Journal of the National Cancer Center最新文献

Objective: We investigated the relation between man papillomavirus (HPV) integration status and the immediate risk of cervical intraepithelial neoplasia (CIN), as well as the triage strategy based on HPV integration test.

Methods: 4086 women aged 20 to 65 years in China were enrolled in 2015 for a prospective, population-based, clinical observational study to evaluate the triage performance of HPV integration. Cervical exfoliated cells were collected for HPV testing and cytologic test. If high-risk HPV was positive, HPV integration test was performed at baseline, 2-year and 5-year follow-up.

Results: At baseline, HPV integration was positively correlated with the severity of cervical pathology, ranging from 5.0% (15/301) in normal diagnosis, 6.9% (4/58) in CIN1, 31.0% (9/29) in CIN2, 70% (14/20) in CIN3, and 100% (2/2) in cervical cancer (P < 0.001). Compared with cytology, HPV integration exhibits comparable sensitivity and negative predictive value for the diagnosis of CIN3+, higher specificity (92.8% [90.2%-95.4%] vs. 75.5% [71.2%-79.8%], P < 0.001) and higher positive predictive value (36.4% [22.1%-50.6%] vs. 15.2% [8.5%-21.8%], P < 0.001). HPV integration testing strategy yielded a significantly lower colposcopy referral rate than cytology strategy (10.7% [44/410] vs. 27.3% [112/410], P < 0.001). The HPV integration-negative group exhibited the lowest immediate risk for CIN3+ (1.6%) and accounted for the largest proportion of the total population (89.3%), when compared with the normal cytology group (risk, 1.7%; proportion, 72.7%).

Conclusion: As a key molecular basis for the development of cervical cancer, HPV integration might be a promising triage strategy for HPV-positive patients.

Bone marrow is pivotal for normal hematopoiesis and immune responses, yet it is often compromised by malignancies. The bone microenvironment (BME), composed of bone and immune cells, maintains skeletal integrity and blood production. The emergence of primary or metastatic tumors in the skeletal system results in severe complications and contributes significantly to cancer-related mortality. These tumors set off a series of interactions among cancer, bone, and immune cells, and disrupt the BME locally or distantly. However, the drivers, participants, and underlying molecules of these interactions are not fully understood. This review explores the crosstalk between bone metabolism and immune responses, synthesizing current knowledge on the intersection of cancer and osteoimmune biology. It outlines how bone marrow immune cells can either facilitate or hinder tumor progression by interacting with bone cells and pinpoints the molecules responsible for immunosuppression within bone tumors. Moreover, it discusses how primary tumors remotely alter the BME, leading to systemic immune suppression in cancer patients. This knowledge provides critical rationales for emerging immunotherapies in the treatment of bone-related tumors. Taken together, by summarizing the intricate relationship between tumor cells and the BME, this review aims to deepen the understanding of the diversity, complexity, and dynamics at play during bone tumor progression. Ultimately, it highlights the potential of targeting bone-tumor interactions to correct aberrant immune functions, thereby inhibiting tumor growth and metastasis.

Background: Small cell lung cancer (SCLC) is a highly aggressive disease characterized by early metastasis. Aneuploid CD31^- disseminated tumor cells (DTCs) and CD31⁺ disseminated tumor endothelial cells (DTECs) residing in the bone marrow are generally considered as the initiators of metastatic process. However, the clinical significance of DTCs and DTECs in SCLC remains poorly understood. The aim of this study is to investigate the clinical implications of diverse subtypes of highly heterogeneous DTCs and DTECs in SCLC patients.

Methods: Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) was applied to enrich and perform comprehensive morphologic, karyotypic, and phenotypic characterization of aneuploid DTCs and DTECs in 30 patients. Additionally, co-detection of circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) was conducted on 24 of the enrolled patients. Proof-of-concept of the whole exon sequencings (WES) on precisely selected different subtypes of CTCs or DTCs, longitudinally detected from a representative case with pathologically confirmed bone marrow metastasis, was validated to feasibly reveal genetic mutations in these cells.

Results: DTCs, DTECs and their subtypes were readily detectable in SCLC patients. Comparative analysis revealed that the number of DTCs and DTECs was significantly higher than that of their corresponding CTCs and CTECs (P < 0.001 for both). Positive detection of disseminated tumor microemboli (DTM) or disseminated tumor endothelial microemboli (DTEM) was associated with inferior survival outcomes (P = 0.046 and P = 0.048). Patients with EpCAM⁺ DTCs detectable displayed significantly lower disease control rate (DCR) (16.67% vs 73.33%, P = 0.019), reduced median progression-free survival (mPFS) and median overall survival (mOS) compared with those with EpCAM^- DTCs (P = 0.028 and P = 0.002, respectively). WES analysis indicated that post-treatment DTCs isolated from bone marrow at the time of disease progression shared more homologous somatic gene mutations with pre-treatment CTCs compared with post-treatment CTCs.

