Pathobiology最新文献

Introduction: Metabolites are associated with the biology of cancer; however, no metabolites related to prognosis have been identified in head and neck cancer. This study aimed to identify metabolites associated with prognosis in patients with hypopharyngeal squamous cell carcinoma (HPSCC).

Methods: Fifty-two patients who underwent surgery for HPSCC were included and randomly divided into test and validation cohorts of 26 patients each for further metabolome analysis using capillary electrophoresis/mass spectrometry on tumor and non-tumor tissues of the hypopharynx. Twenty-two patients who received adjuvant therapy after surgery were included. The receiver operating characteristic (ROC) and univariate and multivariate analyses were used to explore the relationship between recurrence-free survival (RFS), clinicopathological factors, and differentiated metabolites.

Results: ROC analysis revealed six metabolites significantly associated with RFS in both cohorts, and multivariate analysis indicated that 2,3-pyridinedicarboxylate was a significantly independent poorer prognostic factor in the cohorts including patients with HPSCC without any adjuvant therapies (p = 0.017).

Conclusion: 2,3-Pyridinedicarboxylate, involved in NAD+ metabolism and genomic stability, suggests the possibility of developing molecular-targeted drugs for the production of metabolites related to prognosis. This study identifies novel prognostic metabolites and their associated metabolic pathways in HPSCC, highlighting potential therapeutic targets for treatment.

Introduction: TP53 mutation is frequently observed in colorectal cancer (CRC) and is often linked to associated with immunohistochemical p53 expression patterns. Recent studies have identified cytoplasmic p53 expression in CRC, but its correlation with TP53 mutation domains and functional properties remains unclear.

Methods: We evaluated nuclear and cytoplasmic p53 staining patterns in 429 stage II and III CRC samples. TP53 mutation status was assessed using targeted next-generation sequencing. Correlations among cytoplasmic expression, mutation domains, functional properties, and clinicopathological features were analyzed.

Results: Cytoplasmic p53 expression was detected in 21 (4.9%) CRCs. All cytoplasmic expressions were accompanied by nuclear staining. TP53 mutations associated with cytoplasmic p53 predominantly involved nonsense mutations within the tetramerization domain (TD, 61.9%) and nuclear localization signals (NLSs, 14.3%). All functionally characterized mutations associated with cytoplasmic p53 exhibit loss-of-function (LOF) without gain-of-function or dominant-negative effects. NLS and TD mutations were significantly associated with BRAF V600E mutation but not with microsatellite instability status.

Conclusion: Aberrant cytoplasmic p53 expression in CRC leads to nonsense mutations in the TD and NLS domains of TP53. These mutations exclusively induced LOF characteristics. Cytoplasmic expression patterns differ functionally and molecularly from classical nuclear staining patterns, highlighting the need for novel interpretation criteria for p53 immunostaining.

Introduction: This study aimed to observe the expression of far upstream element-binding protein 1 (FUBP1) in gastrointestinal stromal tumors (GISTs) and explore its impact on the biological behavior of GIST cells.

Methods: Fifty patients with GIST who underwent surgical resection were selected, and cancer tissues and adjacent normal tissues were gathered. The expression level of FUBP1 and its correlation with clinicopathological data and prognosis in patients with GISTs were assessed. GIST-T1 cell lines in the logarithmic growth phase were transfected with lentiviruses overexpressing FUBP1, small hairpin RNA targeting FUBP1, and their respective negative controls. FUBP1 expression levels in each group, cell biological behavior were tested, and the effect of FUBP1 on tumor growth in vivo were tested.

Results: Compared to adjacent normal tissues, FUBP1 expression level was elevated in GIST cancer tissues and was concerned with tumor size, NIH risk category, and tumor metastasis in patients. Knockdown of FUBP1 inhibited cell malignant behaviors and promoted cell apoptosis, while overexpression of FUBP1 had the opposite effects. FUBP1 facilitated the growth of GIST cells in vivo.

Conclusion: FUBP1 is upregulated in GISTs and facilitates the invasion, migration, and proliferation of GIST cells. This provides a new perspective for understanding the pathogenesis of GIST and lays a foundation for developing potential therapeutic strategies targeting FUBP1.

Introduction: Around 25% of patients with a biopsy diagnosis of pure ductal carcinoma in situ (DCIS) will be upstaged to invasive breast carcinoma (IBC) after surgery. Because of this upstaging risk, patients with high grade DCIS frequently undergo a sentinel lymph node procedure (SLNP), which can cause surgery-induced morbidity. Presentation with a palpable mass increases the upstaging risk, but histopathological predictors are currently unclear. This PROSPERO-registered systematic review aims to identify which biopsy-based histopathological markers can predict the presence of IBC in the subsequent resection. These results might help to reserve SLNPs for selected high-risk patients, aiming to personalize treatment.

