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Open AccessArticle

Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers

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Cancers 2023, 15(7), 2145; https://doi.org/10.3390/cancers15072145 - 04 Apr 2023

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Abstract

Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In [...] Read more.

Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In this study, we analyzed differences in the epigenome of brain metastasis from the colon (n = 4) and lung (n = 14) cancer and we compared these signatures with those found in primary tumors. Results show that CRC tumors showed a high degree of genome-wide methylation compared to lung cancers. Further, brain metastasis from lung cancer deeply activates neural signatures able to modify the brain microenvironment favoring tumor cells adaptation. At the protein level, brain metastases from lung cancer show expression of the neural/glial marker Nestin. On the other hand, colon brain metastases show activation of metabolic signaling. These signatures are specific for metastatic tumors since primary cancers did not show such epigenetic derangements. In conclusion, our data shed light on the epi/molecular mechanisms that colon and lung cancers adopt to thrive in the brain environment. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Open AccessArticle

Melanoma Brain Metastases: A Retrospective Analysis of Prognostic Factors and Efficacy of Multimodal Therapies

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Cancers 2023, 15(5), 1542; https://doi.org/10.3390/cancers15051542 - 28 Feb 2023

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Abstract

Brain metastasis in cutaneous melanoma (CM) has historically been considered to be a dismal prognostic feature, although recent evidence has highlighted the intracranial activity of combined immunotherapy (IT). Herein, we completed a retrospective study to investigate the impact of clinical–pathological features and multimodal [...] Read more.

Brain metastasis in cutaneous melanoma (CM) has historically been considered to be a dismal prognostic feature, although recent evidence has highlighted the intracranial activity of combined immunotherapy (IT). Herein, we completed a retrospective study to investigate the impact of clinical–pathological features and multimodal therapies on the overall survival (OS) of CM patients with brain metastases. A total of 105 patients were evaluated. Nearly half of the patients developed neurological symptoms leading to a negative prognosis (p = 0.0374). Both symptomatic and asymptomatic patients benefited from encephalic radiotherapy (eRT) (p = 0.0234 and p = 0.011). Lactate dehydrogenase (LDH) levels two times higher than the upper limit normal (ULN) at the time of brain metastasis onset was associated with poor prognosis (p = 0.0452) and identified those patients who did not benefit from eRT. Additionally, the poor prognostic role of LDH levels was confirmed in patients treated with targeted therapy (TT) (p = 0.0015) concerning those who received immunotherapy (IT) (p = 0.16). Based on these results, LDH levels higher than two times the ULN at the time of the encephalic progression identify those patients with a poor prognosis who did not benefit from eRT. The negative prognostic role of LDH levels on eRT observed in our study will require prospective evaluations. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Open AccessArticle

Multimodal Treatments for Brain Metastases from Renal Cell Carcinoma: Results of a Multicentric Retrospective Study

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Cancers 2023, 15(5), 1393; https://doi.org/10.3390/cancers15051393 - 22 Feb 2023

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Abstract

The aim of this study was to evaluate the clinical outcomes of a large series of brain metastatic renal cell carcinoma (BMRCC) patients treated in three Italian centers. Methods: A total of 120 BMRCC patients with a total of 176 lesions treated were [...] Read more.

