Citations

Abstract CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in <1% of NC participants across all assays (representing potential undiagnosed cancers). An increasing trend was observed in NC vs stages I-III vs stage IV (nonsyn. SNVs/indels per Mb [Mean±SD] NC: 1.01±0.86, stages I-III: 2.43±3.98; stage IV: 6.45±6.79; WGS score NC: 0.00±0.08, I-III: 0.27±0.98; IV: 1.95± 2.33; methylation score NC: 0±0.50; I-III: 1.02±1.77; IV: 3.94±1.70). These data demonstrate the feasibility of achieving >99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.

Background Platelet microparticles (PMPs) and their abundance in the blood are a prognostic biomarker in thrombotic disorders and cancer. Nanoscale flow cytometry (nFC) is ideal for high-throughput analysis of PMPs but these clinical assays have not been developed previously. Objective This article demonstrates that nFC is a suitable technology to enumerate PMPs present in plasma samples in a clinical setting. Materials and Methods nFC was performed using the Apogee A50-Micro instrument. Instrument settings and acquisition parameters were developed with the use of fluorescent beads and plasma samples. Sample preparation and handling was also optimized. Results nFC allows for linear detection of particles between approximately 200 and 1,000 nm based on calibration beads and was dependent on dilution factor and flow rate. Linearity in event analysis as samples became more diluted was lost when events approximately 100 nm were gated while linearity was maintained despite dilution of sample in events larger than 200 nm in diameter. Higher flow rates lead to an under-estimation of events analysed per microlitre of analyte and this was more pronounced when plasma samples were not diluted more than 1/20×. Conclusion nFC offers multi-parametric analysis of PMPs when optimal calibration of acquisition and sample processing settings is performed. Analysis of plasmas from metastatic prostate cancer patients and leukaemia patients revealed that PMP levels were larger than 100 nm and were equally abundant in patients that responded to or failed androgen deprivation therapy or between patients representing different stages of leukaemia.

ABSTRACT Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper.

Objectives: Ultrasound guided fascia-Iliaca blocks have been used for pain control following hip arthroscopy. There is little evidence regarding their effectiveness in comparison to other pain control modalities in hip arthroscopy patients. To compare efficacy of ultrasound guided fascia iliac block with intra-articular ropivacaine in controlling pain after hip arthroscopy. Methods: Between 2015 and 2017, 95 patients undergoing hip arthroscopy were randomly assigned to 2 groups. The first group received an ultrasound-guided fascia-iliaca block with 50-60mLs of 0.35% ropivacaine. The second group received intra-articular injection of 20 mL of 0.5% ropivacaine at the completion of the surgical case. Primary outcomes were post-operative pain scores in the recovery room, at PACU discharge, at 2 weeks, 6 weeks, and 3 months. Secondary outcomes included intraoperative and PACU narcotic usage (converted to morphine equivalent use) as well as readmission rates, PACU recovery time and postoperative nausea and vomiting (PONV). Results: Postoperative pain across all points did not significantly differ between the 2 groups. Intraoperative and PACU narcotics did not differ significantly between the 2 groups. Readmission rates, PACU recovery time and PONV did not significantly differ between the 2 groups. There were no associated complications in either group. Conclusion: Ultrasound guided fascia iliaca block for hip arthroscopy had no clinical advantage when compared to one time intra-articular ropivacaine injection. Furthermore, an intraarticular injection decreases costs and is a safe and more efficient modality for postoperative pain control following hip arthroscopy.

Abstract BACKGROUND The nasoseptal flap is the main pedicled flap used for endoscopic cranial base reconstruction. For large anterior cranial base defects, the anterior edge is a concern for the nasoseptal flap reach. OBJECTIVE To present a surgical technique that completely releases the vascular pedicle of the nasoseptal flap from the sphenopalatine artery (SPA) foramen improving considerably the reach of the flap. METHODS A patient with left anterior cranial base fracture involving the posterior table of the frontal sinus, who presented with cerebrospinal fluid leak and contused brain herniation to the ethmoid and frontal sinuses. Unilateral endoscopic endonasal anterior cranial base reconstruction was performed with left sided nasoseptal flap. The nasoseptal flap pedicle was dissected and completely released from the SPA foramen. The flap was left attached only to the internal maxillary artery (IMAX) vascular bundle. RESULTS The flap covered the entire left anterior cranial base, from the planum sphenoidale to the posterior table of the frontal sinus. There was complete obliteration of the cerebrospinal fluid fistula postoperatively with resolution of the radiographic pneumocephalus and the patient's rhinorrhea. CONCLUSION The complete release of the nasoseptal flap pedicle from the SPA foramen is feasible and remarkably improves the reach of the flap. It also increases the reconstructive area of the flap since the entire septal mucosa can be used for reconstruction and the pedicle length is based exclusively upon the SPA/IMAX.

