Pre-specified Cut-offs Research Articles

Clinical performance of existing diagnostic criteria for pneumonia in older emergency patients: A prospective cohort study.

Pneumonia accounts for over half a million older adult emergency department (ED) visits annually, but ED pneumonia diagnosis is inaccurate. Geriatric-specific pneumonia diagnostic criteria exist for other settings; no prospective data exist to determine if application in the older adult ED population is feasible. The objective was to prospectively evaluate the utility of four current diagnostic criteria (Loeb; Modified McGeer; Infectious Disease Society of America/American Thoracic Society; American College of Emergency Physicians) in older adult ED patients. This was a prospective, observational cohort study of older adult ED patients ≥65 years of age in two U.S. EDs with suspected pneumonia defined as having chest radiography ordered and treating physician suspicion. The standard we used for defining the presence, absence, or inability to determine a diagnosis of pneumonia diagnosis was expert physician chart adjudication. We report the summary statistics for demographic characteristics and symptoms/exam findings and sensitivity, specificity, and likelihood ratios with 95% confidence intervals of the existing diagnostic criteria. Pre-specified cutoff values of a positive LR >10 and a negative LR <0.3 were considered clinically significant. Of 135 patients enrolled, 27 had pneumonia by adjudicator review. Typical patient-reported pneumonia symptoms, such as fever (18.5%) and new/worse cough (51.9%), were not consistently present in pneumonia. The IDSA/ATS and ACEP criteria had positive LR >10 and negative LR <0.3; however, all confidence intervals included pre-specified cutoffs. Older adults presented to the ED with low frequency of typical pneumonia symptoms. Although existing diagnostic definitions had promising test characteristics, they may not perform well enough for clinical application without refinement.

Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy

The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking. To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs. This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023. The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients. Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.

Abstract PO1-28-10: Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy

Abstract Introduction International guidelines recommend chemotherapy for most patients with stage I triple negative breast cancer (TNBC), except for special histological subtypes. However, the absolute benefit of systemic treatment for all stage I TNBC patients is not well known and no tools are yet available to select patients with an excellent prognosis for whom the chemotherapy can be safely omitted. High levels of stromal tumor infiltrating lymphocytes (sTILs) are strongly associated with favorable prognosis in TNBC, however, data solely focusing on patients with stage I TNBC who did not receive chemotherapy are lacking. Methods Patients with pT1N0M0 TNBC diagnosed between 2005 and 2015 not treated with (neo)adjuvant chemotherapy were identified from the nationwide Netherlands Cancer Registry (NCR) and linked to the national pathology database (PALGA). Newly sectioned hematoxylin &amp; eosin (H&amp;E) slides were used for central review of the histology and sTILs scoring following the International TIL working group guidelines (www.tilsinbreastcancer.org). Cause of death was provided by Statistics Netherlands (CBS). Primary endpoint was breast-cancer specific survival (BCSS) at 5-, 10- and 15-years for prespecified sTILs cut-offs of 30%, 50% and 75% sTILs. Results sTILs were evaluated for 1,041 patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. Mean age at diagnosis was 64.4 years [range 26 – 96] and median sTILs value was 5%. Most tumors (91.5%) were invasive ductal adenocarcinomas of no special type (NST) and 6.6% were of histological special types. In 52% of the patients the tumor was &amp;gt;1cm (pT1cN0). Median follow-up was 9.4 years in which 335 patients had died, of whom 107 due to breast cancer. Patients with pT1abN0 tumors had a favorable prognosis compared with patients with a pT1cN0 tumor (HR 0.47, CI 0.32- 0.72). 10-year BCSS in patients with pT1ab was 91.8% and 85.8% in patients with pT1c tumors. In the overall cohort, sTILs-levels of at least 30% were associated with better BCSS compared to sTILs &amp;lt; 30% (HR 0.45, CI 0.26 – 0.77), with 10year-BCSS of 96% and 87%, respectively (table 1). Patients with TNBC of special histological subtype had low sTILs (median 1%). A univariate cox model showed no association between sTILs (continuous) and BCSS in TNBC of special histological subtype (p = 0.56). Next, the prognostic value of sTILs was evaluated separately for pT1ab and pT1c. High sTILs ≥50% were not associated with improved BCSS compared to low sTILs &amp;lt; 50% in patients with pT1ab (HR 1.35, CI 0.65 – 2.82, p = 0.42). In contrast, high sTILs ≥50% showed a strong prognostic importance over low sTILs &amp;lt; 50% (HR 0.27, CI 0.10 – 0.74) in patients with pT1C tumors. We found excellent 10year-BCSS of 95% for patients if sTILs ≥50%, which further increases to 98% with sTILs ≥75% contrasting 10year-BCSS of 83% for patients with sTILs &amp;lt; 30%. Conclusions sTILs-levels provide important prognostic information in patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. The outcome of patients with pT1c TNBC and sTILs ≥50% was excellent, with 10year-BCSS of 95%, and 98% if sTILs &amp;gt;75%. This large registry study provides a foundation for clinical trials in patients with stage I TNBC with high TILs to prospectively confirm their excellent survival without chemotherapy. Citation Format: Veerle Geurts, Sara Balduzzi, Hugo Horlings, Tessa G Steenbruggen, Sabine Siesling, Sylvia Adams, Gabe Sonke, Roberto Salgado, Marleen Kok. Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-10.

