Citations

AbstractPurposeTo prospectively assess acute differences in patient‐reported outcomes in bowel and urinary domains between intensity‐modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.Methods and MaterialsBowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC‐26 were collected in patients with T1‐T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015‐2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post‐radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.ResultsA total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (−13.0 vs −6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post‐radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (−9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (−1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post‐radiotherapy.ConclusionsPBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

Background: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.

Abstract Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. In this study, COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels in patient biopsy samples. Acetylsalicylic acid (ASA) suppressed BE and EAC growth by targeting the TXA2 pathway in a esophagoduodenostomy mouse model of reflux. Additionally, biopsies from patients showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation in a window opportunity clinical trial. Overall, this study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. ASA targets the TXA2 pathway and suppresses BE and EAC. Citation Format: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong. Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2593.

Abstract The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. Significance: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.

Introduction: Central venous access using peripherally inserted central catheters is frequently used for patients receiving intravenous medications in the hospital or outpatients. Although there are several benefits of peripherally inserted central catheters, such as ease of insertion, low procedure-related risk and higher patient satisfaction, there are complications associated with peripherally inserted central catheter use. Despite some studies evaluating peripherally inserted central catheter line–related complications, the factors associated with peripherally inserted central catheter–related deep venous thrombosis in critically ill medical-surgical patients are poorly described. The objective of this case-control study was to identify the risk factors associated with peripherally inserted central catheter line–related deep venous thrombosis in critically ill medical-surgical intensive care unit patients in a community hospital. Methods: We abstracted relevant clinical data from 21 cases with symptomatic peripherally inserted central catheter–related deep venous thrombosis and 42 controls with peripherally inserted central catheters but no deep venous thrombosis. Results: Of the factors evaluated, female gender, the use of triple lumen peripherally inserted central catheters, larger outer diameter, and open (vs valve) peripherally inserted central catheters were associated with venous thrombosis. In this retrospective study, we did not identify any association of peripherally inserted central catheter–related deep venous thrombosis with a prior history of deep venous thrombosis, use of alteplase, antiplatelet therapy, prophylactic or therapeutic anticoagulation, international normalized ratio, platelet count and the use of peripherally inserted central catheters for total parenteral nutrition. Conclusion: Our study indicates that the catheter size relative to the diameter of the vein could be an important risk factor for the development of peripherally inserted central catheter–related deep venous thrombosis. The study findings should be confirmed in a larger study designed to identify risk factors of peripherally inserted central catheter–related deep venous thrombosis. In the meantime, the peripherally inserted central catheter lines should be used judiciously in critically ill patients.

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .

BackgroundPretreatment determination of renal cell carcinoma aggressiveness may help to guide clinical decision‐making.PurposeTo evaluate the efficacy of residual convolutional neural network using routine MRI in differentiating low‐grade (grade I–II) from high‐grade (grade III–IV) in stage I and II renal cell carcinoma.Study TypeRetrospective.PopulationIn all, 376 patients with 430 renal cell carcinoma lesions from 2008–2019 in a multicenter cohort were acquired. The 353 Fuhrman‐graded renal cell carcinomas were divided into a training, validation, and test set with a 7:2:1 split. The 77 WHO/ISUP graded renal cell carcinomas were used as a separate WHO/ISUP test set.Field Strength/Sequence1.5T and 3.0T/T2‐weighted and T1 contrast‐enhanced sequences.AssessmentThe accuracy, sensitivity, and specificity of the final model were assessed. The receiver operating characteristic (ROC) curve and precision‐recall curve were plotted to measure the performance of the binary classifier. A confusion matrix was drawn to show the true positive, true negative, false positive, and false negative of the model.Statistical TestsMann–Whitney U‐test for continuous data and the chi‐square test or Fisher's exact test for categorical data were used to compare the difference of clinicopathologic characteristics between the low‐ and high‐grade groups. The adjusted Wald method was used to calculate the 95% confidence interval (CI) of accuracy, sensitivity, and specificity.ResultsThe final deep‐learning model achieved a test accuracy of 0.88 (95% CI: 0.73–0.96), sensitivity of 0.89 (95% CI: 0.74–0.96), and specificity of 0.88 (95% CI: 0.73–0.96) in the Fuhrman test set and a test accuracy of 0.83 (95% CI: 0.73–0.90), sensitivity of 0.92 (95% CI: 0.84–0.97), and specificity of 0.78 (95% CI: 0.68–0.86) in the WHO/ISUP test set.Data ConclusionDeep learning can noninvasively predict the histological grade of stage I and II renal cell carcinoma using conventional MRI in a multiinstitutional dataset with high accuracy.Level of Evidence3Technical Efficacy Stage2

