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Special Issue "Brain Metastasis 2016"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Dario Marchetti

Director, Biomarker Research Program, Houston Methodist Research Institute, Professor, Institute of Academic Medicine, Visiting Professor, Baylor College of Medicine, MS: R7-414, 6670 Bertner Avenue, Houston, TX 77030, USA
Website | E-Mail
Interests: the biology and therapeutic utility of circulating tumor cells (CTCs); liquid biopsies; mechanisms of brain metastasis and dormancy in breast and melanoma cancers; roles of heparanase in development and disease

Special Issue Information

Dear Colleagues,

Brain metastasis is the stage of cancer resulting from cancer cell colonization of the brain. Brain metastasis represents a compendium of devastating diseases, arising from several cancer types, mostly fatal, because of the extremely poor prognosis when compared to primary cancers treatment. Furthermore, mechanisms underlying brain metastasis remain largely unknown. This Special Issue is the continuation of Special Issue “Brain Metastasis” and “Brain Metastasis 2014”. This Special Issue will assess, report, and discuss new discoveries in the biology, pathology, and treatment of brain metastasis.

Prof. Dr. Dario Marchetti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • brain metastasis
  • molecular determinants
  • biological systems
  • pre-clinical models
  • therapeutic interventions
  • drug therapy
  • new drug discovery
  • biomarkers
  • brain metastasis prevention and/or treatment
  • genomics
  • proteomics
  • metabolomics

Published Papers (10 papers)

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Research

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Open AccessArticle EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer
Int. J. Mol. Sci. 2016, 17(12), 2132; https://doi.org/10.3390/ijms17122132
Received: 28 September 2016 / Revised: 6 December 2016 / Accepted: 7 December 2016 / Published: 18 December 2016
Cited by 11 | PDF Full-text (234 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive
[...] Read more.
Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessArticle Factors Affecting the Baseline and Post-Treatment Scores on the Hopkins Verbal Learning Test-Revised Japanese Version before and after Whole-Brain Radiation Therapy
Int. J. Mol. Sci. 2016, 17(11), 1834; https://doi.org/10.3390/ijms17111834
Received: 7 July 2016 / Revised: 14 October 2016 / Accepted: 27 October 2016 / Published: 3 November 2016
PDF Full-text (948 KB) | HTML Full-text | XML Full-text
Abstract
Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive
[...] Read more.
Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive function (NCF) after WBRT in different dose fractionation schedules. We administered the HVLT-R (Japanese version) before (baseline) and at four and eight months after WBRT in 45 patients who received either therapeutic (35Gy-in-14, n = 16; 30Gy-in-10, n = 18) or prophylactic (25Gy-in-10, n = 11) WBRT. Sixteen patients dropped out before the eight-month examination, due mostly to death from cancer. The Karnofsky Performance Status (KPS) 80–100 group had significantly higher baseline total recall (TR) scores (p = 0.0053), delayed recall (DR) scores (p = 0.012), and delayed recognition (DRecog) scores (p = 0.0078). The patients aged ≤65 years also had significantly higher TR scores (p = 0.030) and DRecog scores (p = 0.031). The patients who underwent two examinations (worse-prognosis group) had significantly decreased DR scores four months after WBRT compared to the baseline (p = 0.0073), and they were significantly more likely to have declined individual TR scores (p = 0.0017) and DR scores (p = 0.035) at four months. The eight-month HVLT-R scores did not significantly decline regardless of the WBRT dose fractionation. The baseline NCF was determined by age and KPS, and the early decline in NCF is characteristic of the worse-prognosis group. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessArticle Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis
Int. J. Mol. Sci. 2016, 17(4), 524; https://doi.org/10.3390/ijms17040524
Received: 23 February 2016 / Revised: 30 March 2016 / Accepted: 31 March 2016 / Published: 7 April 2016
Cited by 4 | PDF Full-text (216 KB) | HTML Full-text | XML Full-text
Abstract
Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR
[...] Read more.
Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5%) were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6%) were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
Open AccessArticle Retrospective Study of Metastatic Melanoma and Renal Cell Carcinoma to the Brain with Multivariate Analysis of Prognostic Pre-Treatment Clinical Factors
Int. J. Mol. Sci. 2016, 17(3), 400; https://doi.org/10.3390/ijms17030400
Received: 31 December 2015 / Revised: 27 February 2016 / Accepted: 8 March 2016 / Published: 18 March 2016
Cited by 4 | PDF Full-text (701 KB) | HTML Full-text | XML Full-text
Abstract
Patients with brain metastasis from renal cell carcinoma (RCC) or melanoma have historically had very poor prognoses of less than one year. Stereotactic radiosurgery (SRS) can be an effective treatment for patients with these tumors. This study analyzes the effect of pretreatment prognostic
[...] Read more.
Patients with brain metastasis from renal cell carcinoma (RCC) or melanoma have historically had very poor prognoses of less than one year. Stereotactic radiosurgery (SRS) can be an effective treatment for patients with these tumors. This study analyzes the effect of pretreatment prognostic factors on overall survival (OS) for RCC and melanoma patients with metastasis to the brain treated with SRS. A total of 122 patients with brain metastases from either RCC or melanoma were grouped by age at brain metastasis diagnosis, whether they received whole brain radiation therapy (WBRT) in addition to SRS, or they underwent surgical resection, Karnofsky Performance Score (KPS), number of brain metastases, and primary tumor. Median survival times for melanoma patients and RCC patients were 8.20 ± 3.06 and 12.70 ± 2.63 months, respectively. Patients with >5 metastases had a significantly shorter median survival time (6.60 ± 2.45 months) than the reference group (1 metastasis, 10.70 ± 13.40 months, p = 0.024). Patients with KPS ≤ 60 experienced significantly shorter survival than the reference group (KPS = 90–100), with median survival times of 5.80 ± 2.46 months (p < 0.001) and 45.20 ± 43.52 months, respectively. We found a median overall survival time of 12.7 and 8.2 months for RCC and melanoma, respectively. Our study determined that a higher number of brain metastases (>5) and lower KPS were statistically significant predictors of a lower OS prognosis. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Review

