Clinical Significance Of Discrepancies Research Articles

Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression

IntroductionProgrammed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. MethodsWe retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. ResultsIn total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3′-terminal sequences in tumors with the inter-assay discrepancy than in those without. ConclusionThe inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Abstract 5146: Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression

Abstract Introduction: The expression of programmed cell death ligand-1 (PD-L1) is a predictive biomarker for the efficacy of pembrolizumab in advanced non-small cell lung cancer (NSCLC). While several assays have been approved for evaluating PD-L1 expression status, the inter-assay discordances are observed. The clinical significance of these discrepancies is still unclear. Methods: We retrospectively reviewed treatment-naïve NSCLC patients with available PD-L1 expression status by both 22C3 and SP142 assays. Among these patients, efficacy analysis was performed in those with PD-L1 tumor proportion score (TPS) ≥ 50% (22C3) who received the first-line pembrolizumab monotherapy. Additionally, we conducted RNA-sequence analysis in the patients with TPS ≥ 50% to investigate the distinct immune profiles with the inter-assay discordance. Results: A total of 611 patients were evaluated for PD-L1 expression status by both assays. Of 198 patients with TPS ≥ 50%, 91 (46%) had TC score ≤ 1 (SP142, i.e., inter-assay discrepancy). In 52 patients who received the first-line pembrolizumab monotherapy, the efficacy in patients with the inter-assay discrepancy was significantly lower than those without the discrepancy (shown in Table). While there was no difference in tumor microenvironments such as the tumor-infiltrating lymphocytes, the transcriptome analysis revealed significantly more CD274 splicing variants with aberrant 3’-terminal sequences in tumors with the inter-assay discrepancy than those without discrepancy, leading to the suppressed PD-1/PD-L1 pathway in those with the discrepancy. Conclusion: The inter-assay discrepancy in the PD-L1 expression status on tumor cells between the 22C3 and SP142 assays, reflecting an imbalance of the CD274 splicing variants, could be a primary-resistance mechanism to the pembrolizumab monotherapy in highly PD-L1-expressing NSCLCs. PD-L1(22C3) Discrepancy Pts. ORR(%) p value Median PFS(months) 95%CI p value TPS ≥ 50% yes 17 18 &amp;lt; 0.001 3.2 0.8–5.5 &amp;lt; 0.001 no 35 83 8.3 5.7–24.2 Citation Format: Jun Miyakoshi, Jumpei Kashima, Masayuki Shirasawa, Masahiro Torasawa, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Hidehito Horinouchi, Kouya Shiraishi, Takashi Kohno, Noboru Yamamoto, Yasushi Yatabe, Yuichiro Ohe. Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5146.

Discordance between immunofluorescence and immunohistochemistry C4d staining and outcomes following heart transplantation.

Capillary deposition of C4d is an important marker of antibody-mediated rejection (AMR) following heart transplantation (HT). There are two immunopathologic assay methods for detecting C4d: frozen-tissue immunofluorescence (IF) and paraffin immunohistochemistry (IHC). The clinical significance of discrepancy between the results of IF and IHC has not been understood. We reviewed 2187 biopsies from 142 HT recipients who had biopsies with assessment of both IF and IHC staining. Among them, 103 (73%) patients had negative IF and IHC C4d staining (Negative Group) and 32 (23%) patients had positive IF but negative IHC staining (Discordant Group). At the time of positive biopsy, 6 (19%) Discordant patients had graft dysfunction, compared to 5 (5%) Negative patients (p=.022). Cumulative incidence of cellular rejection at 1year was comparable (31% vs. 29%, p=.46); however, cumulative incidence of AMR was significantly higher in the Discordant group (21% vs. 4%, p=.004). Overall 1-year survival was comparable (90% vs. 96%, p=.24); however, freedom from heart failure (HF) was significantly lower in the Discordant group (70% vs. 96%, p<.001). The Discordant group showed higher rates of graft dysfunction, AMR and HF admission than the Negative group.

Clinical Impact of Second Opinion Radiology Consultation for Patients With Breast Cancer

PurposeTo assess the incidence and clinical significance of discrepancy in subspecialty interpretation of outside breast imaging examinations for newly diagnosed breast cancer patients presenting to a tertiary cancer center. Materials and MethodsThis Institutional Review Board–approved retrospective study included patients presenting from July 2016 to March 2017 to a National Cancer Institute–designated comprehensive cancer center for second opinion after breast cancer diagnosis. Outside and second opinion radiology reports of 252 randomly selected patients were compared by two subspecialty breast radiologists to consensus. A peer review score was assigned, modeled after ACR’s RADPEERTM peer review metric: 1—agree; 2—minor discrepancy (unlikely clinically significant); 3—moderate discrepancy (may be clinically significant); 4—major discrepancy (likely clinically significant). Among cases with clinically significant discrepancies, rates of clinical management change (management alterations including change in follow-up, neoadjuvant therapy use, and surgical management as a direct result of image review), and detection of additional malignancy were assessed through electronic medical record review. ResultsA significant difference in interpretation (scores = 3 or 4) was seen in 41 of 252 cases (16%, 95% confidence interval [CI], 11.7%-20.8%). The difference led to additional workup in 38 of 252 cases (15%, 95% CI 10.6%-19.5%) and change in clinical management in 18 of 252 cases (7.1%, 95% CI 4.0%-10.2%), including 15 of 252 with change in surgical management (6.0%, 95% CI, 3.0%-8.9%). An additional malignancy or larger area of disease was identified in 11 of 252 cases (4.4%, 95% CI, 1.8%-6.9%). ConclusionDiscrepancy between outside and second-opinion breast imaging subspecialists frequently results in additional workup for breast cancer patients, changes in treatment plan, and identification of new malignancies.

