Citations

Background: Quadriceps tendon rupture following total knee arthroplasty (TKA) is an infrequent but potentially devastating adverse event. Although uncommon, the long-term sequelae of this injury can result in permanent inability to walk. Despite the severity of this injury, there is no single accepted treatment, with various surgical methods producing mixed results. Therefore, the purpose of this study was to assess the efficacy of a modified V-Y turndown flap as a viable alternative method of treatment for this injury. Methods: Twenty-four quadriceps tendon ruptures in 23 patients (10 men and 13 women) who underwent TKA (8 primary and 15 revision), including 1 tendon rerupture, were treated with use of a modified V-Y turndown. The average patient age at the time of the V-Y flap repair was 61 years (range, 41 to 86 years). Knee Society scores, range of motion, strength, medical comorbidities, nature of the procedure (i.e., primary versus revision), and the ability to walk were all recorded before and after the quadriceps reconstruction, along with general satisfaction and adverse events following the procedure. Results: Twelve patients (52%) had predisposing comorbidities, including obesity, diabetes, chronic dialysis, and steroid dependence. Prior to repair with the V-Y flap, none of the patients were able to walk independently, requiring either a wheelchair or walker. No patient had quadriceps strength greater than 3 (of 5), although all had full passive extension. Following the repair procedure, patients had significant (p < 0.0001) improvements in mean Knee Society knee score (88.7; range, 45 to 95) and mean strength (4.8; range, 3 to 5), and all were able to walk without assistive devices. Twenty knees exhibited active range of motion of 0° to 120°, whereas 4 had residual extensor lag of ≥5° (range, 5° to 35°). Major adverse events were limited to a single hematoma and an unacceptable extensor lag (35°) after repair. Conclusions: The modified V-Y quadriceps tendon turndown flap was a reliable alternative treatment for achieving restoration of the extensor mechanism after complete quadriceps tendon rupture following TKA. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Introduction Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. Methods We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB‐PET), 18 F‐fluorodeoxyglucose PET (FDG‐PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. Results PiB‐PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG‐PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB‐PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non‐Alzheimer's pathophysiology” represented 15% of the group. Discussion PiB‐PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG‐PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non‐Alzheimer's pathophysiology most commonly had primary age‐related tauopathy.

Abstract Pain and physical activity are tightly intertwined. Although their relationship has been explored in chronic pain conditions, we know little about the pattern of recovery in activity and its short- and long-term relationship with pain after surgery. We recruited 103 women undergoing elective cesarean delivery and acquired daily pain assessments and hourly steps in 98 of them for 2 months after surgery. Compliance was good, with 78% of subjects missing less than 7 days of activity. Study personnel required daily checking for compliance and 20 minutes per subject per week in study. Activity increased over the first 2 postoperative months in a log(time) manner. The slope of each modeled individual curve for activity was inversely correlated (r = −0.54; P < 0.0001) with worst daily pain. After removing these 2-month trends, pain and activity within an individual day were negatively associated with each point increase in pain being inversely associated with −119 steps (95% confidence interval [CI] = −214 to −25; P = 0.013). A patient's previous experience of pain was not associated with current activity as well as current activity was not associated with future pain scores. These data, although limited by the study of a single operation in a unique social circumstance with low risk of chronic postsurgical pain, demonstrate feasibility of measuring hourly activity for 2 months after surgery. Recovery from pain and inactivity are tightly correlated, and the negative relationship between within-day pain and activity without interday carryover relationships is in stark contrast to findings in chronic pain conditions.

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.

Abstract Introduction We evaluated whether incident mild cognitive impairment (MCI) subtypes could be empirically derived in the Mayo Clinic Study of Aging. Methods We performed cluster analysis on neuropsychological data from 506 participants with incident MCI. Results The 3‐cluster solution resulted in (1) amnestic, (2) dysexecutive, (3) dysnomic subtypes. The 4‐cluster solution produced these same three groups and a fourth group with subtle cognitive impairment (SCI). The SCI cluster was a subset of the amnestic cluster and distinct from well‐matched cognitively unimpaired participants based on memory and global z‐score area under the receiver operating characteristic curve analyses and probability of progression to MCI/dementia. Discussion We empirically identified three neuropsychological subtypes of MCI that share some features with MCI subtypes identified in the Alzheimer's Disease Neuroimaging Initiative. The fourth subtype with SCI in the Mayo Clinic Study of Aging differed from the fourth cluster‐derived normal group in Alzheimer's Disease Neuroimaging Initiative and could represent a group to target with early interventions.

Background: The Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire has recently been validated to measure the impact of atrial fibrillation on quality of life, but a clinically important difference in AFEQT score has not been well defined. Methods and Results: To determine the clinically important difference in overall AFEQT (score range= 0 [worst] to 100 [best]) and selected subscales, we analyzed data in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry, a United States-based outpatient atrial fibrillation registry. AFEQT was assessed at baseline and 1 year in a subset of 1347 ORBIT-AF patients from 80 US sites participating in ORBIT-AF from June 2010 to August 2011. The mean change method was used to relate changes in 1-year AFEQT scores to clinically important changes in the physician assessment of European Heart Rhythm Association functional status (1 class improvement and separately 1 class deterioration). Clinically important differences and 95% CI corresponding to either a 1 European Heart Rhythm Association class improvement or deterioration were 5.4 (3.6–7.2) and −4.2 (−6.9 to −1.5) AFEQT points, respectively. Similarly, clinically important difference values were seen for a 1 European Heart Rhythm Association class improvement for the AFEQT subscales Activities of Daily Living and Symptoms: 5.1 (2.5–7.6) and 7.1 (5.3–9.0) AFEQT points, respectively. Conclusions: Based on the anchor of 1 European Heart Rhythm Association class change, changes in AFEQT score of + or −5 points are clinically important changes in patients’ health. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT01165710.

