Citations

Abstract Our goal is to identify novel targeted therapies for Ewing sarcoma (ES). ES is a devastating malignancy that predominantly affects children and young adults. It is the second most common cancer of the bone, yet in contrast to many other malignancies, survival rates have not improved for decades. For patients with localized disease, no biomarkers exist to predict recurrence or response to chemotherapy. For those with metastatic disease, chemotherapy is largely ineffective, and 5-year survival rates have stagnated at approximately 20%. Thus, there is an urgent need to identify biomarkers that can predict recurrence and response to therapy, as well as identify novel targeted therapies to combat this lethal disease. USP6 is the key etiologic agent in several benign bone and soft tissue tumors (BSTTs), where its chromosomal translocation results in overexpression. USP6 encodes a deubiquitylating enzyme, and our prior studies identified the tyrosine kinase Jak1 as an essential substrate of USP6 during BSTT development. Jak1 levels are dramatically elevated in USP6-overexpressing cells, leading to phosphorylation and activation of STAT transcription factors. We recently discovered that USP6 is also highly expressed in multiple sarcomas, including ES. Since Jak1-STATs play a central in mediating response to interferon (IFN), we hypothesized that USP6 might cause dysregulated IFN signaling in ES. Microarray and RNA-sequencing analysis revealed that USP6 by itself induced an IFN-response gene signature, both in immortalized, patient-derived ES cells and in primary human ES tumors. USP6+ ES cells were found to be exquisitely sensitive to exogenous IFN compared to USP6- ES cells, with both prolonged and heightened STAT1 and STAT3 activation observed. Furthermore, IFN selectively induced apoptosis of USP6+ but not USP6- ES cells. Gene expression analysis confirmed that in USP6+ ES cells, IFN synergistically induced expression of numerous IFN-stimulated genes (ISGs), including the pro-apoptotic ligand TRAIL. CRISPR-mediated depletion of TRAIL completely abrogated IFN-induced death of USP6+ ES cells. In sum, these results identify USP6 as a potential novel biomarker that may predict sensitivity of ES to targeted IFN therapy. This abstract is also being presented as Poster B11. Citation Format: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou. Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR08.

Abstract Using personalized peptide vaccines (PPVs) to target tumor-specific nonself-antigens (neoantigens) is a promising approach to cancer treatment. However, the development of PPVs is hindered by the challenge of identifying tumor-specific neoantigens, in part because current in silico methods for identifying such neoantigens have limited effectiveness. In this article, we report the results of molecular dynamics simulations of 12 oligopeptides bound with an HLA, revealing a previously unrecognized association between the inability of an oligopeptide to elicit a T cell response and the contraction of the peptide-binding groove upon binding of the oligopeptide to the HLA. Our conformational analysis showed that this association was due to incompatibility at the interface between the contracted groove and its αβ–T cell Ag receptor. This structural demonstration that having the capability to bind HLA does not guarantee immunogenicity prompted us to develop an atom-based method (SEFF12MC) to predict immunogenicity through using the structure and energy of a peptide·HLA complex to assess the propensity of the complex for further complexation with its TCR. In predicting the immunogenicities of the 12 oligopeptides, SEFF12MC achieved a 100% success rate, compared with success rates of 25–50% for 11 publicly available residue-based methods including NetMHC-4.0. Although further validation and refinements of SEFF12MC are required, our results suggest a need to develop in silico methods that assess peptide characteristics beyond their capability to form stable binary complexes with HLAs to help remove hurdles in using the patient tumor DNA information to develop PPVs for personalized cancer immunotherapy.

Linked ContentThis article is linked to Tse et al and Ma and Kotze paper. To view these articles visit https://doi.org/10.1111/apt.14829 and https://doi.org/10.1111/apt.14858.

AbstractBackgroundThe relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood.MethodsUltrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18–100 years). We then identified the subset of 2256 ‘healthy’ subjects to define age- and sex-specific reference ranges (2.5–97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys.ResultsIn the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (<2.5 percentile for age and sex) were male sex, low body mass index, short height, low waist:hip ratio and high serum creatinine (SCr); the independent predictors of larger kidney volume (>97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight.ConclusionsOverall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors.