Evaluation of a Portable Blood Gas Analyzer for Prehospital Triage in Carbon Monoxide Poisoning: Instrument Validation Study.

Carbon monoxide (CO) poisoning is an important cause of morbidity and mortality worldwide. Symptoms are mostly aspecific, making it hard to identify, and its diagnosis is usually made through blood gas analysis. However, the bulkiness of gas analyzers prevents them from being used at the scene of the incident, thereby leading to the unnecessary transport and admission of many patients. While multiple-wavelength pulse oximeters have been developed to discriminate carboxyhemoglobin (COHb) from oxyhemoglobin, their reliability is debatable, particularly in the hostile prehospital environment. The main objective of this pilot study was to assess whether the Avoximeter 4000, a transportable blood gas analyzer, could be considered for prehospital triage. This was a monocentric, prospective, pilot evaluation study. Blood samples were analyzed sequentially with 2 devices: the Avoximeter 4000 (experimental), which performs direct measurements on blood samples of about 50 µL by analyzing light absorption at 5 different wavelengths; and the ABL827 FLEX (control), which measures COHb levels through an optical system composed of a 128-wavelength spectrophotometer. The blood samples belonged to 2 different cohorts: the first (clinical cohort) was obtained in an emergency department and consisted of 68 samples drawn from patients admitted for reasons other than CO poisoning. These samples were used to determine whether the Avoximeter 4000 could properly exclude the diagnosis. The second (forensic) cohort was derived from the regional forensic center, which provided 12 samples from documented CO poisoning. The mean COHb level in the clinical cohort was 1.7% (SD 1.8%; median 1.2%, IQR 0.7%-1.9%) with the ABL827 FLEX versus 3.5% (SD 2.3%; median 3.1%, IQR 2.2%-4.1%) with the Avoximeter 4000. Therefore, the Avoximeter 4000 overestimated COHb levels by a mean difference of 1.8% (95% CI 1.5%-2.1%). The consistency of COHb readings by the Avoximeter 4000 was excellent, with an intraclass correlation coefficient of 0.97 (95% CI 0.93-0.99) when the same blood sample was analyzed repeatedly. Using prespecified cutoffs (5% in nonsmokers and 10% in smokers), 3 patients (4%) had high COHb levels according to the Avoximeter 4000, while their values were within the normal range according to the ABL827 FLEX. Therefore, the specificity of the Avoximeter 4000 in this cohort was 95.6% (95% CI 87%-98.6%), and the overtriage rate would have been 4.4% (95% CI 1.4%-13%). Regarding the forensic samples, 10 of 12 (83%) samples were positive with both devices, while the 2 remaining samples were negative with both devices. The limited difference in COHb level measurements between the Avoximeter 4000 and the control device, which erred on the side of safety, and the relatively low overtriage rate warrant further exploration of this device as a prehospital triage tool.

Association of biomarkers (BMs) with efficacy of adjuvant nivolumab (NIVO) vs placebo (PBO) in patients with resected stage IIB/C melanoma (CA209-76K).

9504 Background: Adjuvant NIVO significantly prolonged recurrence-free survival (RFS) over PBO in stage IIB/C melanoma in the randomized, phase III Checkmate 76K trial (HR; 95% CI: 0.42 [0.30–0.59]). For the first time, select BMs and their association with RFS were analyzed in early-stage melanoma treated with an anti-PD-1 agent. Methods: Baseline primary tumor and serum BMs were analyzed, including interferon gamma-related gene expression signature (IFNγ-sig), TMB, BRAF mutation, % intratumoral CD8+ T cells, tumor cell PD-L1 expression, and serum CRP levels. BMs were evaluated as continuous variables (high vs low levels) and dichotomized by median or prespecified cutoffs. HRs were estimated using a Cox proportional hazards model. Results: Analysis of continuous BM levels within treatment arms showed that higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with prolonged RFS with NIVO but not PBO. The same trend was observed in the dichotomized analyses. No clear association between PD-L1 expression and RFS was identified in either arm. Benefit of NIVO over PBO was seen across all BM subgroups, including by BRAFV600 mutation status. Patients with higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels showed numerically greater relative benefit with NIVO, although CIs overlapped (Table). Conclusions: Higher IFNγ-sig, TMB, and % CD8+ T cells, and lower CRP levels were associated with longer RFS with NIVO treatment. No BMs assessed were prognostic for RFS in the PBO arm, in contrast to previous reports in melanoma. Prolonged RFS was seen in patients treated with NIVO over PBO across levels of BMs, and irrespective of BRAF mutational status. Composite analyses of BMs with clinical and histopathologic factors will be evaluated for their potential to optimize risk:benefit stratification for NIVO in this patient population. Clinical trial information: NCT04099251 . [Table: see text]

