BMC Cancer最新文献

Purpose: Renal cell carcinoma (RCC) is a common malignancy, with patients frequently diagnosed at an advanced stage due to the absence of sufficiently sensitive detection technologies, significantly compromising patient survival and quality of life. Advances in cell-free DNA (cfDNA) methylation profiling using liquid biopsies offer a promising non-invasive diagnostic option, but robust biomarkers for early detection are current not available. This study aimed to identify methylation biomarkers for RCC and establish a DNA methylation signature-based prognostic model for this disease.

Methods: High-throughput methylation sequencing was performed on peripheral blood samples obtained from 49 primarily Stage I RCC patients and 44 healthy controls. Comparative analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression methods were employed to identify RCC methylation signatures.Subsequently, methylation markers-based diagnostic and prognostic models for RCC were independently trained and validated using random forest and Cox regression methodologies, respectively.

Results: Comparative analysis revealed 864 differentially methylated CpG islands (DMCGIs), 96.3% of which were hypermethylated. Using a training set from The Cancer Genome Atlas (TCGA) dataset of 443 early-stage RCC tumors and matched normal tissues, we applied LASSO regression and identified 23 methylation signatures. We then constructed a random forest-based diagnostic model for early-stage RCC and validated the model using two independent datasets: a TCGA set of 460 RCC tumors and controls, and a blood sample set from our study of 15 RCC cases and 29 healthy controls. For Stage I RCC tissue, the model showed excellent discrimination (AUC-ROC: 0.999, sensitivity: 98.5%, specificity: 100%). Blood sample validation also yielded commendable results (AUC-ROC: 0.852, sensitivity: 73.9%, specificity: 89.7%). Further analysis using Cox regression identified 7 of the 23 DMCGIs as prognostic markers for RCC, allowing the development of a prognostic model with strong predictive power for 1-, 3-, and 5-year survival (AUC-ROC > 0.7).

Conclusions: Our findings highlight the critical role of hypermethylation in RCC etiology and progression, and present these identified biomarkers as promising candidates for diagnostic and prognostic applications.

Purpose: To evaluate the efficacy and safety of induction chemotherapy combined with programmed death protein 1 (PD-1) inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab, and subsequent maintenance with sintilimab (IC-ICCRT-IO) for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a retrospective study.

Methods: Data from patients with histologically confirmed, locally advanced, inoperable ESCC who received IC-ICCRT-IO were retrospectively analyzed. Treatment effects were evaluated after 2 cycles of induction therapy and after CCRT by contrast-enhanced CT scans and esophagograms, followed by subsequent evaluations every 3 months post-treatment. The primary endpoints included progression-free survival (PFS) and PFS rates at 6, 12, and 18 months. Secondary endpoints involved overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The influence of the expression level of programmed death ligand-1 (PD-L1) as well as neutrophil-to-lymphocyte ratio (NLR) on efficacy of the IC-ICCRT-IO was analyzed.

Results: In total, 29 eligible patients were enrolled and analyzed. The median follow-up time was 20.5 months. The median PFS was not reached; the 6-, 12-, and 18-month PFS rates were 100.0%, 93.1%, and 82.8%, respectively. The median OS was not reached, and the 6-, 12-, and 18-month OS rates were all 100.0%. The ORR and DCR were 89.7% and 100.0%. Adverse events (AEs) were manageable, with grade 3 or higher AEs observed in 48.2% of patients, primarily nonimmune-related and clinically manageable. Hematologic toxicity was predominant. Two patients developed grade 3 immune-related rash, and two patients developed grade 3 radiation pneumonitis, all of whom were managed with appropriate symptomatic treatment. No significant differences in survival outcomes were observed with respect to PD-L1 and NLR.

Conclusion: Our results indicated that the IC-ICCRT-IO regimen for unresectable locally advanced ESCC provided a survival benefit with manageable safety profile. More prospective clinical studies should be warranted.

Trial registration: 2024-04-22, No. QYFY WZLL 28,684, retrospectively registered.