Methods: PubMed, Embase, and Scopus were searched for content using predefined search queries. Three reviewers independently screened the literature in Rayyan by applying predefined criteria and retained 36 reports. Studies including DCIS with micro-invasion were excluded.

Results: This systematic review comprised 18,475 patients. The median cohort size was 267 patients (range: 67-3,780). Most studies were retrospective (33/36). The median upstaging risk was 26% (range: 8-52%). The reports studied twenty-three histopathological and immunohistochemical features. Only seven features were investigated in multiple studies, all yielding contradictory results. For instance, thirty-three studies investigated nuclear grade, but only 18 reports demonstrated a significant association with upstaging, independent from cohort size.

Conclusion: No robust histopathological features can be recommended at present to reliably predict the upstaging risk to IBC after a biopsy diagnosis of pure DCIS. We discuss several hypotheses, aiming to explain these contradictory data. Ideally, large-scale multicentre prospective studies should be organized to answer this unmet clinical need.

Introduction: Testicular germ cell tumors (TGCTs) are the most common solid malignancies among young men. Despite good response to cisplatin-based chemotherapy, side effects negatively affect quality of life. Recent development of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors opens opportunity for targeted therapy, but ENPP1 expression in TGCTs has not been characterized. We aimed to assess ENPP1 immunoexpression in a cohort of primary and metastatic TGCTs, and in normal testicular parenchyma, looking into differential immunoexpression patterns among subtypes and clinicopathological correlations.

Methods: Overall, 90 TGCT individual tumor components from 63 patients diagnosed and treated at a comprehensive cancer center were assessed, using immunohistochemistry to ascertain biomarker expression (combined score of stained tumor cells percentage and intensity). In silico analysis of The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) datasets was performed for additional validation.

Results: Significant differences in ENPP1 expression across TGCT subtypes were disclosed. Seminomas and embryonal carcinomas (ECs) showed significantly higher ENPP1 expression compared to other subtypes, the highest levels being found in EC, which was confirmed with in silico analysis of TCGA and HPA. Expression in metastatic samples was overall lower compared to primary TGCTs. ENPP1 was not expressed in germ cells of healthy testicular parenchyma.

Conclusion: We demonstrate that ENPP1 is expressed in TGCTs, mostly EC (a frequently aggressive tumor subtype), followed by seminoma (the most common TGCT subtype), suggesting potential responsiveness to novel ENPP1 inhibitors. Absent expression in germ cells of healthy testicular parenchyma suggest cancer cells specificity and low probability of fertility-related toxicity.

Introduction: Extrahepatic cholangiocarcinoma (eCCA) is an aggressive malignancy with a poor prognosis. Immune checkpoint inhibitors (ICIs) targeting PD-L1 enhance antitumor immunity, but reliable predictive biomarkers remain unclear. This study investigated tumor-infiltrating immune cells, including T cells and macrophages, as potential biomarkers for ICI efficacy in eCCA.

Methods: A retrospective analysis was conducted on 15 eCCA patients who received durvalumab for recurrent or unresectable disease after surgery. Immunohistochemical staining assessed PD-L1, HLA-class I/II, CD8, and CD103 expression in resected tumor specimens. ICI response was evaluated using RECIST 1.1 criteria and classified as partial response (PR), stable disease (SD), or progressive disease (PD). Correlations between immune cell infiltration and clinical outcomes were analyzed.

Results: Five patients achieved PR, five SD, and five PD. CD8+ and CD103+ T-cell infiltration within tumor nests was significantly higher in PR and SD groups than in PD (p = 0.032, p = 0.0147). High HLA-class I expression correlated with response, while PD-L1 and HLA-class II showed no significant association. Patients with increased CD8+CD103+ T cells demonstrated better disease control.

Conclusion: Intratumoral CD8+ and CD103+ T cells may serve as predictive biomarkers for ICI efficacy in eCCA, highlighting tissue-resident immune cells as therapeutic targets.

Background: Lung cancer is the leading cause of cancer related death in the USA. A proven risk factor for the development and progression of lung cancer is human immunodeficiency virus (HIV).

Summary: HIV persists within the lung in alveolar macrophages and bronchial epithelial cells, reducing mucociliary function and decreasing epithelial integrity. This persistence yields chronic inflammation by way of matrix metalloproteinases, which causes pulmonary injury. Over time, this progresses to pulmonary disease and allows for the development of superimposed pulmonary infections and chronic inflammatory states. This injury is a risk factor for the development of dysplasia, and chronic pulmonary disease and infections further increase the risk for developing lung cancer. HIV persistence and chronic inflammation also lead to CD8+ T cell exhaustion and alterations to macrophages and dendritic cells that blunt the physiologic antitumor response. As such, HIV infection promotes initial dysplasia and allows for progression on preinvasive lesions to frank malignancy.