Exploratory biomarker analysis of the phase 3 KEYNOTE-604 study of pembrolizumab plus etoposide for extensive-stage SCLC.

8503 Background: In the phase 3 KEYNOTE-604 study of extensive-stage small-cell lung cancer (ES-SCLC; NCT03066778), first-line pembrolizumab (pembro) plus etoposide and platinum (EP) significantly improved PFS vs placebo (pbo) plus EP (HR, 0.75; P = 0.0023), with favorable OS (significance threshold not met; HR, 0.80; P = 0.0164). PFS/OS were similar regardless of PD-L1 CPS. In this exploratory analysis, tumor mutational burden (TMB), 18-gene T cell–inflamed gene expression profile (TcellinfGEP) and SCLC transcriptional subtypes were assessed as correlates of survival. Methods: Patients (pts) eligible for this analysis of KEYNOTE-604 had previously untreated ES-SCLC with evaluable pretreatment tumor samples. TMB was assessed by whole-exome sequencing (WES) of tumor and matched normal DNA. RNA-seq was used to determine TcellinfGEP and SCLC transcriptional subtypes (ASCL1, POU2F3, NEUROD1, YAP1, or inflamed). Associations of TMB, TcellinfGEP, and SCLC subtype with OS were analyzed using an adjusted Cox proportional hazards model. 1-sided (pembro + EP) and 2-sided (pbo + EP) P values were calculated for TMB and TcellinfGEP (prespecified α = 0.05); 2-sided P values were calculated for SCLC subtype (multiplicity-adjusted, α = 0.10). Clinical utility was assessed using prespecified cutoffs of ≥175 mut/exome for TMB and the first tertile for TcellinfGEP. Clinical data cutoff date was Dec 2, 2019. Results: Of 453 pts randomized in KEYNOTE-604 (ITT), 318 had WES data (pembro + EP, n = 167; pbo + EP, n = 151), and 316 had RNA-seq data (pembro + EP, n = 159; pbo + EP, n = 157). High TMB was positively associated with OS in the pbo + EP group ( P = 0.005) but not the pembro + EP group ( P = 0.450). There was a positive association between higher TcellinfGEP and OS in the pembro + EP ( P = 0.003) and pbo + EP ( P &lt; 0.005) groups. SCLC subtypes were not associated with OS in either group (pembro + EP, P = 0.960; pbo + EP, P = 0.999). Clinical benefit of pembro + EP over pbo + EP was demonstrated for TMB &lt;175 mut/exome, but not for TMB ≥175 mut/exome. Pembro + EP benefit over pbo + EP was consistent across TcellinfGEP subgroups. Conclusions: In this exploratory analysis of biomarker subgroups of KEYNOTE-604, TMB and SCLC subtypes were not associated with OS in the pembro + EP group in pts with ES-SCLC. While TcellinfGEP was positively associated with OS in both treatment groups, no additional OS benefit was observed with pembro + EP. Further research is warranted to better identify predictive biomarkers to immunotherapy. Clinical trial information: NCT03066778 . [Table: see text]

Development and Validation of Entrustable Professional Activities for Provisionally Registered (Intern) Pharmacists in Australia

ObjectiveThe purpose of this study was to describe the development and validation of entrustable professional activities (EPAs) for a pharmacy intern training program in Australia. MethodsPerformance outcomes with EPAs suggested as an assessment in the intern year were identified and EPAs were developed. The EQual rubric, designed for EPAs in graduate medical education settings, was used to validate the EPAs. Eight subject matter experts were recruited to validate 14 EPAs using prespecified cutoffs in the EQual rubric to determine the degree of alignment with established key domains of the EPA construct. Descriptive statistics for the EQual rubric scores were calculated for each of the 14 EPAs overall and for each of the 3 domains. Any EPA falling below the prespecified cut score required revisions and a second round of validation. ResultsEight responses were recorded for the first round of validation. Seven EPAs were below the discrete units of work cutoff (4.17); 2 of these EPAs were also below the EPA curricular role cutoff (4.00). All scores described in the EPAs as entrustable, essential, and important tasks of the profession were above the cutoff (4.00). Seven subject matter experts responded to the second round of validation. All 7 revised EPAs scored above the EQual rubric’s overall cutoff of 4.07. ConclusionFourteen EPAs were validated for use with provisionally registered (intern) pharmacists. To our knowledge, this is the first time that the EQual rubric has been used in the evaluation and validation of pharmacy EPAs.

