Journal of Pathology Clinical Research最新文献

Current European/US guidelines recommend that molecular testing in advanced non-small cell lung cancer (aNSCLC) be performed using next-generation sequencing (NGS). However, the global uptake of NGS is limited, largely owing to reimbursement constraints. We compared real-world costs of NGS and single-gene testing (SGT) in nonsquamous aNSCLC. This observational study was conducted across 10 pathology centers in 10 different countries worldwide. Biomarker data collected via structured questionnaires (1 January–31 December 2021) were used to feed micro-costing analyses for three scenarios [‘Starting Point’ (SP; 2021–2022), ‘Current Practice’ (CP; 2023–2024), and ‘Future Horizons’ (FH; 2025–2028)] in both a real-world model, comprising all biomarkers tested by each center, and a standardized model, comprising the same sets of biomarkers across centers. Testing costs (including retesting) encompassed personnel costs, consumables, equipment, and overheads. Overall, 4,491 patients with aNSCLC were evaluated. Mean per-patient costs decreased for NGS relative to SGT over time, with real-world model costs 18% lower for NGS than for SGT in the SP scenario, and 26% lower for NGS than for SGT in the CP scenario. Mean per-biomarker costs also decreased over time for NGS relative to SGT. In the standardized model, the tipping point for the minimum number of biomarkers required for NGS to result in cost savings (per patient) was 10 and 12 in the SP and CP scenarios, respectively. Retesting had a negligible impact on cost analyses, and results were robust to variation in cost parameters. This study provides robust real-world global evidence for cost savings with NGS-based panels over SGT to evaluate predictive biomarkers in nonsquamous aNSCLC when the number of biomarkers to be tested exceeds 10. Widespread adoption of NGS may enable more efficient use of limited healthcare resources.

Pulmonary typical carcinoids (TCs) are uncommon, well-differentiated neuroendocrine tumors of the lung that do not exhibit necrosis and have fewer than two mitoses per 2 mm², as defined by the current World Health Organization classifications. Despite their low-grade status and favorable prognostic impact, the protein expression profile and morphological characteristics associated with tumor progression and metastatic spread remain largely unidentified. Oncocytic and spindle cell histological variants are acknowledged for their role in differential diagnosis, though their clinical significance remains a topic of debate. We centrally reviewed a multicenter series of 297 TCs to identify cases of oncocytic and spindle cell variants. We examined associations with clinicopathological features and immunohistochemical markers (orthopedia homeobox protein, thyroid transcription factor 1, mammalian achaete-scute homologue 1, somatostatin receptor 2A, Ki-67, anti-mitochondria, and S100); these data were further related to disease-free survival (DFS), overall survival, and cancer-specific survival (CSS). Our analysis identified oncocytic TCs (n = 36, 12.1%), spindle cell TCs (n = 55, 18.5%), and ordinary TCs, defined as those without either variant or with variants that were not prominent (n = 206, 69.4%). Interestingly, ordinary tumors were associated with a higher number of tumor-related deaths (p = 0.01) compared to the other histological variants. Additionally, patients with spindle cell morphology had longer CSS compared to those with ordinary morphology (p = 0.04). Parameters such as histological variant, age, tumor stage, and Ki-67 were significantly linked to DFS on multivariable analysis, even after accounting for differences between centers. In conclusion, oncocytic, spindle cell, and ordinary TCs are linked to distinct clinicopathological characteristics and exhibit varying clinical outcomes.