305 Background: Toxicity due to radiotherapy (RT) may differ in patients (pts) with prostate cancer who receive intensity-modulated radiotherapy (IMRT) or proton beam therapy (PBT). Methods: Patient-reported bowel function (BF), urinary incontinence (UI), and urinary irritative/obstructive symptoms (UO) domains of the Expanded Prostate Index Composite Questionnaire (EPIC-26) were prospectively collected in pts with localized prostate cancer receiving either IMRT (n=157) or PBT (n=105) to the prostate +/- proximal seminal vesicles for clinical stage T1-T2 N0 prostate cancer at a single tertiary cancer center between 2015 and 2018. Changes in domain scores were analyzed from pretreatment to the end of RT and 3 months post-RT, assessing the acute effects of each modality. A clinically relevant change was defined as a score change that exceeded 50% of the standard deviation of a baseline value. Results: At baseline there was no difference in the scores of BF, UI, and UO domains between IMRT and PBT cohorts. At the end of RT, pts treated with either modality had a statistically significant and clinically relevant worsening of BF and UO compared to baseline. Pts treated with IMRT experienced a significantly greater decrement in BF compared to the PBT cohort (-13 vs -9, p<0.01), including significantly more IMRT pts having a clinically relevant deterioration in BF compared to PBT pts (58% vs 40%, p=0.01). Though there was a statistically significant deterioration in UI in the IMRT cohort (-4, p<0.001), this did not reach the predefined threshold for clinical relevance. Three months following RT, the IMRT group continued to have statistically significant and clinically relevant worsening of BF (-9, p<0.001), whereas the change in BF domain score of the PBT cohort was no longer statistically significant or clinically relevant compared to baseline (-1, p=0.25). There were no statistically significant or clinically relevant changes in UO or UI in either cohort at three months when compared to baseline. Conclusions: Pts who received IMRT or PBT reported unique patterns of toxicity, and pts treated with IMRT had worse decrement in BF immediately after and three months following RT, compared to those treated with PBT.

Abstract Purpose: With increasing incidence of renal mass, it is important to make a pretreatment differentiation between benign renal mass and malignant tumor. We aimed to develop a deep learning model that distinguishes benign renal tumors from renal cell carcinoma (RCC) by applying a residual convolutional neural network (ResNet) on routine MR imaging. Experimental Design: Preoperative MR images (T2-weighted and T1-postcontrast sequences) of 1,162 renal lesions definitely diagnosed on pathology or imaging in a multicenter cohort were divided into training, validation, and test sets (70:20:10 split). An ensemble model based on ResNet was built combining clinical variables and T1C and T2WI MR images using a bagging classifier to predict renal tumor pathology. Final model performance was compared with expert interpretation and the most optimized radiomics model. Results: Among the 1,162 renal lesions, 655 were malignant and 507 were benign. Compared with a baseline zero rule algorithm, the ensemble deep learning model had a statistically significant higher test accuracy (0.70 vs. 0.56, P = 0.004). Compared with all experts averaged, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.60, P = 0.053), sensitivity (0.92 vs. 0.80, P = 0.017), and specificity (0.41 vs. 0.35, P = 0.450). Compared with the radiomics model, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.62, P = 0.081), sensitivity (0.92 vs. 0.79, P = 0.012), and specificity (0.41 vs. 0.39, P = 0.770). Conclusions: Deep learning can noninvasively distinguish benign renal tumors from RCC using conventional MR imaging in a multi-institutional dataset with good accuracy, sensitivity, and specificity comparable with experts and radiomics.

Abstract Hypoxia‐induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF‐κB pathway through the NF‐κB transcription‐activating group P65 by phosphorylation and nuclear translocation. NF‐κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia‐induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF‐κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF‐1α/HE4/NF‐κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia‐induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.