The aim of this study was to evaluate the clinical outcomes of a large series of brain metastatic renal cell carcinoma (BMRCC) patients treated in three Italian centers. Methods: A total of 120 BMRCC patients with a total of 176 lesions treated were evaluated. Patients received surgery plus postoperative HSRS, single-fraction SRS, or hypofractionated SRS (HSRS). Local control (LC), brain distant failure (BDF), overall survival (OS), toxicities, and prognostic factors were assessed. Results: The median follow-up time was 77 months (range 16–235 months). Surgery plus HSRS was performed in 23 (19.2%) cases, along with SRS in 82 (68.3%) and HSRS in 15 (12.5%). Seventy-seven (64.2%) patients received systemic therapy. The main total dose and fractionation used were 20–24 Gy in single fraction or 32–30 Gy in 4–5 daily fractions. Median LC time and 6 month and 1, 2 and 3 year LC rates were nr, 100%, 95.7% ± 1.8%, 93.4% ± 2.4%, and 93.4% ± 2.4%. Median BDF time and 6 month and 1, 2 and 3 year BDF rates were n.r., 11.9% ± 3.1%, 25.1% ± 4.5%, 38.7% ± 5.5%, and 44.4% ± 6.3%, respectively. Median OS time and 6 month and 1, 2 and 3 year OS rates were 16 months (95% CI: 12–22), 80% ± 3.6%, 58.3% ± 4.5%, 30.9% ± 4.3%, and 16.9% ± 3.6, respectively. No severe neurological toxicities occurred. Patients with a favorable/intermediate IMDC score, a higher RCC-GPA score, an early occurrence of BMs from primary diagnosis, absence of EC metastases, and a combined local treatment (surgery plus adjuvant HSRS) had a better outcome. Conclusions: SRS/HSRS is proven to be an effective local treatment for BMRCC. A careful evaluation of prognostic factors is a valid step to manage the optimal therapeutic strategy for BMRCC patients. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Open AccessArticle

Re-Irradiation by Stereotactic Radiotherapy of Brain Metastases in the Case of Local Recurrence

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Cancers 2023, 15(3), 996; https://doi.org/10.3390/cancers15030996 - 03 Feb 2023

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Abstract

Purpose: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society [...] Read more.

Purpose: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society for Radiotherapy and Oncology guidelines. Methods: From December 2014 to May 2021, 32 patients with 34 brain metastases received salvage SRT2 after failed SRT1. A total dose of 21 to 27 Gy in 3 fractions or 30 Gy in 5 fractions was prescribed to the periphery of the PTV (99% of the prescribed dose covering 99% of the PTV). After SRT2, multiparametric MRI, sometimes combined with 18F-DOPA PET-CT, was performed every 3 months to determine local control (LC) and radionecrosis (RN). Results: After a median follow-up of 12 months (range: 1–37 months), the crude LC and RN rates were 68% and 12%, respectively, and the median overall survival was 25 months. In a multivariate analysis, the performance of surgery was predictive of a significantly better LC (p = 0.002) and survival benefit (p = 0.04). The volume of a normal brain receiving 5 Gy during SRT2 (p = 0.04), a dose delivered to the PTV in SRT1 (p = 0.003), and concomitant systemic therapy (p = 0.04) were associated with an increased risk of RN. Conclusion: SRT2 is an effective approach for the local recurrence of BM after initial SRT treatment and is a potential salvage therapy option for well-selected people with a good performance status. Surgery was associated with a higher LC. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Open AccessArticle

Quantitative Relaxometry Metrics for Brain Metastases Compared to Normal Tissues: A Pilot MR Fingerprinting Study

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Amaresha Shridhar Konar

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Cancers 2022, 14(22), 5606; https://doi.org/10.3390/cancers14225606 - 15 Nov 2022

Cited by 1 | Viewed by 791

Abstract

The purpose of the present pilot study was to estimate T1 and T2 metric values derived simultaneously from a new, rapid Magnetic Resonance Fingerprinting (MRF) technique, as well as to assess their ability to characterize—brain metastases (BM) and normal-appearing brain tissues. Fourteen patients [...] Read more.

The purpose of the present pilot study was to estimate T1 and T2 metric values derived simultaneously from a new, rapid Magnetic Resonance Fingerprinting (MRF) technique, as well as to assess their ability to characterize—brain metastases (BM) and normal-appearing brain tissues. Fourteen patients with BM underwent MRI, including prototype MRF, on a 3T scanner. In total, 108 measurements were analyzed: 42 from solid parts of BM’s (21 each on T1 and T2 maps) and 66 from normal-appearing brain tissue (11 ROIs each on T1 and T2 maps for gray matter [GM], white matter [WM], and cerebrospinal fluid [CSF]). The BM’s mean T1 and T2 values differed significantly from normal-appearing WM (p < 0.05). The mean T1 values from normal-appearing GM, WM, and CSF regions were 1205 ms, 840 ms, and 4233 ms, respectively. The mean T2 values were 108 ms, 78 ms, and 442 ms, respectively. The mean T1 and T2 values for untreated BM (n = 4) were 2035 ms and 168 ms, respectively. For treated BM (n = 17) the T1 and T2 values were 2163 ms and 141 ms, respectively. MRF technique appears to be a promising and rapid quantitative method for the characterization of free water content and tumor morphology in BMs. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Review

