Pathologie (Heidelberg, Germany)最新文献

A stroma a‑reactive invasion front area (SARIFA) is a new prognostic biomarker in carcinomas. Essentially, SARIFA describes the occurrence of direct contact between at least five tumor cells and adipocytes. This phenomenon is extremely easy and quick to identify, shows an extremely low interobserver variability, and does not require any additional staining as it can be identified on standard HE sections. The prognostic efficiency has now been demonstrated in gastric, colorectal, pancreatic, and prostate carcinoma.

Background: Pancreatic neuroendocrine tumors (PanNETs) show pronounced heterogeneity in terms of hormone and transcription factor (TF) expression. TFs such as ARX and PDX1 are related to alpha- and beta-cell-type features, respectively, and partly associate with patient outcome. However, detailed studies correlating hormone expression, histology, and clinical data are lacking.

Objective: The aim of this study was to identify subtypes of PanNETs that associate with histological, hormonal, and prognostic findings.

Methods: A total of 185 resected PanNETs were divided into five subtypes (types A1, A2, B, C, and D) by cluster analysis based on expression of four TFs (ARX, PDX1, ISL1, and CDX2) and correlated to the expression of hormones and DAXX/ATRX as well as ALT activation status, histology, and progression-free survival.

Results: Subgroup A1 (ISL1+/ARX+/PDX-/CDX2-) was most frequent (46%), followed by type B (18%; ISL1+/ARX-/PDX+/CDX2-), A2 (15%; ISL1+/ARX+/PDX+/CDX2-), C (15%; ISL1-/ARX-/PDX-/CDX2-), and D (5%; ISL1-/ARX-/PDX+/CDX2+). Subgroups A1 and A2 showed a strong association with a trabecular growth pattern and glucagon and pancreatic polypeptide (PP) expression (p < 0.001), while A2 was in addition associated with gastrin expression. Subgroup B was associated with insulin production (p < 0.001) and included all 17 insulinomas. Subgroup C was associated with solid morphology and expression of serotonin, calcitonin, and adrenocorticotropic hormone (ACTH). Subgroup D showed solid morphology, expression of ACTH, somatostatin, or serotonin and had the shortest disease-free survival (p < 0.01). ALT positivity was associated with poorer outcome in types A1 and A2 but not in other types.

Conclusion: PanNETs can be categorized into five subgroups based on different TF signatures, which associate strongly with histology, hormone production, functionality, and patient outcome.

Background: Homologous recombination deficiency (HRD) in tumors correlates with poor prognosis and metastases development. Determining HRD is of major clinical relevance as it can be treated with PARP inhibitors (PARPi). HRD remains poorly investigated in sarcoma, a rare and heterogeneous cancer of mesenchymal origin.

Objective: We aimed (i) to investigate predictive biomarkers of HRD in several independent sarcoma cohorts using a cross-functional strategy by combining genomic, transcriptomic and phenotypic approaches and (ii) to evaluate the therapeutic potential of PARPi and DNA damage response (DDR)-based therapies ex vivo.

Materials and methods: We performed a comprehensive genomic and transcriptomic characterization of sarcoma using datasets from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and our own bone and soft tissue sarcoma cohorts. We evaluated PARP1/2 and WEE1 inhibition ex vivo in patient-derived sarcoma cell models as monotherapy and in combination with chemotherapeutic agents to identify synergistic effects.

Results: Firstly, we identified genomic traits of HRD in a subset of sarcomas associated with molecular alterations in homologous recombination repair (HRR) pathway genes and high chromosomal instability. Secondly, we identified and validated distinct SARC-HRD transcriptional signatures that predicted sensitivity to PARPi. Finally, we showed functional defects in HRR in sarcoma cells that were associated with functional dependency towards PARPi and WEE1i and support the clinical use of RAD51 as a predictive biomarker for PARPi sensitivity.

Conclusion: We provide a personalized oncological approach to potentially improve the treatment of sarcoma patients. We encourage the evaluation of gene expression signatures to enhance the identification of patients who might benefit from DDR-based therapies.

