalizable classifier for predicting cancer recurrence and TTP in early stage NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141152PMC
April 2020

The virome of HPV-positive tonsil squamous cell carcinoma and neck metastasis.

Oncotarget 2020 Jan 21;11(3):282-293. Epub 2020 Jan 21.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Oropharyngeal squamous cell carcinoma (OPSCC) represents the most common HPV-related malignancy in the United States with increasing incidence. There is heterogeneity between the behavior and response to treatment of HPV-positive oropharyngeal squamous cell carcinoma that may be linked to the tumor virome. In this prospective study, a pan-pathogen microarray (PathoChip) was used to determine the virome of early stage, p16-positive OPSCC and neck metastasis treated with transoral robotic surgery (TORS) and neck dissection. The virome findings of primary tumors and neck lymph nodes were correlated with clinical data to determine if specific organisms were associated with clinical outcomes. A total of 114 patients were enrolled in the study. Double-stranded DNA viruses, specifically Papillomaviridae, showed the highest hybridization signal (viral copies) across all viral families in the primary and positive lymph node samples. High hybridization signals were also detected for signatures of Baculoviridae, Reoviridae, Siphoviridae, Myoviridae, and Polydnaviridae in most of the cancer specimens, including the lymph nodes without cancer present. Across all HPV signatures, HPV16 and 18 had the highest average hybridization signal index and prevalence. To our knowledge, this is the first study that has identified the viral signatures of OPSCC tumors. This will serve as a foundation for future research investigating the role of the virome in OPSCC. Further investigation into the OPSCC microbiome and its variations may allow for improved appreciation of the impact of microbial dysbiosis on risk stratification, oncologic outcomes, and treatment response which has been shown in other cancer sites.
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http://dx.doi.org/10.18632/oncotarget.27436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980631PMC
January 2020

Editorial Commentary: Bankart Lesion in an Adolescent Athlete? Not So Fast.

Arthroscopy 2020 02;36(2):345-346

With the desire to remain athletically competitive, many adolescent athletes with shoulder instability are turning to early surgical invention. But is surgical repair always necessary and are all Bankart lesions identical? Using 3-dimensional, frequency-selective, fat-suppressed gradient recalled echo magnetic resonance imaging (MRI) scans, the authors noted that the anterior glenoid rim secondary ossification center peaks at age 16 years in male patients but is only fused in 70% of male patients at age 17 years. Therefore, relying on MRI alone to guide surgical treatment may result in procedures that may otherwise be avoided because normal glenoid development may be mistaken for a bony Bankart lesion. A thorough history and physical examination are still essential in adolescents with shoulder injuries. Relying on MRI alone to guide surgical treatment may result in procedures that may otherwise be avoided.
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http://dx.doi.org/10.1016/j.arthro.2019.10.004DOI Listing
February 2020

Deep-learning approaches for Gleason grading of prostate biopsies.

Lancet Oncol 2020 02 8;21(2):187-189. Epub 2020 Jan 8.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1016/S1470-2045(19)30793-4DOI Listing
February 2020

Breast Cancer F-ISO-1 Uptake as a Marker of Proliferation Status.

J Nucl Med 2020 05 13;61(5):665-670. Epub 2019 Dec 13.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The σ receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using -(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1)-yl)butyl)-2-(2-F-fluoroethoxy)-5-methylbenzamide (F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of F-ISO-1 was quantitated by SUV and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Tumor SUV (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUV, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUV greater than the low-Ki-67 (<20%) group ( = 0.02). SUV exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, = 0.01, = 29). Partial-volume-corrected SUV was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, = 0.02, = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 ( > 0.05). F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.
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http://dx.doi.org/10.2967/jnumed.119.232363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198384PMC
May 2020

Clinical Implications of Carcinoma In Situ in Sinonasal Inverted Papilloma.

Otolaryngol Head Neck Surg 2019 12 22;161(6):1036-1042. Epub 2019 Oct 22.

Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA.

Objective: Sinonasal inverted papilloma (IP) is a typically benign sinonasal tumor with a tendency to recur and the potential for malignant transformation. Varying degrees of dysplasia may be present, of which carcinoma in situ (CIS) is most advanced. We hereby describe the biological and clinical behavior of IP with CIS (IPwCIS).

Study Design: Retrospective cohort.

Setting: Tertiary academic referral center.

Subjects And Methods: Patients who underwent surgical resection for IP between 2002 and 2017. Pertinent clinical data were obtained, and all IPwCIS cases were histologically confirmed.

Results: In total, 37 of 215 cases (17.2%) were identified with IPwCIS. Mean age was 57 years and 86.5% of patients were male. Median follow-up was 82 months, and the recurrence rate was 27%. The maxillary sinus was the most common primary site (37.8%) and 14 tumors (37.8%) demonstrated multifocal attachment, which was associated with recurrence (odds ratio [OR], 9.7; 95% confidence interval [CI], 1.4-112.8; = .028). IPwCIS was also associated with multiple recurrences (OR, 2.71; 95% CI, 1.246-5.814; = .021). Most patients were treated with surgery alone (89.1%) and 4 patients received adjuvant radiotherapy (8.1%). Only 1 patient (2.7%) demonstrated malignant transformation after definitive surgery.

