Citations

Background: Calcaneus fractures have serious potential complications. Tongue type calcaneus fractures, in particular, are at risk for secondary soft tissue breakdown due in part to the tension placed on the soft tissue by the forces of the Achilles tendon on the superior fragment of the posterior calcaneal tuberosity. The current literature is limited regarding outcomes in pure tongue type calcaneus fractures. The purpose of this study is to report injury details, treatment, and complications in this group of fractures. Methods: The study is a retrospective study of patients between 2007 and 2015 with tongue type calcaneus fractures. Demographic data and comorbidities were collected for each patient. Clinical data including details of the injury, time to surgery, length of hospital stay, wound complications, additional surgical procedures, and follow-up data were evaluated. Results: There were 25 patients with 26 fractures included in this study, including 7 open fractures. Wound complications occurred in 7 (27%) patients, and fixation failure occurred in 4 (21%) patients. Patients with open fractures reached full healing in less time (2.8±0.4 mo) compared with patients with closed fractures (4±1.3 mo). The difference in time to full healing was not statistically significant (P>0.05) when comparing smokers and nonsmokers. Conclusions: The literature is limited regarding outcomes of pure tongue type calcaneus fractures. We found these fractures had similar or even higher rates of wound complications compared with other studies investigating intra-articular calcaneus fractures. This is one of the first studies to report on the complication rates associated specifically with these fractures. Level of Evidence: Level IV.

PURPOSE Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose ( P < .001) and boost margin ( P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed ( P = .003). CONCLUSION To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.

4 Background: Membrane expression of PD-L1 on tumor cells is associated with poor survival in patients with advanced malignancies including metastatic melanoma (MM). In addition, tumor-associated PD-L1 has been proposed as a predictor of response to anti-PD-1 therapy, although responses are observed in some cases of PD-L1 negative MM. We hypothesize that tumor-derived PD-L1 has additional systemic effects through the release of biologically active soluble forms of PD-L1 (sPD-L1) into the circulation, which further impedes the anti-tumor immune response and contributes to poor clinical outcomes in MM. Methods: We developed a sPD-L1 ELISA and biochemically confirmed the identity of the detected protein. We measured the levels of sPD-L1 in 276 patients with MM enrolled on 3 clinical trials who had stored pre-treatment plasma samples and 37 healthy volunteers (HV) undergoing blood donation at Mayo Clinic. We also measured sPD-L1 in baseline samples from 38 MM patients treated with anti-PD1 (pembrolizumab) 2 mg/kg every 3 weeks. ROC analysis was used to compute sPD-L1 concentration cut-off value and Wald test was used to asses the difference of overall survival (OS) in patients with low versus high sPD-L1 concentration. Results: We found that sPD-L1 levels were significantly elevated in MM patients compared with HV (p=0.0011). Mean sPD-L1 level in MM was 1.73 ng/mL (range: 0.13-18.29) compared with 0.77 ng/mL (range: 0.11–6.02) for HV. Patients with higher levels (>0.293 ng/mL) had a median OS of 11.3 months compared to 14.8 months for patients with sPD-L1 level ≤ 0.293 ng/mL (p=0.040). Similarly to tumor-related PD-L1 findings, patients who had clinical benefit (OR/PR/SD) after 4 cycles of anti-PD1 had higher sPD-L1 levels at baseline (2.1 vs. 1.1 ng/mL). Conclusions: To our knowledge, our study is the first to report a correlation of sPD-L1 with MM patient outcome, although a larger study is needed to establish the utility of sPD-L1 as an independent prognostic and possibly predictive biomarker.

112 Background: CD47 delivers an anti-phagocytic (“do not eat”) signal by binding SIRPα on macrophages and is overexpressed on many cancers enabling immune surveillance evasion. TTI-621 is a decoy receptor that promotes phagocytosis of tumors by blocking CD47 and engaging activating FcR on macrophages. A first-in-human, phase 1a, open label, multicenter study (NCT02663518) evaluating safety and tolerability of weekly, intravenous infusions of TTI-621 was conducted. As of October 12, 2016, 18 subjects were treated with TTI-621 with doses of 0.05-0.3 mg/kg. Multiple pharmacodynamic and hematologic assessments were performed to characterize the effects of TTI-621 and better understand the mechanism of action. Methods: Serial blood draws were analyzed for CD47 receptor occupancy (RO), complete blood counts, cytokines, T cell repertoire changes and CD47, SIRPα and FcR sequences. CD47 expression, macrophage and T cell infiltration was assessed on biopsies by IHC. Results: Peripheral CD47 levels varied considerably between subjects and were inversely correlated with RO. A maximum of 80% RO was achieved on peripheral leukocytes. Circulating monocytes, neutrophils, and lymphocytes were transiently decreased at the end of the TTI-621 infusion and generally returned to baseline levels by 24 to 72 hours. Platelet counts decreased immediately after TTI-621 infusions, typically recovering to baseline levels prior to the subsequent treatment cycle. Hemoglobin levels did not meaningfully change during treatment. Cytokines associated with macrophage activation or phagocytosis, notably MIP-1α, MIP-1β, TNF-α and IP-10 were elevated in a dose dependent manner. Conclusions: Systemic administration of TTI-621 leads to CD47 blockade and dose dependent increases in cytokines associated with phagocytosis, temporally associated with reversible thrombocytopenia, suggesting enhanced macrophage mediated clearance of circulating platelets followed by a robust marrow regenerative response. Enrollment into multiple expansion cohorts addressing a wide range of hematopoietic cancers is ongoing. Clinical trial information: NCT02663518.

Background The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. Methods Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web‐based questionnaires, clinicians enter the participant’s ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow‐up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient’s sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache‐related disability, comorbidities, and treatments. Results Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth‐Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18‐84). The most common provider‐reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache‐related disability); however, 17% of the ARMR population had MIDAS scores suggesting “no” or “mild” disability. The most common non‐headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non‐medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene‐related peptide ligand or receptor‐targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non‐steroidal anti‐inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. Conclusions ARMR is a source of real‐world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Objective: This article examines how visual exposure to patients predicts patient-related communication among staff members. Background: Communication among healthcare professionals private from patients, or backstage communication, is critical for staff teamwork and patient care. While patients and visitors are a core group of users in healthcare settings, not much attention has been given to how patients’ presence impacts staff communication. Furthermore, many healthcare facilities provide team spaces for improved staff teamwork, but the privacy levels of team areas significantly vary. Method: This article presents an empirical study of four team-based primary care clinics where staff communication and teamwork are important. Visual exposure levels of the clinics were analyzed, and their relationships to staff members’ concerns for having backstage communication, including preferred and nonpreferred locations for backstage communication, were investigated. Results: Staff members in clinics with less visual exposure to patients reported lower concerns about having backstage communication. Staff members preferred talking in team areas that were visually less exposed to patients in the clinic, but, within team areas, the level of visual exposure did not matter. On the other hand, staff members did not prefer talking in visually exposed areas such as corridors in the clinic and visually exposed areas within team spaces. Conclusions: Staff members preferred talking in team areas, and they did not prefer talking in visually exposed areas. These findings identified visually exposed team areas as a potentially uncomfortable environment, with a lack of agreement between staff members’ preferences toward where they had patient-related communication.

Abstract Background Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores. Methods In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf). Results Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P &lt; 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of −0.81 mL/min/1.73 m2 [95% confidence interval (CI) −1.44 to −0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (−3.99 mL/min/1.73 m2; 95% CI −6.9411 to −1.0552, P = 0.008), after similar adjustments. Conclusion Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed.