Citations

AimsThere is little literature about total knee arthroplasty (TKA) after distal femoral osteotomy (DFO). Consequently, the purpose of this study was to analyze the outcomes of TKA after DFO, with particular emphasis on: survivorship free from aseptic loosening, revision, or any re-operation; complications; radiological results; and clinical outcome.Patients and MethodsWe retrospectively reviewed 29 patients (17 women, 12 men) from our total joint registry who had undergone 31 cemented TKAs after a DFO between 2000 and 2012. Their mean age at TKA was 51 years (22 to 76) and their mean body mass index 32 kg/m2(20 to 45). The mean time between DFO and TKA was ten years (2 to 20). The mean follow-up from TKA was ten years (2 to 16). The prostheses were posterior-stabilized in 77%, varus-valgus constraint (VVC) in 13%, and cruciate-retaining in 10%. While no patient had metaphyseal fixation (e.g. cones or sleeves), 16% needed a femoral stem.ResultsThe ten-year survivorship was 95% with aseptic loosening as the endpoint, 88% with revision for any reason as the endpoint, and 81% with re-operation for any reason as the endpoint. Three TKAs were revised for instability (n = 2) and aseptic tibial loosening (n = 1). No femoral component was revised for aseptic loosening. Patients under the age of 50 years were at greater risk of revision for any reason (hazard ratio 7; p = 0.03). There were two additional re-operations (6%) and four complications (13%), including three manipulations under anaesthetic (MUA; 10%). The Knee Society scores improved from a mean of 50 preoperatively (32 to 68) to a mean of 93 postoperatively (76 to 100; p < 0.001).ConclusionA cemented posterior-stabilized TKA has an 88% ten-year survivorship with revision for any reason as the endpoint. No femoral component was revised for aseptic loosening. Patients under the age of 50 years have a greater risk of revision. The clinical outcome was significantly improved but balancing the knee was challenging in 13% of TKAs requiring VVC. Overall, 10% of TKAs needed an MUA, and 6% of TKAs were revised for instability. Cite this article: Bone Joint J 2019;101-B:660–666.

AbstractObjectiveTo assess the association between elevated ventricular‐end diastolic pressures (VEDP) and pulmonary artery wedge pressure (PAWP) on long‐term survival in adult Fontan patients.BackgroundThe impact of ventricular filling pressures on long‐term survival in adults post‐Fontan palliation is unknown.MethodsWe included 148 adult Fontan patients (age ≥ 18 years) without atrioventricular valve prosthesis or pulmonary vein stenosis undergoing arterial and venous catheterization between December 1999 and November 2017. VEDP was defined as ≥12 mmHg and PAWP as >12 mmHg based on optimal cut‐offs for prediction of mortality on receiver‐operator curves (AUC 0.63 and 0.66, respectively).ResultsMean age was 31.3 ± 9.2 years and 48.6% of patients were females. Most common congenital defects were tricuspid atresia (36.4%) and double‐inlet left ventricle (28.3%); 59.5% patients had atriopulmonary Fontan connections. Mean VEDP was 11.5 ± 4.7 mmHg and PAWP 10.6 ± 4.5 mmHg (correlation coefficient .76). During a follow‐up of 6.0 ± 4.8 years (median 5.4, IQR 1.4–9.4), there were 45 deaths (30.4%). Overall survival was lower in patients with VEDP ≥ 12 compared to those with VEDP < 12 mmHg (p = .02). Similarly, survival was lower in patients with PAWP>12 compared to patients with PAWP ≤ 12 mmHg (p < .0001). In the multivariate model, PAWP was an independent predictor of death (HR 1.1 per mmHg, 95% CI 1.02–1.15, p = .009) whereas VEDP was not (HR 1.1 per mmHg, 95% CI 1.0–1.13; p = .08).ConclusionPAWP but not VEDP was independently associated with long‐term overall mortality in adult Fontan patients. Perhaps PAWP rather than VEDP should be used in the risk stratification of these patients.

Aim: Compare the effect of Latarjet and Trillat procedures on glenohumeral stability and range of motion. Background: Little is known about the impact of the location of the sling effect on joint stability and range of motion. Methods: 12 cadaveric shoulders were cleaned of soft tissue except for the subscapularis, conjoined tendon, and anterior capsule. A custom-made apparatus generating anterior humeral translation and joint compression was used. The machine applied compression load in the medial direction. The subscapularis and conjoint tendon were loaded. Internal/external range of motion and joint stability were assessed at 0°, 30° and 60° glenohumeral abduction. Range of motion was assessed by rotating the humeral shaft. Joint stability was assessed at maximum external rotation, translating the humerus. Specimen were tested in five conditions: 1) intact shoulder, 2) 6-mm bony glenoid defect (20% defect) 3) Trillat procedure, 4) Latarjet procedure with subscapularis split at the junction between its superior 2/3rds and inferior 1/3 rd, 5) Latarjet procedure with subscapularis split at the superior 1/3rds and inferior 2/3rds. Means were compared with a full factorial-repeated measures ANOVA with pairwise post hoc comparisons. Results: Peak translation force and stability ratio were significantly lower with the glenoid defect when compared to the intact and all the repaired conditions at all levels of glenohumeral abduction. The level of the subscapularis split had no significant influence on these values and no significant difference could be found between Trillat and Latarjet procedures. Range of motion in internal and external rotation were not significantly different between the different conditions. Conclusions: Joint stability and range of motion after a Latarjet are not impacted by the location of the subscapularis muscle split. Trillat and Latarjet techniques provide comparable stabilization of the joint, even in the presence of a critical bony defect of the glenoid.