Abstract ctDNA analysis offers a non-invasive approach for monitoring response and resistance to treatment. Serial ctDNA testing during neoadjuvant therapy (NAT) may provide early indicators of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesize that (1) assessment of ctDNA levels early in treatment will improve the performance of molecular and imaging-based predictors of pathologic complete response (pCR) to NAT; and (2) levels of ctDNA after NAT are associated with residual cancer burden and recurrence [distant recurrence free survival (DRFS)]. Methods: ctDNA analysis was performed in 84 high-risk stage II and III breast cancer patients randomized to neoadjuvant investigational agent (n=52), AKT inhibitor MK-2206 (M) in combination with paclitaxel (T) followed by doxorubicin and cyclophosphamide (AC) (M+T-&gt;AC), or standard-of-care (T-&gt;AC) (n=32). HER2+ patients also received trastuzumab (H). Serial plasma was collected before NAT (T0), early treatment (3 weeks, T1), between regimens (12 weeks, T2), and after NAT prior to surgery (T3). Mutational profiles derived from pretreatment tumor biopsy and normal matched DNA whole exome sequencing were used to design personalized assays targeting 16 patient-specific somatic variants to detect ctDNA in serial plasma. Results: Of the 84 patients in this study, 43% were HR-/HER2- (TNBC), 35% HR+/HER2-, and 23% HER2+. In total, 74% (61 of 83), 35% (28 of 79), 14% (9 of 65), and 8% (5 of 61) were positive for ctDNA at timepoints T0, T1, T2, and T3, respectively. At T0, ctDNA positivity and levels (average number of mutant molecules detected per mL) were significantly associated with increased tumor burden (by clinical and MRI examination), more aggressive tumor biology (as reflected in higher Mammaprint scores and grade) and subtype (HER2+ and TNBC). Twenty-seven percent (27%) of the 84 patients achieved a pCR and all patients who were ctDNA-positive at T3 (n=5) did not achieve a pCR. Currently, data are being collected to: (1) assess the relationship of ctDNA and MRI imaging in predicting tumor response to therapy; (2) examine the relationship of ctDNA levels before and after NAT with 3-year DRFS and event-free survival (EFS). The results of these analyses will be presented at the SABCS 2018 meeting. Conclusions: Our study provides a platform to evaluate the clinical significance of ctDNA for serial monitoring of response to NAT. Accurate and early response prediction by highly sensitive ctDNA analysis can facilitate a timely and judicious change in treatment to improve patients' chances of achieving a pCR. Finally, personalized ctDNA testing may complement imaging and pathologic evaluation of tumor response to fine-tune pCR as a surrogate endpoint for improved DRFS and EFS. Citation Format: Magbanua MJM, Brown-Swigart L, Hirst GL, Yau C, Wolf D, Ma AA, Bergin E, Venters S, Sethi H, Wu H-T, Salari R, Tin T, Sawyer S, Louie M, Zimmermann B, Lin C-HJ, Keats J, Liang WS, Cuyugan L, Enriquez D, Tripathy D, Chien AJ, Forero A, DeMichele A, Liu M, Delson AL, Asare S, Esserman L, van't Veer L, I-SPY 2 Consortium. Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-01.

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors effectively lower LDL (low‐density lipoprotein) cholesterol and have been shown to reduce cardiovascular outcomes in high‐risk patients. We used real‐world electronic health record data to characterize use of PCSK9 inhibitors, in addition to standard therapies, according to cardiovascular risk status. Methods and Results Data were obtained from 18 health systems with data marts within the National Patient‐Centered Clinical Research Network (PCORnet) using a common data model. Participating sites identified >17.5 million adults, of whom 3.6 million met study criteria. Patients were categorized into 3 groups: (1) dyslipidemia, (2) untreated LDL ≥130 mg/dL, and (3) coronary artery disease or coronary heart disease. Demographics, comorbidities, estimated 10‐year atherosclerotic cardiovascular disease risk, and lipid‐lowering pharmacotherapies were summarized for each group. Participants’ average age was 62 years, 50% were female, and 11% were black. LDL cholesterol ranged from 85 to 151 mg/dL. Among patients in groups 1 and 3, 54% received standard lipid‐lowering therapies and a PCSK9 inhibitor was prescribed in <1%. PCSK9 inhibitor prescribing was greatest for patients with coronary artery disease or coronary heart disease and, although prescribing increased during the study period, overall PCSK9 inhibitor prescribing was low. Conclusions We successfully used electronic health record data from 18 PCORnet data marts to identify >3.6 million patients meeting criteria for 3 patient groups. Approximately half of patients had been prescribed lipid‐lowering medication, but <1% were prescribed PCSK9 inhibitors. PCSK9 inhibitor prescribing increased over time for patients with coronary artery disease or coronary heart disease but not for those with dyslipidemia.