Clinical & Experimental Metastasis最新文献

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression. Currently, our understanding of brain metastasis remains limited, primarily due to the absence of appropriate models that can realistically simulate the entire process of tumor cell detachment from the primary site, circulation through the bloodstream, and eventual colonization of the brain. Therefore, there is a pressing need to develop more suitable lung cancer brain metastasis models that can effectively replicate these critical stages of metastasis. Here, based on the traditional carotid artery injection model, we established a novel orthotopic mouse model by using a light-controlled hydrogel to repair the puncture site on the carotid artery, with sustained cerebral blood circulation and the capability of multiple delivery cancer cell to mimic lung cancer brain metastasis. The optimized orthotopic mouse model significantly reduced cerebral ischemia and improved cerebral oxygenation by 60% compared to the traditional orthotopic mouse model, enhancing post-operative survival rates. It also showed a reduction in pro-inflammatory cytokines and featured less inflammatory and more resting states of microglial and astrocyte cells. Furthermore, the optimized orthotopic mouse model markedly increased the success rate and absolute number of the metastatic clones in the brain. Additionally, the multiple delivery model based on the optimized orthotopic mouse model substantially augmented the tumor clone number and formation rates compared to single injection in the optimized orthotopic mouse model. This model overcomes previous limitations by maintaining cerebral circulation, providing a more accurate simulation of the continuous entry of tumor cells into cerebral circulation. It offers a robust platform for studying the interactions of cancer cells with the brain microenvironment and testing new therapeutic approaches.

Patients with metastatic urothelial carcinoma (mUC) are typically elderly and often have other comorbidities that require the use of concomitant medications. In our study we evaluated the association of concomitant use of antibiotics (ATBs), proton pump inhibitors (PPIs), corticosteroids, statins, metformin and insulin with patient outcomes and we validated the prognostic role of a concomitant drug score in mUC patients treated with enfortumab vedotin (EV) monotherapy. Data from 436 patients enrolled in the ARON-2^EV retrospective study were analyzed according to the concomitant medications used at baseline. Finally, the patients were stratified into three risk groups according to the concomitant drug score based on ATBs, corticosteroids and PPIs. Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Inferior survival outcomes were observed in ATB users compared to non-users (OS: 7.3 months, 95%CI 5.0 - 12.3 vs 13.7 months, 95%CI 12.2 - 47.3, p = 0.001; PFS: 5.1 months 95%CI 3.3 - 17.7 vs 8.3 months, 95%CI 7.1 - 47.3, p = 0.001) and also in corticosteroid users compared to non-users (OS: 8.4 months, 95%CI 6.6 - 10.0 vs 14.2 months, 95%CI 12.7 - 47.3, p < 0.001; PFS: 6.0 months 95%CI 4.6 - 7.9 vs 8.9 months, 95%CI 7.2 - 47.3, p = 0.004). In the Cox multivariate analysis, the concomitant drug score was a significant factor predicting both OS (HR = 1.32 [95% CI 1.03 - 1.68], p = 0.026) and PFS (HR = 1.23 [95% CI 1.01 - 1.51], p = 0.044). Our findings suggest detrimental impact of concomitant use of ATBs and corticosteroids on survival outcomes and the prognostic utility of the concomitant drug score in previously treated mUC patients receiving EV.