Study Design: Retrospective database analysis. Objective: To examine the impact of training pathway, either neurosurgical or orthopedic, on complications, readmissions, and revisions in spine surgery. Summary of Background Data: Training pathway has been shown to have an impact on outcomes in various surgical subspecialties. Although training pathway has not been shown to have a significant impact on spine surgery outcomes in the perioperative period, long-term results are unknown. Materials and Methods: A retrospective analysis of 197,682 patients receiving 1 of 3 common spine surgeries [lumbar laminectomy, lumbar fusion, and anterior cervical discectomy and fusion (ACDF)] between 2006 and 2010 was conducted. Patient data were obtained from a large claims database. Postoperative adverse effects, all-cause readmission, revision surgery rates, and intermediary payments in these cohorts of patients were compared between spine surgeons with either neurosurgical or orthopedic backgrounds. Results: Patient demographics, hospital-stay characteristics, and medical comorbidities were similar between neurosurgeons and orthopedic surgeons. The risks of surgical complications, all-cause readmission, and revision surgery were also similar between neurosurgeons and orthopedic surgeons across all procedure types assessed, with several minor exceptions: neurosurgeons had marginally higher odds of any complication for lumbar fusions [odds ratio (OR) 1.14; 95% confidence interval (CI), 1.09–1.20] and ACDFs (OR, 1.09; 95% CI, 1.04–1.15). Neurosurgeons also had slightly higher rates of revision surgery for concurrent lumbar laminectomy with fusion (OR, 1.14; 95% CI, 1.08–1.22), and ACDFs (OR, 1.20; 95% CI, 1.14–1.28). No associations between surgeon type and any particular complication were consistently observed for all procedure groups. There were also no associations between surgeon type and 30-day all-cause readmission. Median total intermediary payments were somewhat higher for neurosurgery patients for all procedure groups assessed. Conclusions: Few significant associations between surgeon type and patient outcomes exist in the context of spine surgery. Those which do are small and unlikely to be clinically meaningful. Level of Evidence: Level 3.

AbstractBackground: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes.Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS).Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03).Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes.Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

Background Non–vitamin K antagonist oral anticoagulants (NOACs) are indicated for stroke prevention in atrial fibrillation (AF) but require lower doses in certain patients. We sought to describe the frequency, appropriateness (according to Food and Drug Administration labeling), and outcomes of patients prescribed reduced doses of NOACs in community practice. Methods and Results We analyzed data from the ORBIT‐AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) registry, a prospective, national, observational registry of AF patients. Among 7925 AF patients receiving NOACs, we assessed patterns of use of reduced NOAC doses and associated cardiovascular and bleeding outcomes at median follow‐up of 1 year. Overall, 6636 patients (84%) received a NOAC at standard dose, which was consistent with US Food and Drug Administration labeling in 6376 (96%). Reduced NOAC dose was prescribed to 1289 (16% overall), which was consistent with Food and Drug Administration labeling in only 555 patients (43%). Compared with those whose NOAC dose was appropriately reduced, patients receiving inappropriate dose reductions were younger (median age 79 versus 84, P <0.0001) and had lower ORBIT bleeding risk scores (26% ≥4 versus 45%, P <0.0001). Compared with those appropriately receiving standard dosing, patients receiving inappropriately reduced‐dose NOACs had higher unadjusted rates of thromboembolic events (2.11 versus 1.35 events per 100 patient years, hazard ratio 1.56, 95% confidence interval 0.92‐2.67) and death (6.77 versus 2.60, hazard ratio 2.61, 95% confidence interval 1.86‐3.67). After adjustment, outcomes were not significantly different but tended to favor patients dosed appropriately. Conclusions The majority of dose reductions of NOACs in AF are inconsistent with US Food and Drug Administration recommendations. There appear to be opportunities to improve current NOAC dosing in community practice. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.