American journal of cancer research最新文献

Gemcitabine (Gem) is approved for use in pancreatic cancer chemotherapy. However, Gem undergoes rapid metabolism in the blood, producing an inactive metabolite. Due to this rapid metabolism, the effective dose of Gem is high, thereby predisposing patients to severe adverse effects. This study aimed to improve Gem's metabolic and therapeutic stability by modifying the amine group (4-NH₂) with hydroxylamine to form 4-N-hydroxylGem hydrochloride (GemAGY). Micro-elemental analysis and Nuclear Magnetic Resonance (NMR) were used to characterize GemAGY, and its anticancer activity was investigated against MiaPaCa-2, BxPC-3, and PANC-1 pancreatic cancer cell lines. The GemAGY metabolic stability was evaluated in human liver microsomal solution. In the 2D cytotoxicity assay, the IC₅₀ values of GemAGY-treated MiaPaCa-2, PANC-1, and BxPC-3 cells were significantly lower when compared to GemHCl-treated cultures. More so, in 3D spheroid assay results, GemAGY IC₅₀ values were found to be 9.5 ± 1.1 µM and 12.6 ± 1.0 µM when compared to GemHCl IC₅₀ values of 24.1 ± 1.6 µM and 30.2 ± 1.8 µM in MiaPaCa-2 and PANC-1 cells, respectively. GemAGY was stable, with 60% remaining intact after 2 hours of digestion in microsomal enzymes, compared to GemHCl, which had less than 45% remaining intact after 30 minutes. GemAGY-treated MiaPaCa-2 and PANC-1 cells at 3.12 and 6.25 μM concentrations demonstrated a significantly reduced cell migration towards the wound area compared to the GemHCl-treated cultures at the same concentrations. Further, GemAGY-treated MiaPaCa-2 cells significantly increased the expression of p53 and BAX compared to GemHCl-treated cells. GemAGY demonstrated significant anticancer activity and improved metabolic stability compared to GemHCl and is most likely to have potential anticancer activity against pancreatic cancer.

Pleomorphic adenoma (PA), the most common benign salivary gland tumor, is rarely found in the nasal cavity and paranasal sinuses, particularly in pediatric patients. This report presents a case of PA in the nasal septum of a 14-year-old girl who presented with unilateral epistaxis and progressive nasal obstruction. The tumor was excised from the left anterior nasal septum via endoscopic sinus surgery, and PA was confirmed through histopathological examination. This case emphasizes the importance of including PA in the differential diagnosis of pediatric sinonasal masses, despite its rarity, and underscores the necessity of meticulous surgical planning to prevent recurrence. Further studies are needed to better understand the long-term outcomes and optimal management strategies for this rare condition in children.

Nasopharyngeal carcinoma (NPC) initially responds well to platinum-based therapy but often develops resistance. Combining therapies may offer a viable approach to address this resistance. Heat shock protein 90 (Hsp90) has shown promising anticancer activity in various cancer types. This study aimed to investigate the efficacy of an Hsp90 inhibitor, luminespib (AUY922), and evaluate the synergistic effect of combining AUY922 with cisplatin on two cisplatin-resistant human NPC cell lines. The response of cisplatin-resistant NPC cells to AUY922 and/or cisplatin was assessed through proliferation assay, cell cycle analysis, Annexin V apoptosis detection, Western blot analysis, in vivo investigation, and histological analysis. Our results indicated that AUY922/cisplatin combination significantly inhibited the proliferation of both non-resistant and resistant NPC cells. Moreover, Annexin V analysis indicated apoptosis when AUY922 was administered alone or in combination with cisplatin. Consistently, Western blot analysis revealed increased cleavage of PARP. Most importantly, the combination treatment demonstrated enhanced tumor growth inhibition in nude mice xenograft models, without notable adverse effects. These findings highlight the antiproliferative effects and anticancer activity of the AUY922/cisplatin combination in cisplatin-resistant NPC cells. The combination treatment of AUY922 and cisplatin holds promise as a strategy to overcome drug resistance in NPC patients.

Growth differentiation factor 15 (GDF15) is upregulated in most cases of epithelial ovarian cancer (EOC); however, its functions in EOC are not fully understood. In this study, we knocked down GDF15 in EOC cells before performing high-throughput sequencing to identify genes regulated by GDF15. GDF15 was overexpressed to determine its effect on the viability, migration, and response of EOC cells to gemcitabine, carboplatin, and paclitaxel. Reprogramming of glucose and cholesterol metabolism in EOC cells was evaluated based on oxygen consumption, lactic acid production, complex I activity, and free and esterified cholesterol levels. The activities of ATP-binding cassette (ABC)B1 and ABCC1 were assessed based on the expulsion efficiency of rhodamine 12. GDF15 overexpression promoted cell viability, migration, and resistance to gemcitabine. In addition, GDF15 induced glycolysis and increased cholesterol levels in EOC cells. Cholesterol metabolism regulated by GDF15 contributed to the resistance of EOC cells to gemcitabine by elevating ABCB1 and ABCC1 levels in lipid rafts. DHCR24 plays an important role in cholesterol synthesis. DHCR24 was identified as a downstream effector of GDF15, because knockdown of DHCR24, but not treatment with statins, suppressed the cancer-promoting effect of GDF15. Overall, GDF15 promoted the resistance of EOC cells to gemcitabine via DHCR24-mediated cholesterol metabolism to elevate ABCB1 and ABCC1 levels in lipid rafts. Therefore, GDF15 and DHCR24 are potential therapeutic targets for suppressing the growth of EOC cells and improving their sensitivity to gemcitabine.