Breast cancer affects millions globally, necessitating precise biomarker testing for effective treatment. HER2 testing is crucial for guiding therapy, particularly with novel antibody-drug conjugates (ADCs) like trastuzumab deruxtecan, which shows promise for breast cancers with low HER2 expression. Current HER2 testing methods, including immunohistochemistry (IHC) and in situ hybridization (ISH), have limitations. IHC, a semi-quantitative assay, is prone to interobserver variability. While ISH provides higher precision than IHC, it remains more resource-intensive in terms of cost and workflow. However, turnaround time is typically faster than that of other advanced molecular methods such as next-generation sequencing. We adapted the clustering-constrained-attention multiple-instance deep learning model to improve IHC testing and reduce dependence on reflex fluorescence ISH (FISH) tests. Using 5,731 HER2 IHC images, including 592 cases with FISH testing, we trained two models: one for predicting HER2 scores from IHC images and another for predicting FISH scores from equivocal cases. The HER2 IHC score prediction model achieved 91% ± 0.01 overall accuracy and a receiver operating characteristic (ROC) area under the curve (AUC) of 0.98 ± 0.01. The FISH score prediction model had an ROC AUC of 0.84 ± 0.07, with sensitivity at 0.37 ± 0.13 and specificity at 0.96 ± 0.03. External validation on cases from 203 institutions showed similar performance. The HER2 IHC model maintained a 91% ± 0.01 accuracy and an ROC AUC of 0.98 ± 0.01, while the FISH model had an ROC AUC of 0.75 ± 0.03, with sensitivity at 0.28 ± 0.04 and specificity at 0.93 ± 0.01. Our model advances HER2 scoring by reducing subjectivity and variability in current scoring methods. Despite lower accuracy and sensitivity in the FISH prediction model, it may be a beneficial option for settings where reflex FISH testing is unavailable or prohibitive. With high specificity, our model can serve as an effective screening tool, enhancing breast cancer diagnosis and treatment selection.

We previously showed that Warburg subtyping (low/moderate/high), based on the expression of six glycolytic proteins and transcriptional regulators [glucose transporter 1 (GLUT1), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), p53, and PTEN], holds independent prognostic value in colorectal cancer (CRC) patients. The present study aimed to investigate whether the expression level of one of the proteins (GLUT1, PKM2, LDHA, MCT4, p53, and PTEN) can act as a proxy for our previously identified six protein-based Warburg subtypes. Protein expression levels for individual Warburg-related proteins were available for 2,251 CRC patients from the Netherlands Cohort Study. Kaplan–Meier curves and Cox regression were used to explore associations between individual Warburg-related proteins and CRC-specific and overall survival. Previously identified associations between Warburg subtypes and CRC-specific and overall survival were adjusted for individual proteins, showing a significant association with survival in the current study. Multivariable-adjusted analyses showed that the expression of GLUT1, LDHA, MCT4, PKM2, or p53 was associated with neither CRC-specific nor overall survival. Decreasing PTEN expression was associated with significantly poorer overall survival (p-trend_categories = 0.026). Additional adjustment for PTEN expression had minimal impact on the previously identified association between Warburg subtypes and survival, and the six protein-based Warburg-high subtype remained a statistically significant predictor of overall survival (hazard ratio 1.15; 95% CI 1.01–1.32). In conclusion, our results emphasise that individual Warburg-related proteins cannot serve as a proxy or surrogate marker for Warburg subtyping, thereby highlighting the importance of combining the expression levels of multiple Warburg-related proteins when examining the prognostic significance of a complex biological pathway such as the Warburg effect.

Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies, with varying levels of risk and clinical behavior. A better understanding of the molecular characteristics could improve molecular diagnosis and risk assessment. In this study, we performed whole transcriptomic sequencing on 113 PTC cases, including 70 high-risk and 43 low-risk Chinese patients. Comparative transcriptional profiling analysis revealed two functionally distinct patterns of gene dysregulation between the risk subtypes. Low-risk PTCs showed significant upregulation of immune-related genes and increased immune cell infiltration, whereas high-risk PTCs presented extensive alterations in gene expression and activation of oncogenic signaling pathways. Additionally, we developed a 31-gene transcriptomic signature (PTCrisk) for differentiating high-risk from low-risk PTCs, which was validated across both in-house and external multicenter cohorts. PTCrisk scores were positively correlated with key clinicopathological features, including tumor size, lymph node metastasis, TNM stage, and BRAF mutation status. Overall, our study provides further molecular insights into PTC risk stratification and may contribute to the development of personalized therapeutic strategies for PTC patients.