Postoperative radiotherapy improves local control (LC) after resection of brain metastases. In comparison to whole brain radiotherapy (WBRT) stereotactic radiosurgery (SRS) to resection cavity significantly reduces cognitive side effects. However, two phase-III trials have reported suboptimal LC with SRS, leading to increased interest in hypofractionated stereotactic radiotherapy (SRT) as an alternative to improve outcomes. This single-centre study, based on a prospective quality assurance protocol, included 161 patients with 185 resected brain metastases treated with either SRS or SRT between February 2018 and June 2023. Patients were assigned to treatment based on cavity size, with SRS typically used for cavities < 10 cc and SRT for larger volumes. Primary and secondary endpoints were LC and radiation necrosis (RN), respectively. Data analysis was conducted retrospectively. Median cavity size was 13.3 cc, with 20% of cavities receiving SRS and 80% SRT. 12-month LC was 92.6% (95-CI: 88.2 - 97.3%), 12-month RN incidence was 9% (95-CI: 3-14%), with RN limited to CTCAE v5 ≤ 2. In cavities < 10 cc, no significant difference in LC was found between SRS and SRT. For cavities > 10 cc, PTV volume was the only significant predictor of LC, while fractionation and dose did not significantly impact outcomes. SRS and SRT both offer excellent LC for resection cavities < 10 cc with low rates of RN, suggesting SRS as the preferred treatment in this collective, in consideration of patient comfort and resource allocation. In larger cavities, PTV volume significantly influences LC. Dose escalation might be beneficial in improving outcomes in these cases.

Combining radiotherapy (RT) with Ipilimumab, a CTLA-4 inhibitor, holds promise in treating metastatic brain melanoma (MBM). Despite promising preclinical evidence, clinical studies evaluating their combined efficacy are limited and varied, necessitating a systematic review and meta-analysis to consolidate evidence and identify predictors of response or resistance in this challenging patient population. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The electronic databases of PubMed, Embase, Scopus, and Web of science were searched on July 9th, 2024, using the relevant key terms without filters. All statistical analysis was performed by STATA v.17. A total of 26 studies with 1059 participants were included. The 1, 2, and 3-year overall survival rates were 0.44 [95% CI: 0.32-0.55], 0.28 [95% CI: 0.17, 0.39], and 0.19 [95% CI: 0.06-0.32], respectively. The pooled 12-month local control and 1-year progression-free survival rate were 0.53 [95% CI: 0.34-0.71] and 0.20 [95%CI: 0.10-0.30]. The pooled overall response rate, partial response rates, and stable disease rate were 0.26 [95% CI: 0.10-0.41], 0.10 [95% CI:0.05-0.15], 0.17 [95%CI:0.10-0.23], and 0.58 [95%CI: 0.45-0.70]. This study demonstrated promising results regarding adding RT to ipilimumab which was associated with significantly higher 1-year OS, 18-month OS, 2-year OS, 3-year OS, overall radiological response rate, and stable disease rate and significantly lower rate of progressive disease rate compared to ipilimumab without RT. However, no significant difference was observed between two groups in 6-month OS, 12-month LC, 1-year PFS, and partial response rate.

Identifying metastatic lymph nodes (LNs) in patients with cervical cancer treated with definitive radiotherapy may inform treatment strategy and determine prognosis, but available methods have limitations, especially in developing regions. Herein, we aimed to evaluate the performance of quantitative parameters in spectral computed tomography (CT) scanning in this context, focusing on its complementary role alongside conventional diagnostic approaches like 18-fluorine-fuorodeoxyglucose positron emission tomography computed tomography (18 F FDG-PET/CT). Patients with cervical cancer, who underwent pretreatment spectral CT simulation scanning and planned radiotherapy, were enrolled in this prospective study. The LNs were categorized as "metastatic" and "non-metastatic", based on a procedure that included 18 F FDG-PET/CT as well as CT, magnetic resonance imaging, Node Reporting and Data System and follow-up results. Iodine concentrations (IC), normalized IC (NIC), effective atom number (effZ), and spectral curve slope (λ_HU) in the arterial (AP) and venous (VP) phases, were compared between metastatic and non-metastatic LNs. IC were derived from iodine-based material decomposition through manual delineation and normalized to the iodine concentration in the adjacent artery (NIC). effZ and λ_HU were calculated based on the effective atom number image and virtual monochromatic images. Univariate and multivariate logistic regression analyses were used to determine spectral CT factors independently associated with LNs metastasis, and their diagnostic efficacies were assessed using the area under the curve (AUC) analysis. The diagnostic efficiency of 18 F FDG-PET/CT and spectral CT was compared. A total of 115 metastatic and 97 non-metastatic LNs were detected, and spectral CT parameters (IC, NIC, effZ, λ_HU) significantly differed between the two groups. In univariate and multivariable logistic regression analysis, λ_HU in the AP and NIC in the VP were independent predictors for metastatic LNs and their combination improved AUC to 0.923, with a sensitivity of 84.4%, and a specificity of 85.6%. Spectral CT could achieve similar sensitivity as 18 FFDG-PET/CT in total LNs, and, more importantly, a higher sensitivity (95.5% vs. 59.1%) and diagnostic accuracy (92.9% vs. 67.9%) for para-aortic LNs. Quantitative spectral CT parameters can help distinguish metastatic from non-metastatic LNs in patients with cervical cancer treated with definitive radiotherapy. Combination of λ_HU in AP and NIC in VP further improves diagnostic performance. Spectral CT, while promising, complements rather than replaces PET/CT, especially for diagnosing para-aortic LNs, where PET/CT may have limitations. It could be a valuable adjunct to conventional imaging, particularly in settings with limited access to advanced tools.