Subgroups of cognitively affected and unaffected breast cancer survivors after chemotherapy: a data-driven approach.

It is assumed that a segment of breast cancer survivors are cognitively affected after chemotherapy. Our aim is to discover whether there is a qualitatively different cognitively affected subgroup of breast cancer survivors, or whether there are only quantitative differences between survivors in cognitive functioning. Latent profile analysis was applied to age-corrected neuropsychological data -measuring verbal memory, attention, speed, and executive functioning- from an existing sample of 62 breast cancer survivors treated with chemotherapy. Other clustering methods were applied as sensitivity analyses. Subgroup distinctness was established with posterior mean assignment probability and silhouette width. Simulations were used to calculate subgroup stability, posterior predictive checks to establish absolute fit of the subgrouping model. Subgrouping results were compared to traditional normative comparisons results. Two subgroups were discovered. One had cognitive normal scores, the other -45%- had lower scores. Subgrouping results were consistent across clustering methods. The subgroups showed some overlap; 6% of survivors could fall in either. Subgroups were stable and described the data well. Results of the subgroup clustering model matched those of a traditional normative comparison method requiring small deviations on two cognitive domains. We discovered that almost half of breast cancer survivors after chemotherapy form a cognitively affected subgroup, using a data-driven approach. This proportion is higher than previous studies using prespecified cutoffs observed. A larger group of cancer survivors may be cognitively affected than previously recognized, and a less strict threshold for cognitive problems may be needed in this population.

Biomarkers predictive of response to pembrolizumab in head and neck cancer.

We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored. We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Two hundred and fifty-seven patients (KEYNOTE-012, n=106; KEYNOTE-055, n=151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ=-0.03 and ρ=-0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ=0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.

Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy

BackgroundHead computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA. Methods/designThis is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely examined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of “severe HIE”. Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0–3) and poor (modified Rankin Scale 4–6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and specificities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter- and intra-rater reliabilities according to STARD guidelines. ConclusionsThe results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients.The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065.

Serum IGF-1 Scores and Clinical Outcomes in the Phase III IMbrave150 Study of Atezolizumab Plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma.

PurposeChild-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study.Patients and MethodsBaseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients’ IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses.ResultsBaseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20–0.56; P<0.001) and sorafenib (HR, 0.32; 95% CI, 0.16–0.65; P=0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20–0.55; P<0.001) and sorafenib (HR, 0.48; 95% CI, 0.26–0.89; P=0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56–8.77; P=0.003) and sorafenib (HR, 5.83; 95% CI, 1.88–18.12; P=0.0023) arms.ConclusionBaseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.

PCR-based analysis of PD-L1 RNA expression in lung cancer: comparison with commonly used immunohistochemical assays

BackgroundPD-L1 testing is currently performed by immunohistochemistry (IHC). We questioned whether the results of PCR-based measurement of PD-L1 RNA expression correlate with IHC scores obtained by different commercial assays. Materials and methods167 consecutive non-squamous non-small cell lung carcinomas (NSCLCs) were analyzed for PD-L1 RNA expression and 22C3, SP263, and SP142 IHC scoring using recommended cut-offs. RNA expression was divided into low, moderate, and high categories. ResultsRNA and protein expression demonstrated moderate correlation as continuous variables. Using prespecified RNA cut-offs, PCR testing showed a high negative predictive value towards the IHC analysis: the share of PD-L1 protein-negative tumors among cases classified as PD-L1-low by the PCR test reached 92–99% for all three antibodies. Meanwhile, about half of cases with moderate to high PD-L1 RNA expression had IHC staining in less than 1% tumor cells as determined by 22C3 or SP263 antibodies. Among the 51 discordant cases, which had <1% tumor staining by both 22C3 and SP263 clones but high RNA level, 29 (57%) showed ≥1% positive immune cells by SP263 and/or 22C3, 14 cases (27%) had detectable IHC expression in 0.1–0.9% tumor or immune cells by SP263 and/or 22C3, and 8 (16%) were entirely negative by IHC. ConclusionSome NSCLCs demonstrate readily detectable PD-L1 expression on the level of RNA, but fall below commonly accepted cut-offs by IHC. It remains to be studied whether these discrepancies are attributed to technical or biological reasons. Clinical sensitivity of these tumors to immune therapy deserves additional investigations.