Conclusions: Our findings suggest that bone marrow sampling and characterization of DTC subtypes provided a valuable tool for predicting treatment response and the prognosis in SCLC. Moreover, DTCs inherit a greater amount of homologous somatic information from pre-treatment CTCs, indicating their potential role in disease progression and treatment resistance.

Background: Tumor-derived exosomes are involved in tumor progression and immune invasion and might function as promising noninvasive approaches for clinical management. However, there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma (ccRCC).

Methods: The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC patients were correspondingly deregulated in ccRCC tissues. We adopted a two-step strategy, including Lasso and bootstrapping, to construct a novel risk stratification system termed the TDERS (Tumor-Derived Exosome-Related Risk Score). During the testing and validation phases, we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS. In addition, enrichment analysis, immune infiltration signatures, mutation landscape and therapy sensitivity between the high and low TDERS groups were compared. Finally, the impact of TDERS on the tumor microenvironment (TME) was also analysed in our single-cell datasets.

Results: TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC. TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor (ICI) response across all ccRCC cohorts and other pathological types, since the average area under the curve (AUC) to predict 5-year overall survival (OS) was larger than 0.8 across the four cohorts. Patients in the TDERS high group were resistant to ICIs, while mercaptopurine might function as a promising agent for those patients. Patients with a high TDERS were characterized by coagulation and hypoxia, which induced hampered tumor antigen presentation and relative resistance to ICIs. In addition, single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited. Finally, PLOD2, which is highly expressed in fibro- and epi‑tissue, could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.

Conclusion: As a novel, non-invasive, and repeatable monitoring tool, the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.

Background: Completely endophytic renal tumors (CERT) pose significant challenges due to their anatomical complexity and loss of visual clues about tumor location. A facile scoring model based on three-dimensional (3D) reconstructed images will assist in better assessing tumor location and vascular variations.

Methods: In this retrospective study, 80 patients diagnosed with CERT were included. Forty cases underwent preoperative assessment using 3D reconstructed imaging (3D-Cohort), while the remaining 40 cases were assessed using two-dimensional imaging (2D-Cohort). Vascular variations were evaluated by ascertaining the presence of renal arteries > 1, prehilar branching arteries, and arteries anterior to veins. The proposed scoring system, termed RAL, encompassed three critical components: (R)adius (maximal tumor diameter in cm), (A)rtery (occurrence of arterial variations), and (L)ocation relative to the polar line. Comparison of the RAL scoring system was made with established nephrometry scoring systems.

Results: A total of 48 (60%) patients exhibited at least one vascular variation. In the 2D-Cohort, patients with vascular variations experienced significantly prolonged operation time, increased bleeding volume, and extended warm ischemia time compared with those without vascular variations. Conversely, the presence of vascular variations did not significantly affect operative parameters in the 3D-Cohort. Furthermore, the 2D-Cohort demonstrated a notable decline in both short- and long-term estimated glomerular filtration rate (eGFR) changes compared with the 3D-Cohort, a trend consistent across patients with warm ischemia time ≥ 25 min and those with vascular variations. Notably, the 2D-Cohort exhibited a larger margin of normal renal tissue compared with the 3D-Cohort. Elevated RAL scores correlated with larger tumor size, prolonged operation time, extended warm ischemia time, and substantial postoperative eGFR decrease. The RAL scoring system displayed superior predictive capabilities in assessing postoperative eGFR changes compared with conventional nephrometry scoring systems.

Conclusions: Our proposed 3D vascular variation-based nephrometry scoring system offers heightened proficiency in preoperative assessment, precise prediction of surgical complexity, and more accurate evaluation of postoperative renal function in CERT patients.

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with advanced driver-negative non-small cell lung cancer (NSCLC). However, targeted therapy remains the preferred treatment for advanced driver-positive NSCLC, including cases with epidermal growth factor receptor (EGFR) mutations. Considering the variability in EGFR-mutant NSCLC, including expression levels of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and other immunological features, the application of immunotherapy in this group is still a subject of investigation. Therefore, we have summarized and analyzed the immunological characteristics and regulatory mechanisms of different EGFR mutations in NSCLC, as well as the current clinical application of immunotherapy in the EGFR-mutant population, to provide a reference for future research.