Clinical Significance of Discrepancy between Arterial Spin Labeling Images and Contrast-enhanced Images in the Diagnosis of Brain Tumors.

In the imaging of intra-axial brain tumors, we sometimes found areas of high signal intensity around the enhanced tumor lesions on arterial spin labeling (ASL) magnetic resonance (MR) imaging. We undertook this study to investigate the relationship between high signal intensity on ASL imaging outside the area of contrast enhancement (CE) and histological diagnosis of intra-axial brain tumors. We examined images from 28 consecutive patients with intra-axial brain tumors who underwent ASL and CE MR imaging-three with low grade glioma (LGG), 13 with high grade glioma (HGG), six with metastasis, and six with primary central nervous system lymphoma (PCNSL)-and divided imaging findings into an "ASL dominant" group when hyperintensity on ASL was found outside the CE area and a "CE dominant" group when hyperintensity on ASL was not found outside the area of enhancement. We then analyzed the relationship between imaging findings and the histological diagnosis of the tumors. Four cases were excluded because of poor quality of ASL images, 7 cases were classified as ASL dominant, and 17 cases were classified as CE dominant. The histological diagnoses of ASL dominant cases were LGG in 3 cases, HGG in 3 cases, and PCNSL in one case. Those of CE dominant cases were HGG in 10 cases, metastasis in 5 cases, and PCNSL in 2 cases. All cases with brain metastasis were classified as CE dominant. The high signal intensity outside the area of contrast enhancement is probably caused by increased perfusion or vascular proliferation, which indicates the presence of glioma or PCNSL and not metastasis. This finding indicates a new utility for ASL images in the diagnosis of brain tumors as a supplement to the conventional measurement of perfusion obtained from ASL images.

Application of the RADPEER™ Scoring Language to Interpretation Discrepancies Between Diagnostic Radiology Residents and Faculty Radiologists

The objectives of this study were to assess the rate of discrepancies between radiology residents and faculty radiologists at an academic hospital using the RADPEER(™) scoring language and to determine if a correlation existed between assigned RADPEER score (2, 3, or 4) and the clinical significance of the error. Over 19 months, preliminary resident interpretations were graded using the RADPEER scoring system. A retrospective review of discrepant cases was performed to assess the percentage of discrepancy, change in clinical management, and identification of error patterns. Of 2,255 preliminary interpretations, 29 discrepancies (1.29%) were judged to be potentially clinically significant. Of these, 14 (0.62%) resulted in immediate changes in clinical management. Discrepancies assigned RADPEER scores of 3 or 4 were significantly more likely to be judged clinically significant than those assigned scores of 2 (54.5% of 33 studies graded 3 or 4 and 7.7% of 142 studies graded 2, P < .0001). CT imaging generated a higher percentage of discrepancies that were predicted to be clinically significant than plain-film radiography, as well as a higher percentage of discrepancies that resulted in immediate changes in management, but the incidence of each remained low overall (≤2.1%). Discrepancy rates in this study are comparable with previously reported data for discrepancies between attending radiologists and those between attending radiologists and residents data. A significant correlation was observed between increasing RADPEER scores and the clinical significance of discrepancies. This study supports the use of the RADPEER scoring language as both a resident quality assurance measure and an educational tool for quality improvement.

Discrepancy between total white blood cell counts and serum C-reactive protein levels in febrile children

Total white blood cell (WBC) counts and serum C-reactive protein (CRP) are used as inflammatory markers in febrile children. We studied the occurrence and clinical significance of discrepancy in these markers. From a 2-y period, we retrospectively reviewed the medical records of febrile children (> or =1 month of age) with WBC > or =15 x 10(9)/l and/or CRP levels > or =80 mg/l, as well as of children with lower values in both these parameters. WBC and CRP were discordant in 556 children and concordantly high in 194 children. A severe bacterial disease was presumed in 57% of children with concordantly high WBC and CRP, in 20% of those with discordant values, and in 5% of those with low levels of these markers (p<0.001). Non-streptococcal tonsillitis was the most common viral infection associated with elevated WBC and CRP. In conclusion, WBC and CRP are commonly discrepant in febrile children. Measuring both markers increases substantially the detection rate of bacterial infections.