Citations

Abstract Background: Targeted therapies are increasingly under evaluation in clinical trials for the treatment of biliary tract cancer (BTC), and cell-free tumor DNA assays are an emerging technology for the detection of actionable alterations. Methods: ctDNA analysis was performed in patients with BTC using the CLIA-certified Guardant360 liquid biopsy assay as part of routine clinical care. The assay screens up to 73 genes for single-nucleotide variants (SNVs), 23 for insertions or deletions (INDELs), 18 for copy number variations (CNVs), and 6 for fusions. Results: 855 samples were analyzed from 751 unique BTC patients. Median age was 64 years (range, 29-89), 53% were female, and 631 (84%) had at least one alteration in their first sample. In the 751 patients, the most common genes altered were TP53 (39%), KRAS (15%), PIK3CA (13%), ARID1A (13%), EGFR (11%), FGFR2 (11%), ERBB2 (11%), NF1 (10%), IDH1 (10%), APC (9%), BRAF (9%), MYC (8%), MET (7%), CCNE1 (7%), and FGFR1 (7%). Alterations in DNA damage response genes were also seen, including BRCA2 (6%), BRCA1 (5%), ATM (4%), and MLH1 (1%). The median number of alterations per sample was 3 (range, 0-40). In a clinically annotated dataset from the Massachusetts General Hospital Cancer Center, 112 samples were obtained from 61 unique patients. Among these, 52 (85%) had intrahepatic cholangiocarcinoma (ICC), 3 (5%) had extrahepatic cholangiocarcinoma, and 6 (10%) had gallbladder cancer. 20/61 (33%) patients were treated with targeted therapy. Among 20 patients with both ctDNA and tumor sequencing results, the targetable mutation was found in both ctDNA and tumor tissue in 7/20 (35%), solely in ctDNA in 1/20 (5%), and solely in tissue in 12/20 (60%) patients. The patient with the alteration detected solely in ctDNA had insufficient tissue for analysis; she was found to have an FGFR2 F276C mutation and benefited for 8.5 months from an FGFR inhibitor on a clinical trial. Of the 12 patients whose targetable mutation was not detected in plasma, 10 (83%) had an FGFR2 fusion, 1 had an INDEL in FGFR2 (Leu262_Ala266delinsAsp), and 1 had an FGFR3 splice site mutation. 15/20 (75%) patients treated with targeted therapy were followed with serial ctDNA analysis, and a potential resistance mechanism was identified in 5/15 (33%). All 5 patients had FGFR2-fusion positive ICC and developed mutations in the FGFR2 kinase domain as a potential resistance mechanism to FGFR inhibition, including the FGFR2 V564F gatekeeper mutation in 4/5 patients. Conclusions: In patients with BTC, ctDNA-based genomic profiling can detect alterations in IDH, FGFR, PIK3CA, ERBB2, BRAF, and MET. The technology is still evolving for the detection of FGFR2 fusions, which is hindered in capture-based methods in plasma by the large number of unique breakpoints and fusion partners. ctDNA analysis may also provide a noninvasive mechanism to study resistance to targeted therapy and clonal dynamics in BTC. Citation Format: Lipika Goyal, Robin Kate Kelley, Lesli Kiedrowski, Daniel Catenacci, Kabir Mody, Rachna Shroff, Aparna Parikh, Stephanie Reyes, Jordan R. Maurer, Ryan B. Corcoran, Paul Fanta, Mike Cusnir, Becky Nagy, Richard Lanman, Michael Morse, Benjamin Tan, Milind Javle, Andrew Zhu. Blood-based genomic profiling of cell-free tumor DNA (ctDNA) in patients with biliary tract cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A183.

Abstract Objective This study investigates high‐frequency oscillations ( HFO s; 65–600 Hz) as a biomarker of epileptogenic brain and explores three barriers to their clinical translation: (1) Distinguishing pathological HFO s (path HFO ) from physiological HFO s (phys HFO ). (2) Classifying tissue under individual electrodes as epileptogenic (3) Reproducing results across laboratories. Methods We recorded HFO s using intracranial EEG ( iEEG ) in 90 patients with focal epilepsy and 11 patients without epilepsy. In nine patients with epilepsy putative phys HFO s were induced by cognitive or motor tasks. HFO s were identified using validated detectors. A support vector machine ( SVM ) using HFO features was developed to classify tissue under individual electrodes as normal or epileptogenic. Results There was significant overlap in the amplitude, frequency, and duration distributions for spontaneous phys HFO , task induced phys HFO , and path HFO , but the amplitudes of the path HFO were higher ( P < 0.0001). High gamma path HFO had the strongest association with seizure onset zone ( SOZ ), and were elevated on SOZ electrodes in 70% of epilepsy patients ( P < 0.0001). Failure to resect tissue generating high gamma path HFO was associated with poor outcomes ( P < 0.0001). A SVM classified individual electrodes as epileptogenic with 63.9% sensitivity and 73.7% specificity using SOZ as the target. Interpretation A broader range of interictal path HFO (65–600 Hz) than previously recognized are biomarkers of epileptogenic brain, and are associated with SOZ and surgical outcome. Classification of HFO s into physiological or pathological remains challenging. Classification of tissue under individual electrodes was demonstrated to be feasible. The open source data and algorithms provide a resource for future studies.

