Pathobiology最新文献

Introduction: Galectin-1 is a lectin with immunosuppressive effect in different solid tumors. We investigated galectin-1 expression in triple-negative breast cancer (TNBC) to determine its prognostic value.

Methods: We examined 95 TNBC surgical samples in tissue microarrays with galectin-1 immunohistochemistry (intensity and percentage of staining) and looked for influences on overall and progression-free survivals (PFSs) with the help of Kaplan-Meier estimates. Univariable and multivariable Cox regressions were also analyzed.

Results: According to Kaplan-Meier curves, a significantly worse overall survival (OS) was found for TNBC patients showing intense or ≥50% galectin-1 stromal interface staining versus those lacking it. Cox regression analyses suggested that galectin-1 expression was an independent prognosticator in TNBC. According to the quantity of stromal tumor-infiltrating lymphocytes (sTILs), significant survival differences depending on galectin-1 status were only seen in the low sTILs (<30%) subset. Multivariable analysis suggested that galectin-1 expression was an independent prognosticator for PFS.

Discussion: The immunosuppressive effects of galectin-1 forming a shield around tumor nests may form an immune escape mechanism and can explain the worse OS and PFS we found in TNBC. Owing to the exploratory nature of the study, the results need confirmation in order to investigate the potentials of anti-galectin-1 therapies.

Introduction: We report a case of relapse and refractory acute B-lymphoblastic leukemia (r/r B-ALL) apparently turned into acute myeloid leukemia, which is occasional and fatal during CAR-T treatment. There are still limited data to clarify the molecular mechanism of myeloid blast populations proliferation during CAR-T treatment.

Case presentation: A 21-year-old man with an established history of r/r B-ALL with a complex chromosome karyotype and renal extramedullary infiltration presented to our institution. He exhibited a rapid relapse with acute monocytic leukemia 19 days after CD19 CAR-T cell infusion with extensive infiltration of skin and brain. Salvage chemotherapy was ineffective, and he subsequently succumbed to the uncontrolled invasion and infiltration of leukemia cells and hemorrhage. RNA velocity analysis predicted that HSCs differentiated into GMPs and then GMPs differentiated into myeloid lineage cells. The ANXA1-FPR1/2 axis expression was significantly increased post-treatment, which promotes tumor cell proliferation, invasion, and angiogenesis. 6q deletion (6q-) was the common genetic abnormality across all cell populations, indicating that 6q- conferred a survival ability to HSCs during CAR-T cell therapy.

Conclusions: This case demonstrates potential mechanisms of clone evolution molecular events that CD19 CAR-T cell infusion accelerated the existing myeloid lineage evolution via ANXA1-FPR1/2 axis expression from HSCs with 6q-. (Cyto-)genetic aberrations and/or pathways previously not included in the risk stratification of B-ALL might well be predictive for response and outcome in the era of immunotherapy.

Background: Type 1 diabetes mellitus (T1D) is an autoimmune disease marked by the destruction of pancreatic β cells, necessitating lifelong management. Current therapies, such as insulin injections and pancreas transplants, are effective but impose significant burdens, driving the need for innovative solutions. Among these, the bioartificial pancreas (BAP) stands out as a promising approach. By integrating living insulin-producing cells with synthetic matrices, BAP technology aims to replicate natural pancreatic function, offering the potential for more physiologically relevant and patient-friendly treatment. Summary: This review highlights recent advancements in BAP technology, emphasizing innovations in design, materials, and encapsulation techniques that enhance cell viability and function. Key developments include the use of biocompatible materials for cell encapsulation, continuous glucose monitoring systems, and closed-loop control algorithms, which collectively enable real-time glucose regulation. These breakthroughs address critical challenges such as immune rejection and suboptimal device performance, paving the way for clinical translation. Key Messages: BAP technology represents a paradigm shift in T1D treatment, with the potential to alleviate the daily burdens of insulin management. However, challenges remain, including improving device longevity, bolstering immune protection, and reducing production costs to ensure broader accessibility. Future advancements may emerge from integrating BAP systems with cell-protective therapies, further enhancing their efficacy. While hurdles persist, the BAP signifies a transformative step toward simplifying diabetes management and improving the quality of life for millions worldwide.