Clinical data of 1,780 patients with epithelial ovarian carcinoma (EOC) in the Surveillance, Epidemiology and End Results (SEER) database were retrospectively analyzed. A random survival forest model and a nomogram model were built based on the prognostic factors. The clinical data of 140 patients with EOC treated in Liuzhou Worker's Hospital were collected for the validation of the prognostic model. Age (≥75 years), histology grade (poor differentiation or undifferentiation), histologic types (clear cell carcinoma or carcinosarcoma), T stage (T2 or T3), M stage (M1), surgical conditions, and chemotherapy situation (without chemotherapy) were identified as independent risk factors. Based on these factors, a random forest survival prediction model was established. In the training set, the area under the curve (AUC) for the random forest survival prediction model in predicting 1-, 3- and 5-year survival were 0.848, 0.859 and 0.890, respectively. In the test set, the AUCs for 1-, 3- and 5-year survival were 0.992, 0.795 and 0.883, respectively. A nomogram prediction model was also established. In the training set, the AUCs for the nomogram prediction model for 1-, 3- and 5-year survival were 0.789, 0.803 and 0.838, respectively. In the test set, the AUCs for 1-, 3- and 5-year survival were 0.926, 0.748 and 0.836, respectively. The results indicated that the random forest survival model established in this study holds significant clinical value. Physicians can develop personalized follow-up strategies or treatment regimens for patients based on the predicted survival risk, potentially improving long-term outcomes.

Objectives: The advent of immunotherapy has transformed the therapeutic landscape for advanced non-small cell lung cancer (NSCLC); nonetheless, the emergence of resistance to immunotherapy poses a considerable obstacle. Our research sought to identify factors contributing to immunotherapy resistance and to assess the effectiveness of subsequent treatments in patients with advanced NSCLC who have been exposed to immune checkpoint inhibitors (ICIs).

Methods: This retrospective study analyzed data from 232 individuals with advanced NSCLC who were treated with ICIs during January 2020 to December 2023. Based on their response to ICIs, these patients were classified into two groups: immunoresistance group (IM group) and non-immunoresistance group (NIM group). Data collected included demographics, clinical parameters, cytokine profiles, tumor mutational burden (TMB), PD-L1 expression, overall survival (OS), progression-free survival (PFS), and adverse events. The association between risk factors and immunoresistance were assessed, and second-line treatment outcomes were evaluated.

Results: Key risk factors for immunoresistance included lower TMB, higher levels of interleukin-10 (IL-10), and PD-L1 expression ≥ 50%. TMB was inversely correlated with immunoresistance (rho = -0.838, P < 0.001). In multivariate analysis, IL-10 remained a significant risk factor (OR = 33.654, P = 0.021), whereas TMB was protective (OR = 0.786, P < 0.001). Second-line targeted therapy significantly improved OS (8.72 ± 2.02 months) and PFS (5.37 ± 2.15 months) compared to chemotherapy (OS: 7.93 ± 2.13 months; PFS: 4.86 ± 1.68 months) (P < 0.05). The targeted therapy group experienced distinct side effects, notably increased hypertension and hand-foot syndrome, while chemotherapy group had higher rates of fatigue (P < 0.05).

Conclusion: Immunoresistance in advanced NSCLC is influenced by IL-10, TMB, and PD-L1 expression. Targeted therapies offer superior outcomes than chemotherapy, though side effect management remains crucial.

This study evaluated the economic value of administering trilaciclib to prevent myelosuppression in extensive-stage small cell lung cancer (ES-SCLC) patients receiving etoposide, carboplatin, and atezolizumab (E/P/A) from both the Chinese and the United States (US) perspectives. A decision tree model was constructed to estimate and compare costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs). One-way and probabilistic sensitivity analyses were conducted to assess the robustness and uncertainty of the economic analysis. The base case analysis indicated that from the perspective of US payers, trilaciclib was cost-saving at the WTP threshold of $241,230.00, with an incremental cost of $-12,626.08, an INMB of $16,788.02, and an INHB of 0.07 QALYs. Conversely, from the perspective of Chinese payers, the use of trilaciclib was not economical at the WTP threshold of $35,817.44, with an ICER of $691,541.63/QALY, an INMB of -$8,765.52, and an INHB of -0.24 QALYs. Sensitivity analysis confirmed the stability of these results. Probabilistic sensitivity analysis indicated that, from the Chinese payers' perspective, trilaciclib treatment was not economical, with a probability of 100%. In contrast, from the US payers' perspective, it was economical, with a probability of 90.05%. Given the limited clinical data available for trilaciclib in the Chinese population, the cost-effectiveness of trilaciclib may improve with the inclusion of new data or changes in health insurance policies.