Intraductal papillary mucinous neoplasm (IPMN) can progress into malignant pancreatic cancer, posing challenges in accurately assessing the risk of malignancy. While the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome pathway's role in pancreatic ductal adenocarcinoma (PDAC) has been extensively studied, its implications in IPMN remain unexplored. This study aimed to investigate the prognostic significance of NLRP3 inflammasome-related proteins across IPMN subtypes and their associations with tumor characteristics, with a secondary focus on comparing expression patterns in IPMN and PDAC. A cohort of 187 patients (100 IPMN and 87 PDAC) underwent high-dimensional histopathological imaging using the multiplexed immunohistochemical consecutive staining on single slide method and a semi-automated image analysis workflow. Expression levels of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1, interleukin-1 beta, interleukin-18 (IL-18), interleukin-1 receptor antagonist, and interleukin-18 binding protein (IL-18BP) were evaluated and compared between IPMN and PDAC samples. The relationships between protein expression and tumor characteristics were examined. Principal component analysis distinguished between intestinal and nonintestinal clusters based on NLRP3-associated proteins. Lower IL-18 expression was linked to the intestinal subtype, while higher caspase-1 was linked to the pancreatobiliary subtype. Elevated caspase-1 and ASC expression were associated with invasiveness in IPMN. No significant correlation was found between the examined proteins and later-stage tumor characteristics in invasive cases. The IL-18/IL-18BP ratio was an independent prognostic factor in invasive IPMN. Our findings highlight the prognostic significance of IL-18 and the IL-18/IL-18BP ratio in invasive IPMNs. These results point to a complex regulation of NLRP3 inflammasome proteins, especially effector cytokines, in pancreatic neoplasms, which are strongly linked to subtype and prognosis.

Sarcomatoid urothelial carcinoma (SUC) is a rare histologic subtype with poor prognosis. While there is known intra-tumoral heterogeneity between individual SUC tumors, the relationship between sarcomatoid and conventional urothelial carcinoma (CUC) within the same patient is poorly understood. The objective of this study was to identify differences between the sarcomatoid and CUC tumor microenvironment components that may drive this aggressive phenotype. Using tissue microarrays from eight patient tumors with mixed CUC and SUC, we examined paired CUC, mixed urothelial carcinoma (UC) regions, and SUC using the Nanostring Digital Spatial Profiling platform. We found SUC and mixed UC had higher levels of stromal cells, predominately macrophages and fibroblasts, when compared with CUC within the same tumor. CD14, CD163, and transforming growth factor-beta levels were significantly higher in SUC than in CUC. Immunohistochemical analysis revealed consistently moderate to strong expression of CD163-positive antigen-presenting cells (APCs) in SUC regions, whereas CD68-positive APC expression was generally absent. Thus, in mixed histology SUC, the SUC component preferentially expressed CD163-positive APCs and fibroblasts compared to the CUC component. As CD163-positive APCs and fibroblasts are known to be tumor-promoting and immune-suppressive, this infiltration may contribute to epithelial to mesenchymal transition and other aggressive properties of SUC.

CXC chemokine receptor 4 (CXCR4) and programmed cell death-ligand 1 (PD-L1) are two critical molecules involved in the tumor immune microenvironment. However, the impact of platinum drugs, such as cisplatin, on CXCR4 or PD-L1 expression and the underlying mechanisms in gastric cancer (GC) remain unknown. Moreover, the correlation between their expression levels in GC remains elusive. Immunohistochemistry, western blot, and RT-qPCR were performed to determine the expression pattern of CXCR4 and PD-L1 in GC. Clinical samples, patient-derived xenografts, and cell-derived xenografts were utilized to investigate the effects of platinum drugs on the expression levels of CXCR4 and PD-L1. Postchemotherapy resected GC tumor tissues showed higher CXCR4 and PD-L1 expression levels than pretreatment biopsies (p < 0.05). Similarly, GC xenografts treated with platinum-based chemotherapy exhibited increased CXCR4 and PD-L1 expression levels compared to saline-treated controls (p < 0.05). A positive correlation was detected between the expression levels of CXCR4 and PD-L1 in GC tumor tissues. Increased levels of CXCR4 and PD-L1 expression, in a dose- and time-dependent manner upon cisplatin treatment, were observed in GC cells (p < 0.05). Cisplatin-induced CXCR4 upregulation relies on ROS/HIF-1α and ROS/NF-κB pathways, while cisplatin-induced PD-L1 upregulation is cyclic GMP-AMP synthase/stimulator of IFN genes-dependent and associated with elevated ROS levels in GC cells. CXCR4 expression was found to be positively correlated with PD-L1 expression in GC. Platinum drugs upregulated the levels of CXCR4 and PD-L1 expression in GC. A combined strategy targeting CXCR-4 and PD-L1 might have clinical prospects for GC patients.