Citations

Abstract Background: We aimed to analyse clinical characteristics and find potential factors predicting poor prognosis in patients with coronavirus disease 2019 (COVID-19). Methods: We analyzed the demographic and clinical data of COVID-19 patients and detected SARS-CoV-2 RNA in urine sediments collected from 53 COVID-19 patients enrolled in Renmin Hospital of Wuhan University from January 31, 2020 to February 18, 2020 with qRT-PCR analysis, and then classified those patients based on clinical conditions (severe or non-severe syndrome) and urinary SARS-CoV-2 RNA (URNA- or URNA+). Results: We found that COVID-19 patients with severe syndrome (severe patients) showed significantly higher positive rate (11 of 23, 47.8%) of urinary SARS-CoV-2 RNA than non-severe patients (4 of 30, 13.3%, p = 0.006). URNA+ patients or severe URNA+ subgroup exhibited higher prevalence of inflammation and immune discord, cardiovascular diseases, liver damage and renal disfunction, and higher risk of death than URNA- patients. To understand the potential mechanisms underlying the viral urine shedding, we performed renal histopathological analysis on postmortems of patients with COVID-19 and found that severe renal vascular endothelium lesion characterized by increase of the expression of thrombomodulin and von Willebrand factor, markers to assess the endothelium dysfunction. We proposed a theoretical and mathematic model to depict the potential factors determining the urine shedding of SARS-CoV-2. Conclusions: This study indicated that urinary SARS-CoV-2 RNA detected in urine specimens can be used to predict the progression and prognosis of COVID-19 severity.

Abstract Background: Next-generation sequencing provides comprehensive information about individuals’ genetic makeup and is commonplace in precision oncology practice. Due to the heterogeneity of individual patient’s disease conditions and treatment journeys, not all targeted therapies were initiated despite actionable mutations. To better understand and support the clinical decision-making process in precision oncology, there is a need to examine real-world associations of patients’ genetic information and treatment choice.Methods: To fill the gap of insufficient use of real-world data (RWD) in electronic health records (EHRs), we generated a single Resource Description Framework (RDF) resource, called PO2RDF (precision oncology to RDF) by integrating information regarding gene, variant, disease, and drug from genetic reports and EHRs. Results: There are total 2,309,014 triples contained in the PO2RDF. Among them 32,815 triples are related to Gene, 34,695 triples are related to Variant, 8,787 triples are related to Disease, 26,154 triples are related to Drug. We performed one use case analysis to demonstrate the usability of the PO2RDF: we examined real-world associations between EGFR mutations and targeted therapies to confirm existing knowledge and detect off-label use. Conclusions: In conclusion, our work proposed to use RDF to organize and distribute clinical RWD that is otherwise inaccessible externally. Our work serves as a pilot study that will lead to new clinical applications and could ultimately stimulate progress in the field of precision oncology.

Abstract Background Out‐of‐field neutron dissemination during double‐scattered proton therapy has raised concerns of increased second malignancies, disproportionally affecting pediatric patients due to the proportion of body exposed to scatter dose and inherent radiosensitivity of developing tissue. We sought to provide empiric data on the incidence of early second tumors. Methods Between 2006 and 2019, 1713 consecutive children underwent double‐scattered proton therapy. Median age at treatment was 9.1 years; 371 were ≤3 years old. Thirty‐seven patients (2.2%) had tumor predisposition syndromes. Median prescription dose was 54 Gy (range 15–75.6). Median follow‐up was 3.3 years (range 0.1–12.8), including 6587 total person‐years. Five hundred forty‐nine patients had ≥5 years of follow‐up. A second tumor was defined as any solid neoplasm throughout the body. Results Eleven patients developed second tumors; the 5‐ and 10‐year cumulative incidences were 0.8% (95% CI, 0.4–1.9%) and 3.1% (95% CI, 1.5–6.2%), respectively. Using age‐ and gender‐specific data from the Surveillance, Epidemiology, and End Results (SEER) program, the standardized incidence ratio was 13.5; the absolute excess risk was 1.5/1000 person‐years. All but one patient who developed second tumors were irradiated at ≤5 years old ( p < .0005). There was also a statistically significant correlation between patients with tumor predisposition syndromes and second tumors ( p < .0001). Excluding patients with tumor predisposition syndromes, 5‐ and 10‐year rates were 0.6% (95% CI, 0.2–1.7%) and 1.7% (95% CI, 0.7–4.0%), respectively, with all five malignant second tumors occurring in the high‐dose region. Conclusion Second tumors are rare within the decade following double‐scattered proton therapy, particularly among children irradiated at >5 years old and those without tumor predisposition syndrome.