Key messages: The purpose of this review is to highlight HIV as an under-appreciated risk factor and summarize the biologic and immunologic role of HIV in lung cancer initiation and progression. Further research regarding risk reduction and surveillance in this population and the potential increased role of immunotherapy is warranted.

Introduction: Prostate cancer (PCa) is the most frequently diagnosed cancer among men. A major clinical need is to accurately predict clinically significant PCa (csPCa). A proteomics-based 19-biomarker model (19-BM) was previously developed using capillary electrophoresis-mass spectrometry (CE-MS) and validated in close to 1,000 patients at risk for PCa. This study aimed to validate 19-BM in a multicenter prospective cohort of 101 biopsy-naive patients using current diagnostic pathways.

Methods: Urine samples from 101 patients with suspicious of PCa were analyzed using CE-MS. All patients underwent multiparametric or magnetic resonance imaging (mpMRI) using a 3-T system. The 19-BM score was estimated using support vector machine-based software (MosaCluster v1.7.0), employing the previously published cut-off criterion of -0.07. Diagnostic nomograms were investigated along with mpMRI.

Results: Independent validation of 19-BM yielded a sensitivity of 77% and a specificity of 85% (AUC:0.81). This performance surpassed those of prostate-specific antigen (PSA; AUC:0.56) and PSA density (AUC:0.69). For PI-RADS≤ 3 patients, 19-BM showed a sensitivity of 86% and a specificity of 88%. Integrating 19-BM with mpMRI resulted in significantly better accuracy (AUC:0.90) compared to individual investigations alone (AUC19BM = 0.81; p = 0.004 and AUCmpMRI: 0.79; p = 0.001). Examining the decision curve analysis, 19-BM with mpMRI surpassed other approaches for the prevailing risk interval from a 30% cut-off.

Conclusions: 19-BM exhibited favorable reproducibility for the prediction of csPCa. In patients with PI-RADS ≤3, 19-BM correctly classified 88% of the patients with insignificant PCa at the cost of 1 missed csPCa patient. Utilizing the 19-BM test could prove valuable in complementing mpMRI and reducing the need for unnecessary biopsies.

Introduction: There is evidence for the anticancer effects of l-arginine (arginine); however, the direct effects on cancer cells and mechanism of action are unclear.

Methods: Various upper gastrointestinal cancer cells (OE19, OE33, MKN1, MKN45, MKN74, and AGS) were divided into arginine-treated and -untreated groups and cultured using two-dimensional and three-dimensional culture systems. Proliferation was evaluated using the MTT assay to identify arginine-sensitive (OE33) and arginine-insensitive (OE19) strains. Furthermore, the effects of arginine were evaluated using a mitochondrial stress test, cell cycle assay, comprehensive metabolic analysis, and tracer study using (13C6) l-arginine.

Results: In OE33 (but not in OE19), the maximal respiratory capacity of mitochondria was lower in the treated group than in the control group. In OE33, S phase cells (determined using BrdU) were significantly reduced. In a comprehensive metabolic analysis of OE33, citrulline/ornithine levels were significantly lower in arginine-treated than in untreated cells. Using OE33, carbamoyl aspartic acid (CAA) levels were significantly lower in arginine-treated than in untreated cells. A tracer study suggested that arginine promotes the urea cycle.

Conclusion: Arginine affected urea cycle metabolism, thereby decreasing CAA, which is required for pyrimidine nucleotide synthesis. These findings provide insight into the mechanism underlying the anticancer effects of arginine.

Introduction: Cervical cancer is the fourth common cancer in women worldwide. In most cases, the disease is induced by persistent high-risk human papillomavirus (HPV) infection. This study aimed to assess the role of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) in HPV-induced cervical epithelial lesions using tissue microarray (TMA).

Methods: A retrospective cohort study included females with cervical low-grade intraepithelial lesion (LSIL), high-grade intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC). TMA was constructed using specimens of 270 cases and 233 control tissues. CK7 and CK19 immunohistochemistry was scored as negative or positive. Follow-up information was gathered.

Results: CK7 was negative in about 85% of LSILs and positive in 55% of HSILs (p < 0.001). CK19 showed positivity in about 50% of LSILs and 77% of the HSILs (p < 0.001). For cases with available follow-up data, about 69% of CK7-positive LSILs progressed to higher grade lesions and 64% of CK7-positive HSILs showed progression to higher grades (CIN2 to CIN3) or to SCC. Regarding CK19, nearly 66% positive LSILs progressed to HSIL whereas, 62% of positive HSILs showed progression. LSILs with positivity for both markers progressed to HSIL in 70% of cases.

Conclusion: CK7 and CK19 positivity are significantly associated with higher grade HPV-induced cervical lesions. Lesions with combined CK7 and CK19 positivity have a higher risk of progression to higher grade lesions.