Tumor-to-tumor metastasis is an exceedingly rare phenomenon where secondary deposits of a tumor develops in another one. Our systematic review and meta-analysis aims to uncover and analyze reported cases to enhance our understanding and improve patients' care. A comprehensive search of the literature was conducted to identify 685 cases of tumor-to-tumor metastasis from 543 articles. Key information, including the donor and recipient organs, tumor histology, primary to metastasis time interval, presence of distant metastases and overall survival was extracted and analyzed. The highest incidence of tumor-to-tumor metastasis was observed in breast cancer and lung cancer metastasizing to meningioma (n = 52, 7.6%; n = 49, 6.2%; respectively). There were 131 (19.2%) autopsy cases, 477 (69.6%) cases diagnosed in vivo, and in 77 cases (11.2%), the timing of diagnosis was unavailable. Death of the patient (including autopsy cases) was reported in 256 (37.4%) cases. In 160 (23.35%) patients, the primary of the metastasis (POM) was occult at the time of metastasis, and in 385 (56.2%) cases, the POM was already known. The median period between clinically overt primary cancer diagnosis and tumor-to-tumor metastasis was 2.0 years. Donor metastases to other sites were observed in 328 (47.9%) cases. In multivariate Cox regression analysis, the primary-to-metastasis interval (< 3 vs > 3 years, HR 2.01, 95% CI 1.18-3.43, p = 0.01) and the presence of donor metastases to other sites (present vs absent; HR 0.37, 95% CI 0.23-0.59, p < 0.001) were significantly associated with survival. In summary, our findings emphasize the necessity for heightened clinical vigilance, early detection, and tailored management to effectively address this unique and challenging clinical scenario.

Oligorecurrent prostate cancer (PCa) can be treated with metastasis-directed therapy (MDT), which may be performed using radioguided surgery (RGS) as an experimental approach. These procedures have shown promising outcomes, largely due to the high lesion detection rate of positron emission tomography/computed tomography (PET/CT). We present a case series of patients who underwent RGS following robot-assisted radical prostatectomy (RARP). All excised recurrences were found in unusual anatomical locations, potentially resulting from prior invasive surgical procedures. Although three out of four patients did not exhibit a reduction in prostate-specific antigen (PSA) levels post-procedure, these procedures allowed for the successful removal of tumor metastases, the exclusion of other malignancies through molecular tests, and the administration of systemic targeted therapy. Additionally, no surgical complications were reported.