Abstract Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj &gt; 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus &lt;20 years at first pregnancy [0.79 (0.72–0.86)]; &gt;0–&lt;5 years versus ≥10 years since last full-term birth [1.31 (1.11–1.55)]; ever versus never use of oral contraceptives [0.91 (0.87–0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen–progestin therapy [0.61 (0.54–0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02–1.21) for current versus never smoking. Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

AbstractBackgroundThe subcutaneous implantable cardioverter‐defibrillator (S‐ICD) has a larger generator and its implantation involves more dissection and tunneling compared to traditional transvenous defibrillator system. Liposomal bupivacaine, an extended‐release bupivacaine with 72 h of duration has been used for postoperative pain management in patients undergoing S‐ICD implantation. Our aim was to compare postoperative pain and opioid prescription patterns among patients undergoing S‐ICD implantation who received intraprocedural liposomal bupivacaine and those who did not.MethodsWe performed a retrospective analysis of all patients who underwent subcutaneous ICD implantation from January 1, 2013 to March 30, 2018 at the Mayo Clinic in Rochester, Minnesota. Patients were categorized into those who received liposomal bupivacaine and those who did not. Data on inpatient pain score, outpatient opioid prescription rates at discharge, and doses based on oral morphine equivalents (OME) were collected.ResultsA total of 104 patients underwent S‐ICD implantation. Intraprocedural liposomal bupivacaine was used in 69% of patients. Patients who received intraprocedural liposomal bupivacaine had similar mean inpatient pain scores (2.9 vs. 2.9, p = .786). There was also no difference in the rate of inpatient opioid administration (79.2% vs. 87.5%, p = .4139), outpatient opioid prescription (23.6% vs. 12.5%, p = .29), or mean OME (41.7‐mg vs. 16.6‐mg, p = .188) when comparing patients those who received intraprocedural liposomal bupivacaine and those who did not.ConclusionIntraprocedural liposomal bupivacaine administration was not associated with any significant impact on postoperative pain scores, inpatient opioid administration, and outpatient opioid prescription rates or OME amounts at discharge.

TPS264 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.