The genesis of hepatocellular carcinoma (HCC) is closely related to male factors and hyper-activated Ras signals. A transcriptomic database was established via RNA-Seq of HCC (T) and the adjacent precancerous liver tissue (P) of Hras12V transgenic mice (Ras-Tg, HCC model) and the normal liver tissue of wild-type mice (W) of both sexes. Comparative analysis within W, P, and T and correlation expression pattern analysis revealed common/unique cluster-enriched items towards HCC between the sexes. Specifically, the numbers of differentially expressed genes (DEGs) were much higher in females than in males, and tumor suppressor genes, such as p21^Waf1/Cip1 and C6, were significantly higher in the female P. This finding denotes the higher sensitivity of female hepatocytes to the Ras oncogene and, therefore, the difficulty in developing HCC. Moreover, convergence in HCC between the sexes suggests the underlying mechanisms for the ineffectiveness of sex hormone therapies. Additionally, expression pattern analysis revealed that the DEGs and their relevant pathways were either positively or negatively associated with the HCC/Ras oncogene. Among them, the vital role of glutathione metabolism in HCC was established. This work provides a basis for future research on elucidating the underlying mechanisms, selecting the diagnostic biomarker, and planning the clinical therapy in HCC.

Background: Caffeic acid phenethyl ester (CAPE) is the main bioactive component of poplar type propolis. We previously reported that treatment with caffeic acid phenethyl ester (CAPE) suppressed the cell proliferation, tumor growth, as well as migration and invasion of prostate cancer (PCa) cells via inhibition of signaling pathways of AKT, c-Myc, Wnt and EGFR. We also demonstrated that combined treatment of CAPE and docetaxel altered the genes involved in glycolysis and tricarboxylic acid (TCA) cycle. We therefore suspect that CAPE treatment may interfere glucose metabolism in PCa cells.

Methods: Seahorse Bioenergetics platform was applied to analyzed the extra cellular acidification rate (ECAR) and oxygen consumption rate (OCR) of PCa cells under CAPE treatment. UPLC-MSMS with Multiple Reaction Monitoring (MRM), PCR, and western blot were used to analyze the effects of CAPE on metabolites, genes, and proteins involved in glycolysis, TCA cycle and pentose phosphate pathway in PCa cells. Flow cytometry and ELISA were used to determine the level of reactive oxygen species in PCa cells being treated with CAPE.

Results: Seahorse Bioenergetics analysis revealed that ECAR, glycolysis, OCR, and ATP production were elevated in C4-2B cells under CAPE treatment. Protein levels of glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), glutaminase (GLS), phospho-AMPK Thr172 as well as abundance of pyruvate, lactate, ribulose-5-phosphate, and sedoheptulose-7-phosphate were increased in CAPE-treated C4-2B cells. ROS level decreased 48 h after treatment with CAPE. Co-treatment of AMPK inhibitor with CAPE exhibited additive growth inhibition on PCa cells.

Conclusions: Our study indicated that PCa cells attempted to overcome the CAPE-induced stress by upregulation of glycolysis and G6PD but failed to impede the growth inhibition caused by CAPE. Concurrent treatment of CAPE and inhibitors targeting glycolysis may be effective therapy for advanced PCa.

Background: There is still no consensus regarding the correlation between TLS and the prognosis of lung cancer patients. This meta-analysis aimed to investigate the association between TLS and prognosis in patients with lung cancer. In addition, the prognostic value of TLS for the efficacy of immunotherapy was also studied.

Methods: We systematically searched the PubMed, Embase, Cochrane Library, and Web of Science databases from database inception to November 1, 2023. The hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS) and disease-specific survival (DSS) were extracted and merged with STATA 14.0. The study protocol was registered with PROSPERO (CRD42024502483).

Results: A total of 17 studies comprising 4291 patients were included in this meta-analysis. The pooled results revealed that high TLS/TLS + patients had better OS (HR = 0.66, 95% CI: 0.50-0.88), DFS (HR = 0.46, 95% CI: 0.33-0.64), DSS (HR = 0.48, 95% CI: 0.39-0.60) and RFS (HR = 0.43, 95% CI: 0.33-0.57). High TLS/TLS + patients tended to have longer PFS than low TLS/TLS + patients (HR = 0.68, 95% CI: 0.35-1.35). Interestingly, in the Asia subgroup, the association between TLS and survival was especially significant, whereas there was no significant difference in Europe. In addition, in patients who received neoadjuvant chemoimmunotherapy, high TLS/TLS + was associated with prolonged DFS (HR = 0.21, 95%CI: 0.05-0.93).

Conclusion: High TLS/TLS + was associated with improved survival and an improved response to neoadjuvant chemoimmunotherapy in lung cancer patients, suggesting that TLS may be a prognostic biomarker and may also be a promising predictive marker for the response to neoadjuvant chemoimmunotherapy. However, additional original studies are needed to further confirm these findings.