Conclusions: IPwCIS represents the most severe degree of dysplasia prior to malignant transformation and is associated with higher recurrence rate and multifocal involvement but low rate of conversion to invasive carcinoma. The need for adjuvant therapy remains controversial, and further research into the etiology of the disease is warranted.
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http://dx.doi.org/10.1177/0194599819883298DOI Listing
December 2019

Automated Comparison of Pathology Reports for On-the-job Assessment of Residents.

AMIA Jt Summits Transl Sci Proc 2019 6;2019:495-504. Epub 2019 May 6.

Perelman School of Medicine, University of Pennsylvania.

The clinical competency of residents at teaching hospitals is always under scrutiny. Ideally, assessment should reflect competency on-the-job, under realistic circumstances, and include evaluating their medical reports. Currently, the assessment is done manually by the attending physicians, which adds to the cognitive load. In this study, we developed an automated system for assessing medical resident's pathology reports. Our system used natural language processing (NLP) techniques to identify different lexical and semantic similarity scores at sentence level as well as chunk level. We then used supervised learning to classify the reports into three categories- No Change (NC), Minor Changes (MiC), and major changes (MaC), reflecting how much the attending physician's report differs from that of the resident. Our system was able to classify the reports with an accuracy of 73.6%. Although moderately successful, our work shows the potential and future of automated assessment systems in the biomedical domain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568070PMC
May 2019

Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease.

PLoS One 2019 26;14(6):e0218660. Epub 2019 Jun 26.

Castleman Disease Collaborative Network, Philadelphia, Pennsylvania, United States of America.

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218660PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594611PMC
February 2020

Factors influencing malignant mesothelioma survival: a retrospective review of the National Mesothelioma Virtual Bank cohort.

F1000Res 2018 3;7:1184. Epub 2018 Aug 3.

Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, 15206, USA.

: Malignant mesothelioma (MM) is a rare but deadly malignancy with about 3,000 new cases being diagnosed each year in the US.  Very few studies have been performed to analyze factors associated with mesothelioma survival, especially for peritoneal presentation. The overarching aim of this study is to examine survival of the cohort of patients with malignant mesothelioma enrolled in the National Mesothelioma Virtual Bank (NMVB).    888 cases of pleural and peritoneal mesothelioma cases were selected from the NMVB database, which houses data and associated biospecimens for over 1400 cases that were diagnosed from 1990 to 2017. Kaplan Meier's method was performed for survival analysis. The association between prognostic factors and survival was estimated using Cox Hazard Regression method and using R software for analysis. The median overall survival (OS) rate of all MM patients, including pleural and peritoneal mesothelioma cases is 15 months (14 months for pleural and 31 months for peritoneal).  Significant prognostic factors associated with improved survival of malignant mesothelioma cases in this NMVB cohort were younger than 45, female gender, epithelioid histological subtype, stage I, peritoneal occurrence, and having combination treatment of surgical therapy with chemotherapy. Combined surgical and chemotherapy treatment was associated with improved survival of 23 months in comparison to single line therapies. There has not been improvement in the overall survival for patients with malignant mesothelioma over many years with current available treatment options. Our findings show that combined surgical and chemotherapy treatment in peritoneal mesothelioma is associated with improved survival compared to local therapy alone.
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http://dx.doi.org/10.12688/f1000research.15512.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198263PMC
November 2019

Computational staining of unlabelled tissue.

Nat Biomed Eng 2019 06;3(6):425-426

Center for Biomedical Image Computing and Analytics, Richards Medical Research Laboratories, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s41551-019-0414-3DOI Listing
June 2019

Editorial Commentary: The Arthroscopist's Baton-Can Minimizing Motion Lead to Better Outcomes?

Arthroscopy 2019 04;35(4):1210-1211

Unlike an orchestra conductor, whose fundamental goal is to bring a written score to life through exaggerated arm and body motion, the arthroscopist's goal is to enhance his or her surgical procedure by minimizing wasteful motion. So, the next time you are in the operating room observing or assisting with an arthroscopic procedure, do not just watch the monitor. Look at the surgeon's arm motion and see if you can distinguish between the maestro and the novice!
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http://dx.doi.org/10.1016/j.arthro.2019.01.003DOI Listing
April 2019

Editorial Commentary: Has the Pendulum Swung Yet Again? Allowing Early Active Motion After Arthroscopic Rotator Cuff Repair.

Arthroscopy 2019 03;35(3):761-762

The optimal duration and extent of immobilization during the immediate postoperative period after arthroscopic rotator cuff repair are unknown. The current noninferiority study has shown that early active motion to tolerance can be just as effective as immobilization without increasing the failure rate, allowing for convenience and comfort in performing activities of daily living in the early postoperative period. However, further study is needed to determine which factors are most important to maintain repair integrity to optimize outcomes.
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http://dx.doi.org/10.1016/j.arthro.2018.11.047DOI Listing
March 2019