468 Background: The burden of gastrointestinal (GI) disease is high, costing over $97 billion annually in the United States (U.S.) alone. Yet the methodological rigor and characteristics of trials leading to guideline development are rarely explored. In 2007, the U.S. mandated that all interventional studies (Phase II-IV) register with ClinicalTrials.gov, the largest international clinical trial database. We characterized registered GI trials to identify features associated with early discontinuation, results reporting and increased methodological rigor. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded data for 327 075 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2007 to December 31, 2019. Trials were excluded if registered prior to 2007 (n=38 111) or for non-interventional study design (n=69 233). After applying GI specific Medical Subject Heading terms to the remaining 219 731 trials, 22 339 trials were identified for manual review. 20 548 trials were found to contain true GI content, representing over seven million patients. Primary exposure variables were trial focus (disease process, anatomical location) and funding (industry, U.S. government, academic). Results: Of the 20 548 GI trials, 6.1% were funded by the U.S. government, 35.6% by industry, and 58.3% by academic institutions. The most studied disease process was neoplasia (42.6% of trials), followed by viral hepatitis (10.8%). The majority of neoplasia trials were funded by academic institutions (60.3%) and studied colorectal neoplasms (31.5%), followed by hepatic (17.9%), pancreatic (15.5%), gastric (12.8%), esophageal (10.6%) and biliary tract (4.9%) neoplasms. U.S. government funded trials had the lowest risk of early discontinuation (adjusted Hazard Ratio 0.63, 95% CI: 0.48-0.83, p<0.001) and the highest rates of results reporting (25%, X2 p<0.001). Among all trials, the majority did not report Data Monitoring Committee (DMC) oversight (58.6%). Only 12% of phase III trials employed a rigorous methodology, which we defined as being randomized, double blinded, multi-site, overseen by a DMC, and having enrolled ≥50 patients. Government sponsored trials had the highest proportion of trials meeting this definition (19%). Academic sponsored trials, constituting the majority of trials overall, had the lowest proportion (5.3%), in part due to not meeting the multi-site criteria. Conclusions: Despite constituting the minority of trials overall, U.S. government funded trials displayed the highest methodological rigor. Stakeholders can look to U.S. government funded trials as a model of improvement, but nevertheless must commit to increasing methodological rigor and results dissemination to strengthen trial findings that guide GI clinical recommendations.

239 Background: After trastuzumab (T) approval for advanced HER2-positive E/GEJ-AC, HER2 testing has increased in patients (pts) with resectable disease. Neoadjuvant carboplatin/paclitaxel chemoradiation (nCP-CRT) is a common therapy approach. We performed the largest evaluation, to our knowledge, of the prognostic impact of HER2 in E/GEJ-AC pts treated with nCP-CRT. Methods: We retrospectively reviewed medical records of all trimodality-eligible (T2+ or N+) pts with E/GEJ-AC who started nCP-CRT (usually 50.4 Gy) with planned surgery at Mayo Clinic (2014-2019). HER2 was tested using standard criteria for HER2 positivity (ie, immunohistochemistry 3+ or amplification by in situ hybridization). Clinicopathologic data and time to recurrence (TTR), disease free survival (DFS), overall survival (OS), survival after recurrence (SAR), and pathologic complete response (pCR – ie, no residual tumor in primary or nodes) were collected. Kaplan Meier and multivariate Cox analysis were used. Results: Of 161 consecutive eligible pts, HER2 status was available in 107 pts (HER2-positive n=26, HER2-negative n=81) of whom n=82 had surgery and n=19 had pCR. Most tumors were clinical T3 (80%) or N+ (81%), histologic grade 3 of 3 (62%). HER2 positivity was significantly associated with lower grade, but not with age, clinical T or N, or ECOG performance status (PS). A similar proportion of HER2-positive ( vs negative) pts had surgery. Among pts who had surgery, pCR rates were lower in HER2-positive ( vs negative) pts (11% [2/19] vs 27% [17/63]). After a median follow up of 23 mo, DFS and TTR were significantly shorter in HER2 positive ( vs negative) pts, independent of other pretreatment covariables (Table). Yet OS was comparable. Lung recurrence was enriched in HER2 positive ( vs negative) pts. Among pts with recurrence, SAR was longer in HER2-positive vs -negative pts. A total of 53% (10/19) of previously HER2-positive pts received T-based therapy after recurrence, and these pts were the drivers of favorable SAR (median 22 mo in n=10 HER2-positive pts who received T vs 11 mo in n=9 HER2-positive pts who did not receive T vs 11 mo in n=40 HER2-negative pts; P log-rank=.01). Conclusions: HER2 positivity ( vs negativity) is independently associated with shorter TTR and DFS, but more comparable OS. The adverse association of HER2 on tumor response and TTR may have been largely overcome through enhanced survival after recurrence, although OS data are maturing. These data may have implications for the design of endpoints in future curative-intent anti-HER2 trials. [Table: see text]

AbstractPurpose:Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.Experimental Design:Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.Results:We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).Conclusions:These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.