Association of TMB and PD-L1 with efficacy of first-line pembrolizumab (pembro) or pembro + chemotherapy (chemo) versus chemo in patients (pts) with advanced urothelial carcinoma (UC) from KEYNOTE-361.

540 Background: The 3-arm, open-label, phase 3 KEYNOTE-361 study (NCT02853305) evaluated first-line pembro ± chemo vs chemo in advanced UC regardless of PD-L1 status. The trial did not meet its primary end points of superior PFS and OS with pembro + chemo vs chemo and thus analysis of pembro monotherapy (mono) vs chemo was exploratory. We explored the association of TMB status and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Methods: In pts with TMB and/or PD-L1 data, the association between TMB (via whole exome sequencing) and PD-L1 (via PD-L1 IHC 22C3 pharmDx) and clinical outcomes (ORR, PFS, and OS) was evaluated. In each treatment arm, the hypotheses regarding the associations were evaluated using logistic regression (ORR) and Cox proportional hazards regression (PFS; OS), and 1-sided (pembro; pembro + chemo) and 2-sided (chemo) P values were calculated; significance was prespecified at α = 0.05 without multiplicity adjustment. Clinical utility was assessed using prespecified cutoffs of 175 mut/exome (TMB) and CPS 10 (PD-L1). Clinical data cutoff was April 29, 2020. Results: 820/993 pts (82.6%) had evaluable TMB data (pembro, 252; pembro + chemo, 282; chemo, 286). TMB (log10) was significantly positively associated with ORR, PFS, and OS for pembro ( P &lt; 0.001, &lt; 0.001, and 0.007, respectively) and PFS and OS for pembro + chemo ( P= 0.007 and 0.010, respectively). The area under the receiver operating characteristics (AUROC) curve (95% CI) for discriminating response was 0.64 (0.56-0.71) for pembro, 0.53 (0.46-0.60) for pembro + chemo, and 0.52 (0.45-0.59) for chemo. Efficacy by TMB cutoff is reported in the Table. All 993 pts had PD-L1 data (pembro, 302; pembro + chemo, 349; chemo, 342). PD-L1 was significantly positively associated with PFS for pembro ( P= 0.006) and ORR for pembro + chemo ( P= 0.042) but not chemo. Efficacy by PD-L1 CPS is reported in the Table. Conclusions: Strong associations were observed between TMB and all 3 clinical outcomes (ORR, PFS, and OS) with pembro mono in the first-line setting and a reduced association was observed between TMB and clinical outcomes with pembro + chemo. No consistent associations were observed between PD-L1 and clinical outcomes with pembro mono or pembro + chemo. Clinical trial information: NCT02853305. [Table: see text]

Downregulation of MHC Class II in Relapsed AML Cells after Allogeneic Transplantation