Early-phase clinical trials are the first step in cancer drug development. However, they are becoming difficult to conduct - increased complexity of treatments, multiple stakeholders, and most importantly, the changes imposed by the COVID19 pandemic. We report our experience during and since the pandemic, focusing on early-phase clinical trials for solid tumors. From 2020-2023, our accruals improved by 161% (from 33 to 86). We consented 260 patients; of those, 176 (68%) fulfilled all eligibility criteria and started therapy - trials included immunotherapy (74, 42%), targeted therapy (43, 24%), novel molecules (30, 17%), cellular therapy/oncolytic viruses (19, 11%), and pharmacokinetic assessment trials of standard therapies (10, 6%). We increased staffing from 4 to 12 over this period, instituted hybrid work policies, created a dedicated triage nurse to reduce screen failures, and developed disease-specific sub-teams for better efficiencies and lower error rates. These efforts allowed us to improve the quantity and quality of our accruals.

Locally advanced cervical cancer (LACC) is primarily treated with weekly cisplatin-based concurrent chemoradiotherapy (CCRT); however, predicting acute tumor response remains challenging. This study aimed to identify plasma exosomal microRNAs (miRNAs) and messenger RNAs (mRNAs) that could predict rapid tumor regression in patients with LACC undergoing CCRT. Overall, 41 patients with stage IB-IVB cervical cancer were included. All patients received CCRT, and plasma exosomal RNA samples were collected before treatment and 2 weeks after radiation therapy (RT). Acute tumor response (AR) was defined as the regression rate of tumor volume (TV) (cm³) measured at the fourth week of treatment compared with the initial TV (iTV). The log₂ fold change of miRNA and mRNA was calculated by comparing RNA read counts before and after the second week of CCRT for each patient. A correlation matrix identified RNAs associated with AR. The selected RNAs were validated through linear regression and Wilcoxon rank-sum tests. Leave-one-out cross-validation was performed in subgroups based on iTV. miR-150-3p, NMT2, and PRDM1 were identified as key predictors of AR, demonstrating significant associations with immune-mediated tumor responses. A decrease in post-RT levels of these RNAs was significantly associated with poor AR, particularly in patients with large iTVs. The predictive model combining miR-150-3p, NMT2, and PRDM1 showed strong correlation with AR (R² = 0.831, P < 0.0001) in the test dataset and was validated in an independent cohort (R² = 0.496, P = 0.006). Cross-validation indicated the robustness of these biomarkers in predicting AR across varying TVs. These findings highlight the potential of plasma exosomal miR-150-3p, NMT2, and PRDM1 are promising biomarkers for predicting AR in patients with LACC undergoing CCRT. These findings could facilitate personalized RT strategies and improve patient outcomes. Further multicenter studies are warranted to validate these biomarkers in larger, diverse cohorts.

Radical cystectomy and bladder preservation therapy are effective for muscle-invasive bladder cancer (MIBC); however, many patients over 70 are medically unfit for these options. For such patients, radiotherapy serves as a viable alternative. This study compares survival outcomes of radiotherapy versus supportive care in MIBC patients ineligible for cystectomy or bladder preservation with concurrent chemoradiotherapy. Using the Taiwan Cancer Registry and National Health Insurance Research Database (2011-2020), we identified patients with cT2-T4N0-1M0 urinary bladder urothelial carcinoma. Patients were excluded if they had undergone cystectomy or chemotherapy. Patients received either radiotherapy or supportive care, with endpoints of overall survival (OS) and cancer-specific survival (CSS) analyzed by Kaplan-Meier and multivariate Cox regression. Among 485 MIBC patients, 301 (62%) received radiotherapy, and 184 (38%) supportive care. After 13.93 months of median follow-up, radiotherapy significantly improved OS and CSS (P<0.001). Mortality rates were 26.9% for radiotherapy and 76.1% for supportive care at one year, and 59.5% vs. 94.0% at three years. OS and CSS benefits were confirmed for stages II-IV (adjusted hazard ratios: 5.47, 3.23, and 12.44, respectively), with T3, T4, N1, and chronic obstructive pulmonary disease (COPD) predicting worse OS. In conclusion, radiotherapy offers superior survival benefits compared to supportive care in MIBC patients who are unfit for cystectomy or chemoradiotherapy. These findings provide valuable insights for clinicians in making treatment decisions, particularly for elderly or medically unfit patients with early or locally advanced-stage MIBC.