Objectives: The incidence of 2nd anterior cruciate ligament (ACL) injury after ACL reconstruction (ACLR) and return to sport (RTS) ranges from 25%-33% in young, active populations; with the greatest risk in the first 12 months after RTS. Recent data indicate that failure to successfully meet traditional RTS criteria, inclusive of strength, functional hop testing and patient reported outcome scores, may identify athletes at increased risk of future injury after ACLR. However, these studies have focused on adult populations and it is unknown if similar RTS criteria apply to young, adolescent, pivoting/cutting athletes. The purpose of this study was to determine if meeting all current, standard RTS criteria would identify young athletes at risk for future ACL injury after primary ACLR and RTS. The tested hypothesis was the likelihood of 2 nd ACL injury in the first 2 years after RTS would be lower in patients who met all RTS criteria prior to initiation of pivoting and cutting activity compared to patients who failed to meet all RTS criteria prior to RTS. Methods: One hundred fifty-nine subjects (112 female, 47 male) with a mean age of 17.2±2.6 years old (range: 13-25 y.o.) underwent ACLR and were released to return to pivoting/cutting sport. These patients were enrolled in a prospective, observational cohort study, completed a RTS assessment and were then tracked for occurrence of 2 nd ACL after ACLR for 24 months. The RTS assessment included 6 tests: isometric quadriceps strength, 4 functional hop tests and the International Knee Documentation Committee (IKDC) patient reported outcome survey. Limb symmetry index (LSI) was calculated for strength and hop test assessments [(involved/uninvolved)*100]. The IKDC was reported on a 0-100 scale with 100 representing a perfect score. Subjects were classified into groups that successfully passed all 6 RTS tests at a level of 90 and again at 95 compared to those that failed to meet all 6 criteria. Chi Square tests were used to determine if successfully passing all 6 RTS measures at various levels of symmetry resulted in a reduced risk of 2 nd ACL injury in the first 24 months after RTS. Results: Thirty-five (22.0%) patients suffered a 2 nd ACL injury, with 26 occurring in the first 12 months after RTS. At the time of RTS, 42 patients (26%) achieved LSI values of 90 or greater on all testing as well as an IKDC value of 90 or greater. The remaining 117 subjects (74%) scored below 90 on at least 1 of the 6 assessments. At this level, there was no difference in 2 nd ACL injury prevalence between patients who passed all RTS criteria (12/42; 28.6%) and those who failed at least 1 criteria (23/117; 19.7%) (p=0.23). When the passing criteria was elevated to 95 on all RTS testing, only 15 subjects (9%) successfully passed all 6 tests. There was no significant difference in 2 nd ACL injury prevalence between patients who passed all RTS criteria (5/15; 33%) and those who failed at least 1 test (30/144; 20.8%) (p=0.32). Sub-group analysis which evaluated the group by graft type, also indicated no significant differences between groups (p>0.05). Conclusion: Current criteria to evaluate readiness to return young athletes to pivoting and cutting sports, using quadriceps strength symmetry, functional hop performance symmetry and patient reported outcomes, may not identify young, active patients at high risk for 2 nd ACL injury. Future work must identify more appropriate criteria to assess readiness to RTS in the young, athletic population and incorporate these findings into practice.

Objective: To determine whether the association between overall survival (OS) and response to neoadjuvant chemotherapy (NACT) in breast cancer patients varies with tumor subtype and anatomic extent of pathologic complete response (pCR). Background: pCR after NACT predicts improved OS in breast cancer, but it is unclear whether pCR limited to the breast or axilla is also associated with OS. Methods: Women with cT1-3/cN0-1 breast cancer diagnosed in 2010 to 2014 who underwent surgery following NACT were identified in the NCDB and divided into 4 subtypes based on reported hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Kaplan-Meier curves and Cox proportional hazards models were used to estimate OS. Multivariate logistic regression was used to identify factors associated with post-NACT response, defined as upstage (yp stage>clinical stage); no change (clinical stage = yp stage); overall (breast+axilla, ypT0N0), breast-only (ypT0N1/N1mic), or node-only (ypT1-3N0) pCR. Results: Of 33,162 identified patients, 20,265 experienced overall pCR (n = 6370, 19.2%), breast-only pCR (n = 494, 1.5%), node-only pCR (n = 1133, 3.4%), no stage change (n = 9641, 29.1%), or upstage (n = 2627, 7.9%). Compared with no stage change, breast-only pCR was associated with improved OS in triple-negative disease [hazard ratio = 0.58, 95% confidence interval (95% CI) = 0.37–0.89], and node-only pCR was associated with improved OS in both triple-negative (hazard ratio = 0.55,95% CI = 0.39–0.76) and HR+/HER2− disease (hazard ratio = 0.54, 95% CI = 0.33–0.89). For patients achieving overall (breast+axilla) pCR, unadjusted 5-year OS was 0.94 (95% CI = 0.93–0.95), with no difference between patients who were cN0 (hazard ratio = 0.95, 95% CI = 0.93–0.96) or cN1 (hazard ratio = 0.94, 95% CI = 0.92–0.96) at diagnosis. Conclusions: In node-positive patients, pCR limited to either the breast or axilla predicts survival for select receptor subtypes. In patients achieving pCR in both the breast and axilla, survival is driven by response to NACT rather than presenting cN stage.