The evolutionary model of Acute Myeloid Leukemia (AML) progression suggests that malignant clones survive initial therapy and acquire new genetic and epigenetic changes, ultimately resulting in therapy-resistant disease. Allogeneic hematopoietic stem cell transplant (HCT) is a potent therapy that provides benefit in part through an immune-mediated Graft-vs-Leukemia (GVL) effect, although relapse after HCT remains a major clinical problem. Recent studies have demonstrated the gain and loss of specific AML-associated mutations at the time of relapse, consistent with a model of clonal evolution; however, a comprehensive screen of genetic changes in AML relapsed after HCT has not yet been reported. We hypothesized that the distinctive, immune-mediated GVL effect imposed by HCT may result in distinct patterns of tumor evolution in relapse after this therapy.To test this, we performed enhanced exome sequencing of matched diagnosis and relapse tumors to identify somatic mutations in 15 patients who relapsed after matched related or unrelated donor HSCT. For comparison, we analyzed 20 cases of AML relapsed after chemotherapy alone. In the majority of samples, new somatic variants were identified, and copy number analysis demonstrated gain and loss of genomic regions, as has been previously reported. However, compared to cases relapsed after chemotherapy alone, there were no gene mutations or copy number changes that were specific to relapse after HCT. Specifically, we found no changes in genes involved in antigen presentation, cytokine production, or immune checkpoints, and an unbiased pathway analysis revealed no enrichment for mutations in immune response pathways. Overall, the spectrum of mutations found at relapse after HCT did not differ from that observed in relapse after chemotherapy only.Since no canonical genetic changes were observed in relapsing AML after HCT, we speculated that clonal evolution of AML after HCT may instead occur through selection of randomly occurring epigenetic changes in AML cells that allow them to escape immune surveillance. To test this hypothesis, we performed RNA sequencing on purified AML blasts (CD45 positive, side scatter low) from presentation and relapsed AML sample pairs from both post-HSCT and post-chemo relapses. Interestingly, in the post chemotherapy relapse cases, only 8 genes were identified with expression changes that met pre-specified cutoffs for significance (FDR<0.5). In contrast, in the post relapse cohort, 34 genes were found to be significantly upregulated, and 187 genes were significantly downregulated, compared to the same sample at presentation. Gene pathway analysis revealed significant dysregulation of immune response genes (the most dysregulated pathway, p<10-35) as well as pathways encompassing cell adhesion/motility and the innate immune response.Four classical MHC Class II genes were among the 187 genes that were downregulated after post-HCT relapse: HLA-DPA1 (mean fold change -11.9 in 6/7 cases), HLA-DPB1 (mean fold change -6.5 in 6/7 cases), HLA-DQB1 (mean fold change -9.7 in 6/7 cases), and HLA-DRB1 (mean fold change -11.9 in 6/7 cases) (Figure 1). In these same 6 cases, there was a strong (but not significant) trend towards downregulation in the remaining MHC Class II genes: HLA-DQA1, HLA-DRB3, and HLA-DRA, as well as CIITA, a transcriptional activator believed to act as the “master regulator” of MHC Class II genes (Figure 1). Several other genes involved in MHC Class II antigen processing and presentation were significantly downregulated post-HCT (FDR<.05), including HLA-DMA, HLA-DMB, and CD74 . In contrast, there was no significant downregulation of MHC Class I genes observed after allo-relapse, raising the possibility that loss of MHC Class II presentation may play a particularly important role in immune evasion after HCT. To validate these findings, we performed flow cytometry for Class II and Class I genes on banked post-HCT relapse samples, and this confirmed significant downregulation of MHC Class II (but not Class I) expression on post-HCT relapse samples (Figure 2). Taken together, these results suggest that loss of MHC Class II-mediated antigen presentation may be an important mechanism of immune escape after HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.

Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer.

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Combined lack of blood pressure and lipid control is a major risk factor for mortality in hypertensive patients: a single-center study

Abstract Background Hypertension and dyslipidemia are well-known risk factors for cardiovascular disease (CVD). In such patients, lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) and targeting to values below pre-specified cut-offs prevents CV events and improves prognosis. However, the impact of both BP and LDL-C control as compared to control of only one and/or none of these two risk factors is not well-studied. Methods Among 2,380 treated patients with hypertension and no overt CVD at baseline, we assessed the trajectory of BP control in 1,142 subjects with 4 or more follow up visits; BP control was defined as BP&amp;lt;140/90 mmHg in half or more visits. In the same subgroup, data on lipid control according to LDL-C goals were available in 1,032 patients in 2 or 3 visits. The HeartScore was used to estimate the risk of all-cause death at baseline. Results Across a median follow up of 108 months, 26 deaths (2.44%) were recorded. Despite appropriate anti-hypertensive treatment, 376 patients (32.92%) did not achieve conventional BP control in half or more of follow-up visits. Respectively, 59.83% of the study population did not meet the LDL-C goals in at least one assessment. Patients with suboptimal BP control had almost 3-fold increased risk for all-cause mortality (HR=2.85, 95% CI 1.31–6.21, P=0.008) as compared to subjects with effective control. This association was not attenuated after taking into account age, gender, body mass index, smoking, and diabetes mellitus (adjusted HR=2.54, 95% CI 1.13–5.72, P=0.025). Ineffective LDL-C control was not related to death (HR=1.31, 95% CI 0.688–2.48). However, patients who did not reach treatment goals for both BP and LDL showed substantially increased risk for all-cause mortality (HR=5.42, 95% CI 1.09–26.9, P=0.039). Importantly, suboptimal BP control in our cohort of hypertensive patients was associated with death independently of the HeartScore (adjusted HR=2.65, 95% CI 1.22–5.77, P=0.014) and conferred incremental reclassification value on top of the baseline risk (continuous NRI=0.467, P=0.016). Conclusions Suboptimal BP control was related to all-cause mortality in our cohort of hypertensive patients; importantly, this association was substantially stronger in concurrent presence of LDL-C values above treatment targets, thus, highlighting the need for combined achievement of BP and LDL-C control. Moreover, association of suboptimal BP controlwith death was independent of the HeartScore, suggesting that BP control should be considered in risk stratification of hypertensive patients Funding Acknowledgement Type of funding source: None