Background: Histomorphometry is currently the gold standard for bone microarchitectural examinations. This relies on two-dimensional (2D) sections to deduce the spatial properties of structures. Micromorphometric parameters are calculated from these sections based on the assumption of a plate-like 3D microarchitecture, resulting in the loss of 3D structure due to the destructive nature of classical histological processing.

Materials and methods: To overcome the limitation of histomorphometry and reconstruct the 3D architecture of bone core biopsy samples from 2D histological sections, bone core biopsy samples were decalcified and embedded in paraffin. Subsequently, 5 µm thick serial sections were stained with hematoxylin and eosin and scanned using a 3DHISTECH PANNORAMIC 1000 Digital Slide Scanner (3DHISTECH, Budapest, Hungary). A modified U‑Net architecture was trained to categorize tissues on the sections. LoFTR feature matching combined with affine transformations was employed to create the histologic reconstruction. Micromorphometric parameters were calculated using Bruker's CTAn software (v. 1.18.8.0, Bruker, Kontich, Belgium) for both histological and microCT datasets.

Results: Our method achieved an overall accuracy of 95.26% (95% confidence interval (CI): [94.15%, 96.37%]) with an F‑score of 0.9320 (95% CI: [0.9211, 0.9429]) averaged across all classes. Correlation coefficients between micromorphometric parameters measured on microCT imaging and histological reconstruction showed a strong linear relationship, with Spearman's ρ‑values of 0.777, 0.717, 0.705, 0.666, and 0.687 for bone volume/tissue volume (BV/TV), bone surface/TV, trabecular pattern factor, trabecular thickness, and trabecular separation, respectively. Bland-Altman and mountain plots indicated good agreement between the methods for BV/TV measurements.

Conclusion: This method enables examination of tissue microarchitecture in 3D with an even higher resolution than microcomputed tomography (microCT), without losing information on cellularity. However, the limitation of this procedure is its destructive nature, which precludes subsequent mechanical testing of the sample or any further secondary measurements. Furthermore, the number of histological sections that can be created from a single sample is limited.

As an internationally accepted diagnostic system, the Paris classification has achieved a global breakthrough in the standardization of diagnoses in urine cytology. Based on experience over the past few years since its first publication, the new edition of the Paris classification refines the diagnostic criteria and discusses diagnostic pitfalls. While the detection of high-grade urothelial carcinoma remains the main focus, other aspects of urine cytology, including cytology of the upper urinary tract and the associated challenges, have also been addressed. Low-grade urothelial neoplasia is no longer listed as a separate category but is now included in the category "negative for high-grade urothelial carcinoma" (NGHUC). Essentially, the Paris classification provides an important basis for estimating the risk of malignancy and further clinical management.

Since CRISPR/Cas systems can be easily used to establish new genetically engineered mouse models, application of these models in the translational research field to explore predictive and therapeutic approaches for human diseases is rising.Integrative centers for experimental animal pathology, such as the CMCP in Heidelberg and the CEP in Munich, link the veterinary and human pathology discipline and contribute substantially to meaningful study results by combining the technical, research, and diagnostic expertise for phenotyping, evaluating, and interpretating complex animal models in the context of human pathology. They provide high-quality tissue processing in a broad spectrum of standard and specialized tissue-based technologies. The histopathology platform enables animal model evaluation including phenotyping, scoring, and detecting species-specific "background lesions." By providing essential prerequisites for high-quality, reproducible, and sustainable research in translational medicine, facilities for experimental animal pathology optimally fulfill the requirements for publications in top-class professional journals, contribute to the implementation of the 3R principle for animal welfare, and help to reduce costs in the preclinical research.The importance of animal models reflecting human diseases will increase in the future but the requirements for high-quality tissue processing and comparative pathology/morphological phenotyping cannot be met by single facilities in a niche position. To cover the existing gap and expected rising demand in the German and European translational research landscape, further facilities for experimental animal pathology that are integrated in the human pathology environment should be established.