Citations

Purpose To objectively identify the 50 most influential studies in knee arthroscopy and provide an analysis of their key characteristics. Methods The Clarivate Analytics Web of Knowledge database was used to gather data and metrics of knee arthroscopy research. The search list was sorted by the number of citations, and articles were included or excluded based on relevance to knee arthroscopy. The information extracted for each article included author name, publication year, country of origin, journal name, article type, and the level of evidence. Results For these 50 studies, the total number of citations was calculated to be 12,168, with an average of 243.4 citations per paper. The most‐cited article was cited 1,220 times. The 50 studies included in this analysis were published between 1972 and 2013. All 50 articles were published in English and came from 10 different orthopaedic journals. The United States was responsible for the majority of articles (n = 26); however, many other countries were represented. The most prevalent study designs were case series (n = 20). Conclusions The 50 most influential articles in knee arthroscopy were cited a total of 12,168 times. The study designs most commonly used were case series and cohort studies. This article serves as a reference to direct orthopaedic practitioners to the 50 most influential studies in knee arthroscopy. We hope that these 50 studies and the analysis we provide help health care professionals efficiently assess consensus, trends, and needs within the field. Clinical Relevance This analysis of the 50 most influential studies in knee arthroscopy will provide medical students, residents, fellows, and attending physicians with a comprehensive inventory and citation analysis of the most impactful academic contributions to one of the most important fields within orthopaedic surgery.

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Background: Closed-loop control (CLC) has been shown to improve glucose time in range and other glucose metrics; however, randomized trials >3 months comparing CLC with sensor-augmented pump (SAP) therapy are limited. We recently reported glucose control outcomes from the 6-month international Diabetes Closed-Loop (iDCL) trial; we now report patient-reported outcomes (PROs) in this iDCL trial. Methods: Participants were randomized 2:1 to CLC ( N = 112) versus SAP ( N = 56) and completed questionnaires, including Hypoglycemia Fear Survey, Diabetes Distress Scale (DDS), Hypoglycemia Awareness, Hypoglycemia Confidence, Hyperglycemia Avoidance, and Positive Expectancies of CLC (INSPIRE) at baseline, 3, and 6 months. CLC participants also completed Diabetes Technology Expectations and Acceptance and System Usability Scale (SUS). Results: The Hypoglycemia Fear Survey Behavior subscale improved significantly after 6 months of CLC compared with SAP. DDS did not differ except for powerless subscale scores, which worsened at 3 months in SAP. Whereas Hypoglycemia Awareness and Hyperglycemia Avoidance did not differ between groups, CLC participants showed a tendency toward improved confidence in managing hypoglycemia. The INSPIRE questionnaire showed favorable scores in the CLC group for teens and parents, with a similar trend for adults. At baseline and 6 months, CLC participants had high positive expectations for the device with Diabetes Technology Acceptance and SUS showing high benefit and low burden scores. Conclusion: CLC improved some PROs compared with SAP. Participants reported high benefit and low burden with CLC. Clinical Trial Identifier: NCT03563313.

Since the inception of spinal cord stimulation (SCS) in 1967, the technology has evolved dramatically with important advancements in waveforms and frequencies. One such advancement is Nevro’s Senza® SCS System for HF10, which received Food and Drug and Administration (FDA) approval in 2015. Low-frequency SCS works by activating large-diameter Aβ fibers in the lateral discriminatory pathway (pain location, intensity, quality) at the dorsal column (DC), creating paresthesia-based stimulation at lower-frequencies (30–120 Hz), high-amplitude (3.5–8.5 mA), and longer-duration/pulse-width (100–500 μs). In contrast, high-frequency 10 kHz SCS works with a proposed different mechanism of action that is paresthesia-free with programming at a frequency of 10,000 Hz, low amplitude (1–5 mA), and short-duration/pulse-width (30 μS). This stimulation pattern selectively activates inhibitory interneurons in the dorsal horn (DH) at low stimulation intensities, which do not activate the dorsal column fibers. This ostensibly leads to suppression of hyperexcitable wide dynamic range neurons (WDR), which are sensitized and hyperactive in chronic pain states. It has also been reported to act on the medial pathway (drives attention and pain perception), in addition to the lateral pathways. Other theories include a reversible depolarization blockade, desynchronization of neural signals, membrane integration, glial–neuronal interaction, and induced temporal summation. The body of clinical evidence regarding 10 kHz SCS treatment for chronic back pain and neuropathic pain continues to grow. There is high-quality evidence supporting its use in patients with persistent back and radicular pain, particularly after spinal surgery. High-frequency 10 kHz SCS studies have demonstrated robust statistically and clinically significant superiority in pain control, compared to paresthesia-based SCS, supported by level I clinical evidence. Yet, as the field continues to grow with the technological advancements of multiple waveforms and programming stimulation algorithms, we encourage further research to focus on the ability to modulate pain with precision and efficacy, as the field of neuromodulation continues to adapt to the modern healthcare era.