Background: Iliopsoas fractional lengthening (IFL) continues to be a controversial procedure in hip arthroscopy. Hypothesis: Patients who underwent arthroscopic surgery for femoroacetabular impingement (FAI) and a labral tear either with or without IFL would experience favorable outcomes, and there would be no difference in postoperative patient-reported outcomes (PROs) between the 2 groups at minimum 2-year follow-up. Study Design: Cohort study; Level of evidence, 3. Methods: Data from July 2009 and April 2015 were retrospectively reviewed. Patients were eligible if they had hip arthroscopy for both FAI and labral tear treatment with IFL and without IFL. IFL was indicated for painful internal snapping. Minimum postoperative follow-up was set to 2 years. The authors calculated the modified Harris Hip Score, International Hip Outcome Tool–12, Hip Outcome Score–Activity of Daily Living Score, Hip Outcome Score–Sports Specific Subscale, Non-Arthritic Hip Score, visual analog scale for pain, patient satisfaction, minimal clinically important difference (MCID), and the percentage of patients who achieved patient acceptable symptomatic state (PASS). Revision surgeries and conversions to total hip arthroplasty (THA) were documented. Results: 351 hips (307 patients) met the necessary inclusion criteria in the IFL cohort, with a mean ± SD follow-up time of 42.5 ± 18.1 months. For the control cohort, 392 hips (354 patients) were included, with a mean ± SD follow-up time of 43.9 ± 19.6 months. Both groups showed significant postoperative improvement in 2-year follow-up PROs. The group with iliopsoas lengthening showed comparable results to the control group with respect to PRO improvement, MCID, PASS, and rates of revision or THA conversion. Conclusion: This comparative cohort study demonstrated that treatment of painful internal snapping syndrome with arthroscopic IFL, in the setting of FAI and a labral tear, is a safe procedure with good short- to mid-term follow-up results and associated improvement in PROs. Patients who underwent IFL showed similar outcomes compared with a control group treated for FAI and labral tear without IFL. In appropriately selected patients, arthroscopic IFL did not adversely affect clinical outcomes compared with patients who did not need IFL.

Objectives: To report the minimum two-year outcomes of trans-tendinous repairs of Partial Thickness Undersurface Tears of the Abductor (PUSTA) tendon using patient reported outcomes (PROs), visual analog scale (VAS), and patient satisfaction scores. Methods: All patients who underwent endoscopic trans-tendinous gluteus medius repair between October 2009 and May 2013 at one institution were prospectively evaluated. Exclusion criteria consisted of less than two-year follow-up, previous hip surgery, inflammatory arthritis, open surgery, full thickness abductor tear, and worker’s compensation patients. All patients had a documented pre-operative physical exam with strength testing (0-5) and observation of their gait. Patient satisfaction and PRO scores were recorded preoperatively, at 3 months postoperatively, and annually thereafter. The PRO scores collected were mHHS, HOS-ADL, HOS-SSS, NAHS, and VAS. Preoperative strength and gait were compared to latest follow-up. Results: There were 25 patients that fit our criteria. Significant improvement in PRO scores were demonstrated for mHHS, HOS-ADL, HOS-SSS, NAHS, and VAS from 54.9-76.2, 50.2-80.6, 30.1-67.3, 51.9-82.4, and 7.1-2.7 respectively (p<0.001). There were 11 patients with objective weakness prior to surgery; seven of these patients moved up at least one strength grade by final follow-up. There were 14 patients who had a Trendelenbrug gait pre-operatively, 12 of them had a normal gait at latest follow-up (p-<0.001). Average patient satisfaction was 7.5. There were no revision surgeries, and no complications noted. Conclusion: PUSTA lesions can be treated successfully with endoscopic trans-tendinous repair preserving the intact attachment of superficial fibers of the gluteus medius. We recommend this treatment for partial undersurface tears recalcitrant to non-operative treatment, as patients demonstrated clinical benefit at greater than 2 years follow up that exceeds substantial clinical benefit and minimally clinical important difference.

Clinical treatments of skeletal muscle weakness are hindered by a lack of an approach to evaluate individual muscle force. Intramuscular pressure (IMP) has shown a correlation to muscle force in vivo, but patient to patient and muscle to muscle variability results in difficulty of utilizing IMP to estimate muscle force. The goal of this work was to develop a finite element model of whole skeletal muscle that can predict IMP under passive and active conditions to further investigate the mechanisms of IMP variability. A previously validated hypervisco-poroelastic constitutive approach was modified to incorporate muscle activation through an inhomogeneous geometry. Model parameters were optimized to fit model stress to experimental data, and the resulting model fluid pressurization data were utilized for validation. Model fitting was excellent (root-mean-square error or RMSE <1.5 kPa for passive and active conditions), and IMP predictive capability was strong for both passive (RMSE 3.5 mmHg) and active (RMSE 10 mmHg at in vivo lengths) conditions. Additionally, model fluid pressure was affected by length under isometric conditions, as increases in stretch yielded decreases in fluid pressurization following a contraction, resulting from counteracting Poisson effects. Model pressure also varied spatially, with the highest gradients located near aponeuroses. These findings may explain variability of in vivo IMP measurements in the clinic, and thus help reduce this variability in future studies. Further development of this model to include isotonic contractions and muscle weakness would greatly benefit this work.