Clinical & Translational Oncology最新文献

Background: Breast cancer patients, particularly those with stage IV disease, on immunosuppressive therapy, or with comorbidities, may have an impaired immune response to vaccination. This raises concerns about their vulnerability to severe COVID-19. This study evaluated the effectiveness of COVID-19 vaccination in preventing severe disease in breast cancer patients.

Methods: We conducted a retrospective cohort study of 2,470 patients with invasive breast cancer from our institutional database (January 2020 to January 2024). COVID-19 cases were confirmed by RT-PCR or lateral-flow test. Patients were considered vaccinated if they had received at least one dose within the previous 12 months. Severe COVID-19 was defined as hospitalization for more than 24 h or death from the disease. We analyzed outcomes using a binomial logistic regression model adjusted for potential confounders (age > 85, comorbidities, BMI > 35, stage IV cancer, chemotherapy, and care home residence). Vaccine efficacy (VE) was calculated as 100 × (1 - adjusted odds ratio).

Results: Seventy-eight patients developed severe COVID-19, including 20 fatalities. Vaccinated patients had significantly lower odds of severe disease (adjusted odds ratio: 0.027; VE: 97.3%). Comorbidities and care home residence were also associated with increased risk. In a sub-analysis of cases after vaccine availability (N = 2,437), the adjusted odds ratio was 0.073 (VE: 92.7%), with comorbidities remaining the only significant non-vaccine risk factor. Vaccination uptake in the cohort was high (91.5%).

Conclusions: COVID-19 vaccination was highly effective at preventing severe disease in breast cancer patients, including those receiving active cancer treatment. The vaccine's efficacy was comparable to, or even higher than, that observed in the general population, suggesting that breast cancer and its treatment do not substantially impair the protective immune response.

Objectives: To evaluate how the implementation of intensity-modulated/image-guided RT (IMRT/IGRT) with intraprostatic seeds can impact the risk of late gastrointestinal (LGI) and genitourinary (LGU) toxicity in prostate cancer (PCa) patients treated with dose-escalation RT.

Materials /methods: Retrospective analysis of a prospective cohort of 1,010 men treated within a risk-adapted, intensification program with a minimum follow-up (FU) of 5 years. The median radiation dose to prostate was 79.5 Gy (IQR: 75.0, 80.3). Short-term ADT (STADT, n = 165) and long-term ADT (LTADT, n = 385) were administered to intermediate- and high-risk patients, respectively. Late toxicities were assessed using the EORTC/RTOG criteria. Kaplan-Meier analysis: to calculate the cumulative incidence of late toxicities; Cox proportional regression model: to estimate hazard ratios (HRs).

Results: Median FU was 116 months (IQR: 88-133). The median RT dose for IMRT/IGRT was 80.0 Gy (IQR 79.1, 81.2) and 78.0 Gy (IQR 73.1, 79.6), (p = 0.001) for those treated with 3DCRT. The 10-year Kaplan-Meier grade ≥ 2 LGI and LGU toxicities were 10% (95% confidence interval [CI] 8-12) and 16% (95% CI 14-18), respectively. The multivariate analysis (MVA) showed that the use of IMRT/IGRT with intraprostatic seeds was a significant protective factor for grade ≥ 2 LGI toxicity (HR: 0.66, 95%CI: 0.46-0.95, p = 0.021), despite the higher radiation dose in the IMRT/IGRT group. However, its impact on decreasing grade ≥ 2 LGU toxicity did not achieve statistically significance (13% vs 18%; p = 0.053, HR 0.88). A prior transurethral resection of the prostate (TURP) (HR 1.98, 95% CI: 1.30-2.59, p = 0.002) and the presence of acute grade ≥ 2 GU complications (HR:1.76, 95% CI: 1.20-2.9, p = 0.003) were associated with a higher incidence of grade ≥ 2 LGU toxicity, while LTADT was significantly associated with a lower risk of GU complications (HR:0.66, 95% CI: 0.46-0.95, p = 0.021).

Conclusion: The study confirms that IMRT/IGRT with intraprostatic fiducial markers significantly reduces grade ≥ 2 late GI toxicity, and appears to prevent an increase in GU toxicity rates despite dose escalation.

Purpose: Anticoagulation/ antiplatelet treatment could potentially reduce the metastatic process, however, consistent evidence is lacking. Here we explored an in vivo model of experimental metastasis of murine B16 melanoma to observe tumor cell extravasation under therapy with aspirin or enoxaparin.

Methods: Three treatment groups by 5 C57BL/6 female mice were injected with B16/F10 cells in the retro orbital sinus. After two weeks necropsy was performed.

Results: In the group treated with enoxaparin, a marked reduction in the number of metastatic foci in the lungs, with 6-193 metastases and 0.04-2.3% affected lung area were observed. The control group had 561-1000 metastatic lesions and 13-21% affected area. In the aspirin-treated group, there was a reduction in the number of metastatic lesions (386 - 640) and area (6.4-19%).

Conclusions: Both aspirin and enoxaparin treatment affect the progression of metastases in mice, with enoxaparin being the most effective.