10024 Background: Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy, predominantly seen in children and young adults. Given its rarity, data are limited. We describe the largest cohort of patients with IMT to date, with an aim to further characterize this poorly understood tumor. Methods: A multi-institutional review was performed at 18 North American hospitals participating in the Pediatric Surgical Oncology Research Collaborative to identify IMT patients ≤39 years, diagnosed from 2000-2018. Descriptive statistics are described as median and interquartile range. Multivariable analysis was used to identify predictors of event free survival (EFS). Results: 182 patients were identified with a median age of 11 years (5-17); 52% were female. 33% of tumors were thoracic, 26% abdominal/pelvic, 20% head/neck, and 14% genitourinary. Common presenting symptoms included pain (29%), respiratory symptoms (24%), weight loss (12%), and a palpable mass (10%). Median tumor size was 3.9 cm (1.9-6.5). Anaplastic lymphoma kinase (ALK) overexpression was identified via immunohistochemistry in 53% of patients tested. One third of patients had abnormal cytogenetics, with 12% of the entire cohort having an ALK mutation. 7% of patients had distant disease at diagnosis. 13% of patients received neoadjuvant therapy including chemotherapy (3%), ALK inhibitor (4%), radiation (0.5%), non-steroidal anti-inflammatories (NSAIDs) (7%), or steroids (2%). Of those who underwent resection with known margin status (n = 158), 66% had complete resection, 20% had microscopic positive margins, and 14% had gross residual disease. Just over 40% of patients had an en bloc resection of involved organs, most commonly lung (26%). 21% of patients received adjuvant therapy, including chemotherapy (3%), ALK inhibitor (9%), radiation (0.5%), NSAIDs (8%), or steroids (5%). 12% of all patients received an ALK inhibitor: 24% neoadjuvant, 62% adjuvant, and 14% without surgery. Median follow-up time was 36 months (14-69). Overall 5-year survival (OS) was 95% and 5-year EFS was 80%. Predictors of recurrence included respiratory symptoms, larger tumor size, or distant disease at diagnosis. Gender, race, age and primary site were not predictive of EFS. Likewise, there was no association of ALK overexpression or ALK mutation with EFS. The presence of gross or microscopic margins following resection was not associated with recurrence. Conclusions: IMT is a rare tumor with favorable OS. Five year recurrence rate was 20%. Presenting with respiratory symptoms, larger tumor size, or metastatic disease was associated with recurrence, while ALK positivity was not. Notably, a positive margin after resection was not associated with increased recurrence, indicating that aggressive attempts at surgical resection that would compromise form or function may not be warranted.

e16137 Background: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality in Nigeria. HIV and viral hepatitis B (HBV) and C (HCV) co-infection are common in Nigeria that significantly accelerates liver disease progression including HCC. Aging-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (ccfDNA) extracted from serum/plasma are promising minimally-invasive biomarkers that may inform HIV-associated HCC. We examined the epigenetic age acceleration (EpiAgeAccel) in ccfDNA in HCC patients with HIV. Methods: The study included three groups of participants: a) HIV positive with HCC (n=7); b) HIV positive and cancer-free (n=45); and c) HIV negative with HCC (n=33). Epigenetic age was estimated by Horvath’s calculator using genome-wide ccfDNA methylation data profiled by Illumina EPIC array. EpiAgeAccel was computed as the residuals of a linear model of epigenetic age on chronological age, namely the unexplained portion of epigenetic age by chronological age. We used multiple linear regression to compare EpiAgeAccel between HIV/HCC groups, adjusting for sex, age, education, alcohol intake, and HBV/HCV infection. Results: Among HIV positive participants, there was a higher percentage of men (57% vs. 22%, p<0.001), HBV infection (29% vs. 11%, p=0.004), and HCV infection (57% vs. 2%, p<0.001) in the HCC group compared to the cancer-free group. EpiAgeAccel was 4.8 years higher in HIV positive patients with HCC compared to cancer-free HIV positives (p=0.02). Among HCC patients, EpiAgeAccel was 2.1 years higher in HIV positives compared to HIV negative but not statistically significant. Conclusions: Epigenetic age in ccfDNA is accelerated in HIV-positive HCC patients. EpiAgeAccel measured in ccfDNA may be developed into a surrogate biomarker for minimally invasive HCC detection among HIV-infected patients in low- and middle-income countries.

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer–specific survival. Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer–specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer–specific survival (HD, −1.15; 95% CI, −2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer–specific survival. Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.