Background: Despite approvals of new first-line immunotherapies for advanced/metastatic gastric cancer/gastroesophageal junction cancer (aGC/GEJC), patients' median survival is around 14 months and their health-related quality of life (HRQoL) is affected by disease-related symptoms and treatment-related side effects. Using a targeted literature review (TLR) and patient interviews, this study identified disease- and treatment-related concepts that are important to patients with aGC/GEJC and their HRQoL.

Methods: A TLR was conducted to identify primary qualitative studies from 2018 to 2021 on patients' experiences with aGC/GEJC. The results, supplemented with the results of two previously identified studies from 2017, were used to develop a preliminary conceptual disease model of aGC/GEJC and an interview guide. Next, one-to-one concept elicitation interviews were conducted where patients with aGC/GEJC were asked about symptoms, impacts on daily life, experience of care, treatment expectations, and clinical trials. The conceptual model was refined using these patient experience data.

Results: Four studies selected from the TLR and the two previously summarized studies identified 47 symptoms (15 disease-related, 20 treatment-related, 12 disease- and treatment-related) and 35 impacts. Interviews with 20 patients identified 36 symptoms. The 12 most important symptoms (mentioned by ≥ 50% of patients; average disturbance ratings: ≥5, scale: 0 'not disturbing' to 10 'extremely disturbing') were: nausea, fatigue, temperature sensitivity, indigestion, weakness, diarrhea, vomiting, early satiety, swallowing difficulties, taste alterations, abdominal pain, general pain. Symptoms were mostly attributed to systemic treatments (chemotherapy, immunotherapy and targeted therapy), followed by surgery. Thirty-one impacts emerged from the interviews, the most common being emotional disturbances, impacts on daily activities and families, and requiring assistance from caregivers. Patients were mostly positive about their experience of care, willing to enroll in clinical trials, and keen to receive innovative treatments with few side effects. The final conceptual disease model details the symptoms and impacts of aGC/GEJC.

Conclusions: The conceptual model provides valuable data on signs/symptoms and impacts of aGC/GEJC affecting patients' lives. This can guide the clinical outcome assessment strategy for the development of innovative treatments more comprehensively than input from physicians alone, to ensure treatments improve both patients' survival and HRQoL. Interviews also help understand patients' perspectives on clinical trials.

Background: Primary pulmonary lymphoepithelial carcinoma (pLEC) is a subtype of non-small cell lung cancer (NSCLC) characterized by Epstein-Barr virus (EBV) infection. However, the molecular pathogenesis of pLEC remains poorly understood.

Methods: In this study, we explored pLEC using whole-exome sequencing (WES) and RNA-whole-transcriptome sequencing (RNA-seq) technologies. Datasets of normal lung tissue, other types of NSCLC, and EBV-positive nasopharyngeal carcinoma (EBV+-NPC) were obtained from public databases. Furthermore, we described the gene signatures, viral integration, cell quantification, cell death and immune infiltration of pLEC.

Results: Compared with other types of NSCLC and EBV+-NPC, pLEC patients exhibited a lower somatic mutation burden and extensive copy number deletions, including 1p36.23, 3p21.1, 7q11.23, and 11q23.3. Integration of EBV associated dysregulation of gene expression, with CNV-altered regions coinciding with EBV integration sites. Specifically, ZBTB16 and ERRFI1 were downregulated by CNV loss, and the FOXD family genes were overexpressed with CNV gain. Decreased expression of the FOXD family might be associated with a favorable prognosis in pLEC patients, and these patients exhibited enhanced cytotoxicity.

Conclusion: Compared with other types of NSCLC and NPC, pLEC has distinct molecular characteristics. EBV integration, the aberrant expression of genes, as well as the loss of CNVs, may play a crucial role in the pathogenesis of pLEC. However, further research is needed to assess the potential role of the FOXD gene family as a biomarker.

Background: Co-existent pulmonary tuberculosis and lung cancer (PTB-LC) represent a unique disease entity often characterized by missed or delayed diagnosis. This study aimed to investigate the clinical and radiological features of patients diagnosed with PTB-LC.

Methods: Patients diagnosed with active PTB-LC (APTB-LC), inactive PTB-LC (IAPTB), and LC alone without PTB between 2010 and 2022 at our institute were retrospectively collected and 1:1:1 matched based on gender, age, and time of admission. Symptoms and clinicopathological features were compared among the three groups of patients. Logistic regression was employed for risk factor analysis.