1118-P: Validation of the PromarkerD Test for Predicting Renal Decline in Type 2 Diabetes in the Canagliflozin Cardiovascular Assessment Study (CANVAS)

Chronic kidney disease (CKD) develops in 1 in 3 people with type 2 diabetes (T2D) and is the leading cause of end-stage renal disease (ESRD). The ability of baseline urinary albumin: creatinine ratio or estimated glomerular filtration rate (eGFR) to predict onset and progression of CKD complicating diabetes is limited. PromarkerD is a novel blood test that can predict future renal function decline. This study sought to validate the prognostic utility of PromarkerD in individuals with T2D from CANVAS, a randomized controlled trial of INVOKANA® (canagliflozin). PromarkerD scores were measured at baseline in 3,570 CANVAS participants (n=1,196 placebo arm, n=2,375 canagliflozin arm). Biomarker concentrations (CD5L, ApoA4, IGFBP3) measured by mass spectrometry were combined with clinical data (age, serum HDL-cholesterol, eGFR) using previously defined algorithms to provide PromarkerD scores. The test score (predicted probability) ranges from 0 to 100% and is categorized as low-, moderate- or high-risk as determined by pre-specified cut-offs at 10% and 20%. Renal function decline was defined as incident DKD during the 4 years from randomization. At baseline, the participant sample (mean age 62.7 years, 67% males, median diabetes duration 12.4 years) had a median PromarkerD score of 2.88%, with 70.5% categorized as low-risk, 13.6% as moderate-risk and 15.9% as high-risk for renal function decline. There was no significant difference in baseline PromarkerD scores by allocated treatment (P=0.58). In a model adjusted for treatment, baseline PromarkerD moderate-risk and high-risk scores were increasingly prognostic for renal function decline (OR 5.29 [4.22, 6.64] and OR 13.52 [10.69, 17.11] versus low-risk, respectively; both P&amp;lt;0.001). These data provide further validation of the role of PromarkerD in predicting clinically significant renal function decline and thus to facilitate preventive management strategies. Disclosure K. Peters: Other Relationship; Self; Proteomics International Laboratories Ltd. J. Xu: Employee; Self; Janssen Research &amp; Development, LLC. S. Bringans: Other Relationship; Self; Proteomics International Laboratories Lt. W.A. Davis: Advisory Panel; Spouse/Partner; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Spouse/Partner; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Proteomics International. Other Relationship; Spouse/Partner; Proteomics International. T. Davis: Advisory Panel; Self; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Protemics International. Other Relationship; Spouse/Partner; Protemics International. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. R.J. Lipscombe: Other Relationship; Self; Proteomics International Laboratories Ltd. Funding Janssen Research &amp; Development, LLC

499-P: Clinical Validation of an AI-Enabled Prognostic Test (KidneyintelX) to Accurately Predict Rapid Kidney Function Decline in Patients with Type 2 Diabetic Kidney Disease

The ability to predict rapid kidney function decline (RKFD) in patients with early stages of type 2 diabetic kidney disease (T2DKD) can improve long-term health outcomes through earlier intervention. Our objective was to develop a robust risk score for patients with early stages of T2DKD. We obtained EHR and plasma from patients with T2DKD (Kidney Disease Improving Global Outcomes [KDIGO] G1-G2, A2-A3 or G3a-G3b, A1-A3) from the Mount Sinai BioMe Biobank and the Penn Medicine Biobank and measured soluble tumor necrosis factor receptor (sTNFR1, sTNFR2) and kidney injury molecule-1 (KIM-1) via a validated quantitative electrochemiluminescent assay. A machine learning model was trained using the EHR/biomarker data to predict RKFD, defined as eGFR decline of ≥5 ml/min/year or ≥40% sustained decline in eGFR or kidney failure within 5 years, and performance was compared to a clinical model and KDIGO risk-matrix. A total of 1146 subjects with a mean age of 63, baseline eGFR 54 ml/min, and median UACR 61 mg/g were randomly divided into 60% training (n=686) and 40% validation (n=460) sets. The median follow-up was 4.3 years and 241 (21%) experienced RKFD. The AUC of KidneyIntelX for RFKD was 0.85 (95% CI 0.84-0.86) in training and 0.77 (95% CI 0.76-0.79) in the validation set vs. AUC of 0.67 (95% CI 0.64-0.70) for a clinical model. Using pre-specified cutoffs from the training set, KidneyIntelX stratified 47%, 37% and 16% of the validation set into low-, intermediate- and high-risk strata, with a PPV of 62% (vs. 41% for KDIGO) in the high-risk group (p &amp;lt;0.001), a net reclassification improvement for events of 41% (p &amp;lt;0.05), and a NPV of 91% in the low-risk group (vs. 85% for KDIGO). KidneyIntelX, a machine learning model combining biomarkers and EHR data, improved prediction of RKFD over standard clinical metrics in patients with T2DKD. Future studies will prospectively evaluate KidneyIntelX in clinical decision-making and impact. Disclosure L. Chan: None. G.N. Nadkarni: Advisory Panel; Self; Renalytix AI. Consultant; Self; AstraZeneca, Reata, Renalytix AI. Stock/Shareholder; Self; Renalytix AI. Other Relationship; Self; Renalytix AI. F. Fleming: Board Member; Self; Renalytix AI plc. F.E. Salem: None. B. Murphy: Board Member; Self; RenalytixAI. M.J. Donovan: Consultant; Self; Renalytix AI plc. S. Coca: Advisory Panel; Self; Renalytix AI plc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., CHF Solutions, Relypsa, Inc., Takeda Pharmaceutical Company Limited. Stock/Shareholder; Self; Renalytix AI plc. S.M. Damrauer: Consultant; Spouse/Partner; Rhythm Pharmaceuticals. Research Support; Self; CytoVas LLC, Renalytix AI plc. Funding Renalytix AI plc