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.

6020 Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). > 1 response(s) in the first 21 would trigger accrual to 41; > 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed <4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.

3049 Background: For multi-cancer detection using cfDNA, TOO determination is critical to enable safe and efficient diagnostic follow-up. Previous array-based studies captured < 2% of genomic CpGs. Here, we report genome-wide fragment-level methylation patterns across 811 cancer cell methylomes representing 21 tumor types (97% of SEER cancer incidence), and define effects of this methylation database on TOO prediction within a machine learning framework. Methods: Genomic DNA from 655 formalin-fixed paraffin-embedded (FFPE) tumor tissues and 156 isolated cells from tumors was subjected to a prototype 30x whole-genome bisulfite sequencing (WGBS) assay, as previously reported in the Circulating Cell-free Genome Atlas (CCGA) study (NCT02889978). Two independent TOO models, one with and one without the methylation database, were fitted on training samples; each was used to predict on the test set. A WGBS classifier was used to detect cancer at 98% specificity; reported TOO results reflect percent agreement between predicted and true TOO among those detected cancers (166 cases: 81 stage I-III, 69 stage IV, 16 non-informative). Results: Genome-wide methylation data generated from this database allowed fragment-level analysis and coverage of ~30 million CpGs across the genome (~60-fold greater than array-based approaches). Incorrect TOO assignments decreased by 35% (20% to 13%) after incorporating methylation database information into TOO classification. Improvement was observed across all cancer types and was consistent in early-stage cancers (stage I-III). Respective performances in breast cancer (n = 23) were 87% vs 96%; in lung cancer (n = 32) were 85% vs 88%; in hepatobiliary (n = 10) were 70% vs 90%; and in pancreatic cancer (n = 17) were 94% vs 100%. Results using an optimized approach informed by these results in a large cohort of CCGA participants will be reported. Conclusions: Incorporating data from a large methylation database improved TOO performance in multiple cancer types. This supports feasibility of this methylation-based approach as an early cancer detection test across cancer types. Clinical trial information: NCT02889978.

1545 Background: Screening tests for early cancer detection are often criticized due to risk of overdiagnosis—detection of good prognosis cancers which may not require immediate treatment. We recently reported development of cfDNA sequencing approaches for cancer detection; longitudinal follow-up (F/U) data were utilized here to evaluate prognostic significance of cancer detection using cfDNA. Methods: Plasma cfDNA samples were subjected to whole-genome bisulfite sequencing (WGBS, 30X) as part of a previously-reported Circulating Cell-free Genome Atlas (CCGA; NCT02889978) substudy. This exploratory analysis evaluated the overall survival (OS) of training and test set participants (pts) with cancer (20 cancer types, any stage I-IV). Combining train and test set pts, univariate and multivariate analyses (Cox proportional hazards) assessed OS association with WGBS result (cancer detected vs not detected, set at 98% specificity), clinical stage (IV vs I-III), diagnostic method (symptom- vs screen-detected), sex, age, and histologic grade. Results: Of 827 pts from the training set with F/U (median 12.2 mo), 334 (40.4%) had WGBS-detected cancer. Among 127 (15.4%) pts with cancer that died during F/U, cancer was detected in 104 (81.9%). Results were similar in the test set. In univariate analyses all variables were associated with prognosis, including WGBS result (HR 7.7 p<0.001). In multivariate analyses accounting for other covariates, the three variables that most significantly remained prognostic were WGBS (HR 3.0, p<0.001), clinical stage (HR 3.3, p<0.001), and diagnostic method (HR 3.0, p<0.001). Validation of these findings is ongoing in an independent cohort of ~5,000 cancer pts from CCGA using an optimized assay; updated performance results will be reported. Conclusions: Cancers detected using WGBS of cfDNA had a worse prognosis than cancers not detected. WGBS cancer detection carried comparable prognostic significance as clinical stage. By preferentially detecting higher risk cancers, cancer detection using plasma cfDNA may avoid some of the overdiagnosis that has been seen with some existing cancer screening methods. Clinical trial information: NCT02889978.