Annals of Surgical Oncology最新文献

Background: Next-generation sequencing provides valuable information about mutations within colorectal liver metastases (CRLMs) that impact survival. Existing data focus on prognostic implications of single gene mutations. This study assessed the impact of co-alterations on KRAS/NRAS and TP53 after CRLM resection.

Methods: A retrospective analysis was performed for patients with CRLM who underwent surgical management and had next-generation sequencing (NGS) performed to assess associations with clinical outcomes. Groups were stratified by the presence or absence of RAS-TP53 co-alterations (RTC).

Results: The study cohort consisted of 155 patients with NGS data, with 42 patients (27%) harboring RTC. The baseline characteristics were similar between the groups. The RTC patients had more right-side primary tumors (45% vs. 26%; P = 0.028), presented more frequently with synchronous CRLM (91% vs. 72%; P = 0.017), and were more often deemed initially unresectable (26% vs. 12%; P = 0.038). Medical and surgical management were comparable between the groups, with the majority of the patients receiving systemic therapy (97% overall) and undergoing wedge partial hepatectomies (59% overall). The RTC patients had worse recurrence-free and overall survival, and experienced extrahepatic recurrences sooner (median, 9 vs 14 months; P = 0.014). In the multivariate analyses, RTC (hazard ratio [HR, 2.076; 95% confidence interval [CI], 1.054-4.088; P = 0.035) and post-recurrence locoregional treatments (HR, 0.446; 95% CI 0.222-0.896; P = 0.023) were independently associated with survival.

Conclusions: The RTC patients presented more often with synchronous CRLM, and RTC also was associated with worse oncologic outcomes, suggestive of more aggressive tumor biology. Integration of genome-sequencing data beyond single gene mutations may provide important prognostic information for patients with CRLM to guide management decisions.

Background: High infiltration of CD103⁺ tumor infiltrating lymphocytes (TILs) is associated with improved patient survival in colorectal cancer. However, the spatial distribution and clinical significance of CD103⁺ TILs in colorectal liver metastasis (CRLM) remain unclear.

Methods: This study enrolled 84 patients with CRLM who underwent simultaneous surgical resection of both primary colorectal tumors (PT) and liver metastases (LM). The abundance of CD103⁺ TILs in different intratumoral compartments were evaluated using immunohistochemistry. Additionally, multiplex immunofluorescence analysis was performed to assess CD103⁺ TIL subsets. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic analysis were performed to investigate the functional differences of CD103⁺CD8⁺ T cells between PT and LM using a published dataset.

Results: The presence of CD103⁺ TILs in PT did not correlate with the prognosis of patients with CRLM. Conversely, an increased infiltration of CD103⁺ TILs in LM was associated with improved survival outcomes. Notably, CD103⁺ TILs in the stromal compartments of the tumor center of LM emerged as an independent prognostic factor for CRLM patients. The majority of CD103⁺ TILs in CRLM tissues were identified as CD8⁺CD103⁺ cells, followed by CD4⁺CD103⁺ cells. scRNA-seq analysis showed that the CD103⁺CD8⁺ T cells in the PT exhibit characteristics typical of CD8⁺ cytotoxic T cells, while those in the LM display features of tissue-resident memory T cells.

Conclusions: These findings reveal the heterogeneity in the spatial distribution of CD103⁺ TILs within both PT and LM tissues. Notably, the infiltration of CD103⁺ TILs in LM serves as a prognostic biomarker for CRLM patients.

Background: MUC3A is upregulated in the serum of patients with extrahepatic cholangiocarcinoma (EHCC). Nevertheless, the specific role of MUC3A in EHCC is elusive. Therefore, this study aimed to analyze the role and mechanism of MUC3A in cell proliferation and epithelial-mesenchymal transition (EMT) in EHCC.

Materials and methods: UCHL1 and MUC3A expression levels were measured in EHCC cells and tissues. After gain- and loss-of-function assays in EHCC cells, cell proliferation was assessed with CCK-8, EdU, and colony formation assays, while cell invasion, migration, and apoptosis were examined with transwell, scratch, and flow cytometry assays, respectively. Western blot was implemented to detect the levels of migration- and EMT-related markers, as well as proteins related to the downstream pathways of EGFR. A xenograft tumor model was established for in vitro validation. The relationship between UCHL1 and MUC3A was analyzed with Co-immunoprecipitation (Co-IP), Western blotting, ubiquitination analysis, and immunofluorescence.

Results: UCHL1 and MUC3A were highly expressed in EHCC. MUC3A knockdown inhibited the viability, EMT, migration, and invasion of ECHH cells while accelerating their apoptosis. MUC3A knockdown repressed tumorigenesis of EHCC in mice. Mechanistically, UCHL1 acted as a deubiquitinase to maintain MUC3A stability and activated the downstream pathways of EGFR, namely Ras/Raf/MEK/ERK and PI3K/AKT. UCHL1 overexpression nullified the repressive impacts of MUC3A knockdown on EHCC cell viability, invasion, and EMT, while EGFR activation abrogated the suppressive impacts of UCHL1 depletion on EHCC cell viability, invasion, and EMT.

Conclusions: UCHL1 activates downstream pathways of EGFR by stabilizing MUC3A, thereby fostering EHCC progression.

Background: Brain metastasis (BM) is a leading cause of mortality in non-small-cell lung cancer (NSCLC). The abnormal expression and regulation of circular RNA (circRNA) is involved in the pathogenesis of various tumors. However, the involvement of circRNAs in BM of NSCLC remains to be elucidated.

Methods: In this study, we established an in vitro blood-brain barrier (BBB) model using BM NSCLC cell lines H2030-BrM3 and PC9-BrM3. We investigated the impact of circ_phosphatidic acid phosphatase type 2 domain containing 1A (PPAPDC1A) on BM of NSCLC in vitro. The interaction between circ_PPAPDC1A and sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) axes was validated through RNA pull-down and dual-luciferase reporter assays.

Results: Our findings revealed that circ_PPAPDC1A was significantly upregulated in NSCLC with BM (P=0.018). Moreover, exosomes of circ_PPAPDC1A exhibited high diagnostic accuracy for BM, with an area under the curve of 0.83 (P = 0.003), and were closely associated with shorter progression-free survival (6.15 vs. 9.25 months; P = 0.019) and BM-free survival (5.41 vs. 7.75 months; P = 0.18). Functionally, circ_PPAPDC1A overexpression was associated with enhanced in vitro features related to BM, whereas silencing circ_PPAPDC1A showed opposite trends (P < 0.05). Mechanistically, circ_PPAPDC1A functions as efficient microRNA (miR-30a-3p) sponges, thereby activating its downstream functional target, SPOCK1 (P < 0.05).

Conclusions: For the first time, we identified that circ_PPAPDC1A is significantly upregulated and associated with oncogenic effects in NSCLC with BM, potentially via sponging the miR-30a-3p-SPOCK1 pathway. circ_PPAPDC1A shows potential as a diagnostic biomarker and therapeutic target candidate for patients with NSCLC with BM, pending further validation.