1172 Predictive value of coronary artery calcium score for myocardial ischaemia in positron emission tomography

Abstract Funding Acknowledgements This study received no funding. Introduction Coronary artery calcium score (CACS) is an excellent predictor of long-term adverse cardiac events. However, little is known about its value and thresholds for immediate prediction of myocardial ischaemia. Purpose We tested the ability of CACS to predict myocardial ischaemia in patients with positron emission tomography (PET). In particular, we assessed the negative predictive value (NPV) of low CACS and the positive predictive value (PPV) of high CACS for myocardial ischaemia. Methods All consecutive patients undergoing 82Rb PET myocardial perfusion imaging with CACS from October 2016 to January 2019 at our centre were enrolled. Patients with known coronary artery disease (CAD) were excluded. Ischaemia was defined as a summed difference score (SDS) ≥4 in PET, and severe ischaemia as SDS ≥8 or transient ischaemic dilation. CACS was measured from low-dose computed tomography (CT) scans using the Agatston method. Receiver operating characteristic (ROC) analysis was used to calculate areas under the curves (AUC, with 95% confidence interval) and to assess sensitivity, specificity, PPV and NPV of CACS for ischaemia at pre-specified cut-offs (0, 100, 400, and 1000 Agatston units [AU]). Multivariate logistic regression was used to assess the predictive ability of CACS with clinical and ECG data, using odds ratios (OR, with 95% confidence interval). Prediction models were generated with propensity scores for CACS and clinical data with ECG, and compared using AUC. Results Of 1833 patients, 927 were included, all with CACS and 82Rb PET, without known CAD. Mean age was 64.3 ±11.1 years and median CACS was 55 AU (interquartile range 359). In PET, 179 patients (19.3%) had ischaemia and 87 (9.4%) severe ischaemia. To predict ischaemia, CACS had an AUC of 0.82 (0.79-0.84) and was superior to the clinical and ECG data model (AUC 0.68 [0.65-0.71], P &amp;lt; 0.0001 vs. CACS, Figure 1). For ischaemia, CACS 0 AU had 97% sensitivity and 98% NPV, and CACS 100 AU 81% sensitivity and 94% NPV. But CACS 1000 AU had 94% specificity and 60% PPV. Results were similar for severe ischaemia, with an AUC of 0.81 for CACS (0.79-0.84) and superiority over the clinical and ECG data model (AUC 0.74 [0.71-0.77], P = 0.018 vs. CACS). For severe ischaemia, CACS 0 AU had 98% sensitivity and 99% NPV, and CACS 100 AU 85% sensitivity and 98% NPV. But CACS 1000 AU had 90% specificity and 30% PPV. In multivariate analysis, CACS was the strongest predictor of ischaemia (OR 1.14 [1.11-1.17] by 100 AU, P &amp;lt; 0.0001) and made all clinical and ECG data nonsignificant. Conclusion CACS is a valuable predictor of myocardial ischaemia in PET. In particular, CACS ≤100 AU has an excellent NPV and CACS ≥1000 a good PPV for myocardial ischaemia. These findings can be useful to assess the need for additional cardiac testing after a chest CT showing coronary calcifications and to support the interpretation of borderline myocardial perfusion results. Abstract 1172 Figure 1: Prediction of ischaemia