Introduction: Duodenal adenomas are most commonly associated with polyposis syndromes. Foveolar adenoma is an especially rare entity with an unknown aetiology. We present a case of duodenal foveolar adenoma with coexisting metaplasia, whole exome sequencing results, and the first literature review. Case Presentation: Hereby, we present the case of a 58-year-old man, whose polypectomy specimen revealed a lesion composed of mainly foveolar cells with low-grade dysplasia and was concluded as foveolar adenoma. Due to the incomplete resection, polypectomy was repeated; this time, foveolar adenoma was diagnosed with high-grade dysplasia. Foveolar differentiation was proved with MUC5AC immunohistochemistry; in addition, KRAS and SMAD4 pathogenic mutations were identified. Discussion: Duodenal foveolar adenoma remains a controversial and an enigmatic entity. Our paper presents such a lesion with first low-grade, then high-grade dysplasia, and KRAS mutation, identical to gastric manifestations. The further sample of our patient suggests foveolar metaplasia as an aetiological factor that supports the literature data.

Introduction: Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2, gross cystic disease fluid protein 15, and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. However, their effectiveness decreases in estrogen receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype.

Methods: We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, tubo-ovarian, and stomach.

Results: The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggest that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was found to be 89.29% across all breast cancer subtypes and 92.93% for TNBC.

Conclusions: MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.

Introduction: Curative treatments in early-stage hepatocellular carcinoma (HCC) are limited by high recurrence rates, and targeted therapies against HCC are rare. Tumour microenvironment (TME) plays a crucial role. One strategy is the expression of programmed cell death receptor 1 ligand (PD-L1), whose receptor PD-1 is expressed on activated T cells. The use of immune checkpoint inhibitors (ICIs) has shown antitumour activity. In HCC, ICIs are proposed as a possible first- and second-line therapy. The expression of PD-1 and PD-L1 in the TME is of prognostic importance and can predict response to ICIs. Our study aimed to investigate the impact of intratumoural PD-1 and PD-L1 expression on HCC recurrence and its relation to cancer-immune phenotypes.

Methods: Immunohistochemical staining was performed on archival tissue from 93 HCC, using the antibodies NAT105 (PD-1) and Ventana SP263 (PD-L1). Tumours were classified as immunologically active, excluded, or deserted. PD-1 and PD-L1 immunoreactivity was evaluated as the proportion of positive immune cells compared to the total immune cells (0%, <1%, and >1%).

Results: HCC with PD-1 expression in >1% of immune cells had a significantly lower recurrence rate than tumours with <1% PD-1 expression (78%; 38/49, p = 0.027). HCC classified as immune active was also enriched for PD-1 expression >1% (77%; 48/62). Tumours with both characteristics had a significantly lower recurrence rate (p = 0.039).

Conclusion: PD-1 expression on immune cells is associated with a lower recurrence rate in HCC, suggesting a role in HCC recurrence. The therapeutic use of adjuvant anti-PD-1 antibodies should thus be viewed critically and investigated further.

Introduction: Soft tissue sarcomas (STSs) are a group of rare malignancies with limited treatment options and a persistent lack of effective therapies. Despite the heterogeneous nature of STS, the canonical WNT/β-catenin signalling pathway has been associated with sarcomagenesis and also with the initiation and progression of other cancers.

Methods: Eight patient-derived primary cultures representing different STS histological subtypes were characterized by immunohisto(cyto)chemistry, WNT/β-catenin activation and next-generation sequencing.

Results: Elevated levels of active phospho-β-catenin and its nuclear localization were found in all STS primary cultures, with heterogeneous downstream WNT signalling activation. Genomic analysis of matched STS tumours identified pathogenic or likely pathogenic genetic variants in crucial signalling pathways, including WNT, DNA damage repair, and PI3K/AKT/mTOR-MAPK pathways. Interestingly, 50% of STS tumours studied carried genetic variants in PIK3CA and PTEN genes with potential clinical significance, listed as predictive biomarkers of response to specific drugs (FDA level 3).

Conclusions: This study provides valuable insights into WNT signalling vulnerabilities in STS, offering a foundation for the development of targeted therapeutic strategies and the identification of potential biomarkers for personalized treatment approaches in this challenging group of malignancies.