Introduction: Adenocarcinoma of the esophageal junction and stomach (AEG/S) remains one of the deadliest cancers worldwide. New treatment options are urgently needed. A new target could be trophoblast cell surface protein 2 (TROP2), which is expressed in a variety of solid tumors and can be targeted, e.g., by sacituzumab govitecan, which has shown promising results in triple-negative breast cancer. This study investigates the expression of TROP2 in patients with AEG/S and correlates its expression with clinical and histopathological endpoints.

Methods: TROP2 expression was assessed in a cohort of 250 patients who underwent primary surgery for AEG/S. Immunohistochemistry was performed on tissue microarrays constructed from primary tumors and lymph node metastases to quantify TROP2 expression intensity. Clinical variables, including overall survival and patient demographics, as well as tumor-specific characteristics such as stage and grade, were correlated with TROP2 expression to evaluate its potential prognostic relevance in AEG/S.

Results: TROP2 was expressed in 86% of primary tumors and 81.3% of lymph node metastases. The intensity of TROP2 expression (low vs. medium vs. high) was correlated negatively with overall survival (p < 0.05, 70.9 months vs. 54.2 months vs. 39.5 months), lymphatic invasion (p = 0.05, V = 0.138), and higher grading (p = 0.037, V = 0.143). The intensity of TROP2 expression in lymph node metastases and primary tumors correlated significantly (p < 0.001, ρ = 0.444). There was a non-significant increase in positive lymphonodal status (p = 0.093, V = 0.138) in patients with higher TROP2 expression.

Conclusion: In Caucasian AEG/S patients, TROP2 is expressed in the majority of cases. TROP2 expression intensity itself has an impact on survival, which could be explained by a more aggressive phenotype, which leads to lymphatic invasion and lymph node metastasis.

The evolution of regorafenib from a monotherapy to a cornerstone of combination regimens for advanced solid tumors is fueled by its unique multi-targeted profile. This review systematically delineates the synergistic mechanisms underpinning this evolution, encompassing the potent induction of diverse cell death programs (apoptosis, autophagy, ferroptosis), the vertical and horizontal blockade of oncogenic signaling pathways (MAPK, PI3K/AKT, STAT3), and the critical remodeling of the TME. These mechanistic rationales are critically translated into clinical practice, with combinations, particularly with immune checkpoint inhibitors, demonstrating breakthrough efficacy in challenging settings such as microsatellite-stable colorectal cancer and hepatocellular carcinoma. We further synthesize strategies to overcome resistance-from targeting compensatory pathways to employing novel nanocarriers for optimized drug delivery-and outline the future landscape, emphasizing the imperative for biomarker-driven patient selection and the integration of next-generation agents.

Background:  This study sought to uncover novel targets for fighting drug resistance in breast cancer therapy, such as miRNA that target ABC transporters and decrease the oncogenic activity of breast cancer cells.

Methods: MiRNA ABC transporter targets were predicted using in silico methods after evaluating the ABC transporter route. In addition, miRNA expression, gene annotation, and gene ontology concepts were investigated. The expression levels of ABC transporter genes and miRNAs were determined using QRT-PCR. Dual luciferase activity was assessed to establish the precise ABC transporter-specific interaction. Flowcytometric analysis was used to detect doxorubicin uptake in miR-4330-treated cells, as well as cell cycle analyses. The spreading capacity of miR-4330-upregulated cells was investigated.

Results: The current study identified miR-4330 as an anti-drug and anti-oncogenic molecule in both estrogen receptor positive and negative breast cancer cells. Furthermore, the study identified the mechanism by which miR-4330 restoration reduces drug resistance by drastically decreasing ABCG2 expression (fold change of -0.25), which was accompanied by a considerable increase in doxorubicin accumulation or influx in both cell lines. Furthermore, miRNA-4330 restoration resulted in a considerable reduction in metastatic and spreading capabilities in both cell types.

Conclusion: The current findings identified miR-4330 restoration as a tool for overcoming acquired drug resistance and reducing cancer activity, which might be used to improve therapeutic strategies and treatment regimens for breast cancer patients. miR-4330 may be useful as a diagnostic and prognostic marker for drug-resistant breast cancer.

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is a surrogate for long-term outcomes in breast cancer, yet response rates vary widely. Biomarkers are needed to predict efficacy. Vitamin D, through its receptor-mediated diverse biological effects on tumor biology and immune regulation, has been suggested as a potential predictor of pCR.

Methods: We retrospectively evaluated breast cancer patients who received NACT between December 2022 and December 2024. Baseline serum vitamin D and inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CAR), prognostic nutritional index (PNI), and atherogenic index of plasma (AIP), were assessed. Pathological response was defined as pCR or Miller-Payne grades 4-5. ROC analysis identified optimal cut-offs, and logistic regression was applied to explore factors associated with pathological response.

Results: Among 223 patients, pCR occurred in 39.0%. ROC analysis identified 14.5 ng/mL as the optimal vitamin D threshold (AUC 0.705, p < 0.001). Vitamin D ≥ 14.5 ng/mL was independently associated with higher response, particularly in HR + /HER2 - and HER2 + subtypes; multivariable analyses also supported significance in TNBC. Recent vitamin D supplementation before NACT was significantly correlated with improved outcomes. Elevated CAR and AIP were inversely associated with response.

