Citations

OBJECTIVE To distinguish the effects of hyperglycemia and hyperinsulinemia on exercise-induced increases in Rd and endogenous glucose production (EGP) in type 1 diabetes. RESEARCH DESIGN AND METHODS We studied six participants without diabetes and six participants with type 1 diabetes on three visits in random order for the following: euglycemia, low insulin (EuLoI); euglycemia, high insulin (EuHiI); and hyperglycemia, low insulin (HyLoI). Glucose fluxes were measured using [6,6-2H2] glucose before, during, and after 60 min of exercise. RESULTS Rd increased (P < 0.01) with exercise within groups, while peak Rd during exercise was lower (P < 0.01) in participants with type 1 diabetes than participants without diabetes during all visits. In type 1 diabetes participants, EGP increased (P < 0.001) with exercise during EuLoI and HyLoI but not during EuHiI. This demonstrates that hyperinsulinemia, but not hyperglycemia, blunts the compensatory exercise-induced increase in EGP in type 1 diabetes. CONCLUSIONS The data from this pilot study indicate that 1) exercise-induced compensatory increase in EGP was inhibited in participants with type 1 diabetes with hyperinsulinemia but not with hyperglycemia; 2) in contrast, in participants without diabetes, exercise-induced increase in EGP was inhibited only during combined hyperinsulinemia and hyperglycemia. Taken together, these results suggest that low insulin coupled with euglycemia or modest hyperglycemia appear to be the most favorable milieu for type 1 diabetes during exercise.

AbstractBackgroundLipomatosis of nerve (LN) is a complex peripheral nerve disorder characterized by fibrofatty nerve enlargement. MRI of this pathology is pathognomonic and obviates a diagnostic biopsy. Mutation in PIK3CA has been associated with LN cases with nerve‐territory overgrowth which may occur in some cases. We evaluate an association of LN of the sciatic nerve and early‐onset colonic diverticular disease and discuss the potential pathogenesis.MethodsOur institutional database was searched for LN cases. Available information of identified cases was reviewed, and cases with a confirmed diagnosis of LN affecting the lumbosacral plexus and/or sciatic nerve; available MRI of the affected nerve(s); and diverticular disease occurring in the area supplied by the nerve(s) affected by LN were further analyzed. PIK3CA mutation testing was performed on available tissue samples.ResultsWe identified 10 LN cases of lumbosacral plexus and/or sciatic nerve. Of these, three fulfilled our inclusion criteria. All three patients had concomitant colonic diverticular disease, diagnosed at a relatively young age. MRI studies of these cases showed LN involvement of the sacral nerves innervating the sigmoid colon. All three also had abnormal diagnostic workup including various GI tests and evidence of associated nerve‐territory overgrowth. Colonic tissue samples for PIK3CA mutation were negative.ConclusionWhile the pathogenesis of the colonic diverticular disease is increasingly recognized as being multifactorial, our observations are consistent with the potential role of autonomic nervous system dysfunction affecting either the pelvic floor musculature, or the colon itself (or both) in a subset of patients with early‐onset diverticular disease.

Aims Arthrofibrosis is a relatively common complication after joint injuries and surgery, particularly in the knee. The present study used a previously described and validated rabbit model to assess the biomechanical, histopathological, and molecular effects of the mast cell stabilizer ketotifen on surgically induced knee joint contractures in female rabbits. Methods A group of 12 skeletally mature rabbits were randomly divided into two groups. One group received subcutaneous (SQ) saline, and a second group received SQ ketotifen injections. Biomechanical data were collected at eight, ten, 16, and 24 weeks. At the time of necropsy, posterior capsule tissue was collected for histopathological and gene expression analyses (messenger RNA (mRNA) and protein). Results At the 24-week timepoint, there was a statistically significant increase in passive extension among rabbits treated with ketotifen compared to those treated with saline (p = 0.03). However, no difference in capsular stiffness was detected. Histopathological data failed to demonstrate a decrease in the density of fibrous tissue or a decrease in α-smooth muscle actin (α-SMA) staining with ketotifen treatment. In contrast, tryptase and α-SMA protein expression in the ketotifen group were decreased when compared to saline controls (p = 0.007 and p = 0.01, respectively). Furthermore, there was a significant decrease in α-SMA (ACTA2) gene expression in the ketotifen group compared to the control group (p < 0.001). Conclusion Collectively, these data suggest that ketotifen mitigates the severity of contracture formation in a rabbit model of arthrofibrosis. Cite this article: Bone Joint Res 2020;9(6):302–310.

9045 Background: A minority of the > 40,000 patients (pts) diagnosed with stage III NSCLC annually in the US are cured by CRT, more recently followed by adjuvant immune checkpoint inhibitors (ICI). PD-L1 blockade with CRT may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells. Further, CRT may expose otherwise hidden antigens that present additional targets to the reconstituting immune system. Adjuvant ICI has improved survival. Whether ICI before CRT will further improve outcomes is unknown. Methods: This Alliance Foundation Trials (AFT) study evaluated safety and efficacy of atezolizumab before and after CRT. 4 cycles of atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4 were followed by carboplatin and paclitaxel (C/P) weekly with 60 Gy radiation and C/P consolidation followed by atezolizumab for 1 year of therapy. Primary endpoint is disease control rate (DCR) (complete response + partial response (PR) + stable disease (SD)) at 12 weeks (wks). Secondary endpoints include overall response rate, progression-free survival, overall survival, safety and quality of life assessed by EORTC QLQ-30. Correlatives include PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue was obtained at study entry; plasma and immune cells were isolated at multiple timepoints. Results: 64 pts with stage III NSCLC, performance status (PS) 0-1, no active autoimmune disease or significant organ dysfunction enrolled at 13 Alliance sites from 11/2017 to 7/2019. 62 pts received ≥ 1 dose of atezolizumab and are included in the primary analysis; median age 63.9 years (38.1-86.5), 51.6% female, 77.4% white, 61.3% former smokers, 56.5% PS 0. DCR at 12 wks was 77.4% (80% confidence interval 69.2-84.3%) (30.7% PR, 46.8% SD). 54 pts reported adverse events (AEs) during induction, mostly grade (gr) 1. There were 13 serious AEs, most unrelated to study treatment; 1 gr 3 anaphylactic reaction, 1 gr 3 colitis, and 1 gr 4 Guillain-Barre syndrome were attributable to atezolizumab. Baseline PD-L1 status was available for 49 pts. DCR was 82.4% for pts with PD-L1 negative and 90.9% for pts with PD-L1 positive tumors. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with an encouraging 12-wk DCR. Analysis of secondary endpoints is ongoing. Further study of induction ICI therapy is warranted in patients with unresectable stage III NSCLC. Support: AFT, Genentech; Clinical trial information: NCT03102242.

e17535 Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]