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Open AccessReview

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review

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Anna Margherita Maffione

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Maria Cristina Marzola

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Cancers 2023, 15(7), 2184; https://doi.org/10.3390/cancers15072184 - 06 Apr 2023

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Abstract

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the “Response Assessment in Neuro-Oncology” (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current [...] Read more.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the “Response Assessment in Neuro-Oncology” (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Open AccessReview

The Significance of MicroRNAs in the Molecular Pathology of Brain Metastases

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Cancers 2022, 14(14), 3386; https://doi.org/10.3390/cancers14143386 - 12 Jul 2022

Cited by 1 | Viewed by 1153

Abstract

Brain metastases are the most frequent intracranial tumors in adults and the cause of death in almost one-fourth of cases. The incidence of brain metastases is steadily increasing. The main reason for this increase could be the introduction of new and more efficient [...] Read more.

Brain metastases are the most frequent intracranial tumors in adults and the cause of death in almost one-fourth of cases. The incidence of brain metastases is steadily increasing. The main reason for this increase could be the introduction of new and more efficient therapeutic strategies that lead to longer survival but, at the same time, cause a higher risk of brain parenchyma infiltration. In addition, the advances in imaging methodology, which provide earlier identification of brain metastases, may also be a reason for the higher recorded number of patients with these tumors. Metastasis is a complex biological process that is still largely unexplored, influenced by many factors and involving many molecules. A deeper understanding of the process will allow the discovery of more effective diagnostic and therapeutic approaches that could improve the quality and length of patient survival. Recent studies have shown that microRNAs (miRNAs) are essential molecules that are involved in specific steps of the metastatic cascade. MiRNAs are endogenously expressed small non-coding RNAs that act as post-transcriptional regulators of gene expression and thus regulate most cellular processes. The dysregulation of these molecules has been implicated in many cancers, including brain metastases. Therefore, miRNAs represent promising diagnostic molecules and therapeutic targets in brain metastases. This review summarizes the current knowledge on the importance of miRNAs in brain metastasis, focusing on their involvement in the metastatic cascade and their potential clinical implications. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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Other

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Open AccessSystematic Review

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

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Cancers 2023, 15(7), 2047; https://doi.org/10.3390/cancers15072047 - 29 Mar 2023

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Abstract

(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery [...] Read more.

(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery still plays a primary role. Despite this, the adjunct systems that help to reach the GTR, which are well structured for other tumour forms such as ultrasound and fluorescence systems, are not yet well employed and standardised in surgical practice. The aim of this review is to provide a picture of the current state-of-art of the roles of iOUS and intraoperative fluorescence to better understand their potential roles as surgical tools. (2) Methods: to reach this goal, the PubMed database was searched using the following string as the keyword: (((Brain cerebral metastasis [MeSH Major Topic])OR (brain metastasis, [MeSH Major Topic])) AND ((5-ala, [MeSH Terms]) OR (Aminolevulinicacid [All fields]) OR (fluorescein, [MeSH Terms]) OR (contrast enhanced ultrasound [MeSH Terms])OR ((intraoperative ultrasound. [MeSH Terms]))) AND (english [Filter]) AND ((english [Filter]) AND (2010:2022 [pdat])) AND (english [Filter]). (3) Results: from our research, a total of 661 articles emerged; of these, 57 were selected. 21 of these included BMs generically as a secondary class for comparisons with gliomas, without going deeply into specific details. Therefore, for our purposes, 36 articles were considered. (4) Conclusions: with regard to BMs treatment and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

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