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Open AccessReview Breast Cancer Brain Metastases: Clonal Evolution in Clinical Context
Int. J. Mol. Sci. 2017, 18(1), 152; https://doi.org/10.3390/ijms18010152
Received: 8 November 2016 / Revised: 22 December 2016 / Accepted: 27 December 2016 / Published: 13 January 2017
Cited by 2 | PDF Full-text (1166 KB) | HTML Full-text | XML Full-text
Abstract
Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden
[...] Read more.
Brain metastases are highly-evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely-held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessReview Targeted Therapies for Brain Metastases from Breast Cancer
Int. J. Mol. Sci. 2016, 17(9), 1543; https://doi.org/10.3390/ijms17091543
Received: 24 July 2016 / Revised: 1 September 2016 / Accepted: 8 September 2016 / Published: 13 September 2016
Cited by 16 | PDF Full-text (207 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor
[...] Read more.
The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessReview Ion Channels in Brain Metastasis
Int. J. Mol. Sci. 2016, 17(9), 1513; https://doi.org/10.3390/ijms17091513
Received: 7 August 2016 / Revised: 5 September 2016 / Accepted: 6 September 2016 / Published: 8 September 2016
Cited by 9 | PDF Full-text (670 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes
[...] Read more.
Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessReview Melanoma Brain Metastasis: Mechanisms, Models, and Medicine
Int. J. Mol. Sci. 2016, 17(9), 1468; https://doi.org/10.3390/ijms17091468
Received: 2 August 2016 / Revised: 2 August 2016 / Accepted: 26 August 2016 / Published: 2 September 2016
Cited by 8 | PDF Full-text (1481 KB) | HTML Full-text | XML Full-text
Abstract
The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation,
[...] Read more.
The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessReview Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases
Int. J. Mol. Sci. 2016, 17(9), 1463; https://doi.org/10.3390/ijms17091463
Received: 30 June 2016 / Revised: 22 August 2016 / Accepted: 26 August 2016 / Published: 2 September 2016
Cited by 5 | PDF Full-text (1501 KB) | HTML Full-text | XML Full-text
Abstract
Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most
[...] Read more.
Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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Open AccessReview Molecular Targeted Therapies for the Treatment of Leptomeningeal Carcinomatosis: Current Evidence and Future Directions
Int. J. Mol. Sci. 2016, 17(7), 1074; https://doi.org/10.3390/ijms17071074
Received: 19 May 2016 / Revised: 26 June 2016 / Accepted: 28 June 2016 / Published: 5 July 2016
Cited by 9 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
Leptomeningeal carcinomatosis (LMC) is the multifocal seeding of cerebrospinal fluid and leptomeninges by malignant cells. The incidence of LMC is approximately 5% in patients with malignant tumors overall and the rate is increasing due to increasing survival time of cancer patients. Eradication of
[...] Read more.
Leptomeningeal carcinomatosis (LMC) is the multifocal seeding of cerebrospinal fluid and leptomeninges by malignant cells. The incidence of LMC is approximately 5% in patients with malignant tumors overall and the rate is increasing due to increasing survival time of cancer patients. Eradication of the disease is not yet possible, so the treatment goals of LMC are to improve neurologic symptoms and to prolong survival. A standard treatment for LMC has not been established due to low incidences of LMC, the rapidly progressing nature of the disease, heterogeneous populations with LMC, and a lack of randomized clinical trial results. Treatment options for LMC include intrathecal chemotherapy, systemic chemotherapy, and radiation therapy, but the prognoses remain poor with a median survival of <3 months. Recently, molecular targeted agents have been applied in the clinic and have shown groundbreaking results in specific patient groups epidermal growth factor receptor (EGFR)-targeted therapy or an anaplastic lymphoma kinase (ALK) inhibitor in lung cancer, human epidermal growth factor receptor 2 (HER2)-directed therapy in breast cancer, and CD20-targeted therapy in B cell lymphoma). Moreover, there are results indicating that the use of these agents under proper dose and administration routes can be effective for managing LMC. In this article, we review molecular targeted agents for managing LMC. Full article
(This article belongs to the Special Issue Brain Metastasis 2016)
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