Conclusions: Vitamin D levels above 14.5 ng/mL independently predicted superior pathological response to NACT, with subtype-specific effects. Both baseline status and supplementation may enhance chemosensitivity, supporting vitamin D as a clinically relevant predictive biomarker.

Objective: To establish a patient-derived xenograft (PDX) model of testicular yolk sac tumor (TYST) that faithfully recapitulates the histopathological and molecular features of the primary tumor, thereby providing a robust pre-clinical platform for studying yolk sac tumor pathogenesis and evaluating novel therapeutics.

Methods: Patient-derived TYST tumor tissues were implanted subcutaneously in the right scapular region of immunodeficient mice (NPG and BALB/c nude strains) to generate a PDX model. Engrafted tumors were serially passaged and characterized by hematoxylin and eosin (H&E) staining, immunohistochemistry for AFP and SALL4, and PCR-based species identification to exclude murine lymphoma. The anti-tumor efficacy of the JEB regimen (carboplatin, etoposide, and bleomycin) was assessed using both in vivo experiments with the PDX model and ex vivo experiments utilizing the hydrogel-embedded histoculture drug sensitivity test (HDST).

Results: The patient-derived TYST tumor tissues exhibited higher tumorigenicity in NPG and BALB/c nude mice, maintaining stability through serial passaging. H&E staining confirmed preservation of characteristic yolk sac morphology, including Schiller-Duval bodies. Immunohistochemical analysis demonstrated consistent expression of AFP and SALL4 in PDX tumors, mirroring the diagnostic profile of the original specimen. PCR results confirmed the human origin of the xenografts and ruled out spontaneous murine lymphomas. HDST assays revealed marked sensitivity to the JEB regimen, which was corroborated in vivo: JEB treatment induced significant tumor regression without causing clinically relevant body weight loss.

Conclusion: We successfully established a TYST PDX model that retains tissue structure and protein expression signature of the patient's tumor tissue. Furthermore, this PDX model demonstrates high sensitivity to standard JEB chemotherapy and represents a valuable resource for translational research in pediatric germ cell tumors.

Background: Classic Kaposi's sarcoma (CKS) is an angiogenic tumor with no standardized treatment. Increased mTOR pathway activity in tumors fuels oncogenesis by stimulating anabolic metabolism, cell proliferation, and angiogenesis. This study aimed to assess the therapeutic potential of mTOR inhibitor metformin in CKS patients.

Methods: Two consecutive patients with biopsy-proven, CKS received metformin as monotherapy, and we further leverage single-cell RNA sequencing and spatial transcriptomics to uncover its underlying molecular mechanisms.

Results: Rapid clinical response with no adverse effects was observed in 2 CKS patients. Further investigation identified characteristic spindle cells (SCs) exhibiting heightened activity in VEGF, mTOR, and hypoxia signaling pathways, suggestive of a terminal stromal differentiation state. Besides, the immune landscape was characterized by a high proportion of CD8+ Tex and NK cells displaying suppressed cytotoxicity and migration functions. Crucially, SCs were found to interact with immune cells predominantly via the CXCL9-CXCR3 signaling axis.

Conclusion: This study reveals the mTOR-driven differentiation of SCs in KS pathogenesis aligning with rapid clinical improvement in CKS patients, which provides compelling evidence for metformin's therapeutic potential in CKS.

Purpose: Trastuzumab, the first anti-human epidermal growth factor receptor 2 (HER2)-targeted drug, is limited by adverse drug events (ADEs). The next-generation antibody-drug conjugates trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) exhibit enhanced efficacy and safety profiles compared with trastuzumab. In this study, we utilized US Food and Drug Administration Adverse Event Reporting System (FAERS) data to compare the ADEs of all three drugs, to facilitate personalized clinical decision-making and targeted monitoring.

Methods: ADE reports for patients with breast cancer using trastuzumab, T-DXd, or T-DM1 were retrieved. ADEs were classified using preferred terms (PT), standardized MedDRA queries (SMQs), and system organ classes (SOCs). Data mining using reported odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-Poisson shrinker was conducted.

Results: Overall, 20,829 cases of trastuzumab, 4565 cases of T-DXd, and 2975 cases of T-DM1 were included. With regard to SMQ terms, trastuzumab had a higher signal intensity for cardiac toxicity, and the RORs for "cardiomyopathy" of trastuzumab, T-DXd and T-DM1 were 8.59, 1.33, and 1.84, respectively. Meanwhile, T-DXd showed stronger signals for lung toxicity and T-DM1 showed prominent hepatotoxicity signals. Based on the differences between trastuzumab, T-DXd and T-DM1, this study established an individualized medication selection flowchart.

Conclusions: This study applied four algorithms to analyze and compare ADEs associated with trastuzumab, T-DXd, or T-DM1. By integrating multi-level analysis including PT, SMQ, and SOC, this study provides a comprehensive safety perspective to guide clinical decision-making and medication monitoring for patients with breast cancer receiving HER2-targeted therapy.