The blood-brain barrier and the distinct brain immunology provide challenges in translating commonly used chemotherapeutics to treat intracranial tumors. Previous reports suggest anti-tumoral effects of antipsychotics, encouraging investigations into potential treatment effects of neuroleptics on brain metastases. For the first time, the therapeutic potential of the antipsychotic drug clozapine in treating melanoma brain metastases (MBM) was investigated using three human MBM cell lines. Through in vitro cell culture and viability experiments, clozapine displayed potent anti-tumoral effects on MBM cells with an exploitable therapeutic window when compared to normal human astrocytes or rat brain organoids. Further, it was shown that clozapine inhibited migration, proliferation, and colony formation in a dose-dependent manner. Through flow cytometry and proteome screening, we found that clozapine induced apoptosis in MBM cells and potentially altered the tumor immunological environment by upregulating proteins such as macrophage inflammatory protein-1 alpha (MIP-1α) and interleukin-8 (IL-8). In conclusion, clozapine shows significant and selective anti-tumoral effects on MBM cell lines in vitro. Further in vivo experiments are warranted to translate these results into clinical use.

Background: In recent years, the emphasis has shifted to understanding the role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and its role in the metastasis of colorectal cancer (CRC).

Methods: We performed methylated RNA immunoprecipitation sequencing of tumor tissues and tumor-adjacent normal tissues from three patients with CRC to determine the m1A profile of mRNA in CRC. The expression of diaphanous-related formin 3 (DIAPH3) and its correlation with clinicopathological characteristics of CRC were evaluated using immunohistochemistry and online datasets. The role of DIAPH3 in the migration and invasion of CRC cells was evaluated using wound healing assay, Transwell assay and xenograft metastatic model. The downstream targets of DIAPH3 were screened using mass spectrometry. By co-transfecting DIAPH3 siRNA and a keratin 19 (KRT19) ectopic plasmid into CRC cells, the role of DIAPH3-KRT19 signaling axis was confirmed.

Results: The mRNA level of DIAPH3 and its m1A modifications increased simultaneously in the CRC tissues. In addition, high DIAPH3 expression in CRC tissues is significantly associated with metastasis and progression to an advanced stage. After the knockdown of DIAPH3, the migration and invasion capabilities of CRC cells suffered a notable decline, which could be rescued by overexpressing KRT19. In addition, the proteasome inhibitor MG132 could block the degradation of KRT19 induced by DIAPH3 silencing.

Conclusions: Our study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.

Purpose: Patients with nasopharyngeal carcinoma (NPC) experiencing locoregional recurrence concomitant with distant metastases (rmNPC) after initial treatment represent a unique subgroup with significant management challenges. This study aimed to evaluate overall survival (OS) in rmNPC patients treated with systemic therapies with or without radiotherapy.

Methods: This retrospective multicenter study included patients with locally recurrent and metastatic NPC from five hospitals. Kaplan-Meier analyses and log-rank tests were applied to assess survival outcomes based on recurrence and metastasis profiles, as well as treatment modalities. Independent prognostic factors affecting OS were identified using Cox regression models.

Results: A total of 52 patients were analyzed, with a median follow-up duration of 68.3 months (range: 7-240 months). The median OS was 23.4 months (range: 11.1-35.6 months), and the 1-, 2-, 3-, 4-, and 5-year OS rates were 61.3%, 46.5%, 31.0%, 27.9%, and 10.5%, respectively. The treatment modality did not significantly affect OS overall (P = 0.071). Median OS was 10.8 months (95% CI, 7.7-13.9) for chemotherapy alone, 24.2 months (95% CI, 8.9-39.4) for chemotherapy combined with PD-1 inhibitors, and 47.1 months (95% CI, 10.2-84.0) for chemotherapy combined with radiotherapy. In patients with oligometastasis, radiotherapy significantly improved OS (50.1 vs. 24.1 months, P = 0.021), whereas no significant OS benefit was observed for radiotherapy in polymetastatic patients (8.6 vs. 14.8 months, P = 0.168). Similarly, radiotherapy extended OS in patients with one-organ metastases (50.1 vs. 24.1 months, P = 0.026), while no significant benefit was observed in those with multiple-organ metastases (8.6 vs. 11.0 months, P = 0.831).

Conclusions: Radiotherapy, when combined with other treatment modalities, significantly improves OS in rmNPC patients with oligometastases or one-organ metastases.