Results: Compared to LC or IAPTB-LC, patients with APTB-LC exhibited higher proportions of weight loss (p < 0.001) and fever (p < 0.001) at the time of diagnosis. Additionally, radiological features such as nodules (p = 0.007), tree-in-bud (p < 0.001), cavitation (p < 0.001), and calcification (p < 0.001) were significantly more prevalent in APTB-LC patients compared to the other groups. Patients with APTB-LC were more susceptible to lymph node involvement (p < 0.001) and distant metastasis (p = 0.006) compared to those with IAPTB-LC or LC alone. Additionally, in comparison to LC alone, patients with IAPTB-LC exhibited more complex symptoms, imaging features, and lymph node metastases. Logistic regression results indicated that factors such as BMI, fever, patchy shadow, cavitation, neck or supraclavicular lymph node metastasis, and liver injury favor the diagnosis of APTB-LC over LC alone. The pre-diagnostic model exhibited robust performance, achieving area under the curve (AUC) values of 0.864 in the training set and 0.830 in the test set.

Conclusion: Our results indicate that PTB-LC is a distinct disease characterized by complex clinicopathological features and a more aggressive nature. Based on our findings, we recommend conducting TB-related tests for LC patients who exhibit relevant risk factors or are identified as high-risk cases according to the pre-diagnostic model.

Background: Smoking is a pivotal modifiable risk factor for lung cancer (LC). Previous studies have indicated that a smoking cessation program might be incorporated into the LC screening program. However, the effects of smoking cessation and its duration with the age at onset (AAO) of LC, all-cause mortality, and LC-specific mortality remain unclear. We aimed to comprehensively investigate the association of smoking cessation-related behaviors on the AAO of LC, LC-specific and all-cause mortality.

Methods: A total of 2671 smokers with LC as the primary site from the UK Biobank were included in this study, with a 7:3 ratio assigned randomly to a discovery set (n = 1872) and a validation set (n = 799). Generalized linear regression models were used for AAO of LC outcomes and Cox models for mortality outcomes.

Results: Participants over 60 years old could still benefit from smoking cessation to prolong AAOs (β = 1.613 for men, P = 0.003; β = 1.533 for women, P = 0.018). A cessation duration of > 15 years was associated with a later AAO in men (P < 0.001). Moreover, smoking cessation before 60 years old, especially among those under 40 years, was significantly associated with a lower risk of all-cause mortality (men: hazard ratio (HR): 0.65 [95% confidence interval 0.51-0.83]; women: 0.62 [0.47-0.83]) and LC-specific mortality (men: 0.67 [0.51-0.87]; women: 0.68 [0.50-0.92]). Compared with continuous smokers, former smokers who quit smoking for more than 15 years had a lower risk of all-cause mortality (men: 0.70 [0.59-0.84]; women: 0.68 [0.56-0.84]) and LC-specific mortality (men: 0.71 [0.59-0.87]; women: 0.69 [0.56-0.86]).

Conclusions: Smoking cessation after 60 years old may still be helpful for a later AAO of LC. Former smokers who quit smoking for more than 15 years have a reduced risk of developing LC and mortality.

Background: In recent years, there has been a growing number of case reports documenting delayed seroma in patients with a history of breast surgery and reconstruction. The occurrence of these seromas has been associated with prior SARS-CoV-2 infection or SARS-CoV-2 vaccination. So far, there are few systematic analyses on postoperative complications in breast surgery since the emergence of the SARS-CoV-2 pandemic.

Study design: We conducted a multicenter retrospective analysis to assess the incidence of postoperative complications in two major university breast care centers in Germany during the SARS-CoV-2 pandemic (August 1st, 2021, to January 31st, 2022) compared to a reference period (August 1st, 2019, to January 31st, 2020) before the pandemic.

Results: A total of 987 patients were included in this retrospective analysis, with 492 patients during the SARS-CoV-2 pandemic and 495 patients in the reference period. There was no significant difference in the incidence rate of seroma after breast surgery. However, complications such as erythema, wound infection, and wound healing disorders were notably more frequent during the SARS-CoV-2 pandemic. Multivariate analysis revealed that increasing patient age, smoking, breast implant reconstruction, axillary lymph node dissection, and previous radiation were significant clinical risk factors for seroma development.

Conclusion: While our findings did not indicate an elevated incidence of seroma during the SARS-CoV-2 pandemic, we observed increased rates of erythema, wound healing disorders, and wound infection. Additional real-world evidence is needed for understanding both early and late complications following breast surgery in the context of the ongoing SARS-CoV-2 endemic.