Cancers

Research

15 pages, 2203 KiB

Open AccessArticle

Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

by Renáta Váraljai, Susanne Horn, Antje Sucker, Daniela Piercianek, Verena Schmitt, Alexander Carpinteiro, Katrin Anne Becker, Julia Reifenberger, Alexander Roesch, Jörg Felsberg, Guido Reifenberger, Ulrich Sure, Dirk Schadendorf and Iris Helfrich

Cancers 2021, 13(4), 731; https://doi.org/10.3390/cancers13040731 - 10 Feb 2021

Cited by 14 | Viewed by 2875

Abstract

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases [...] Read more.

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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13 pages, 1536 KiB

Open AccessArticle

Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a ‘Real-Life’ Setting

by Marcus Skribek, Konstantinos Rounis, Dimitrios Makrakis, Sofia Agelaki, Dimitris Mavroudis, Luigi De Petris, Simon Ekman and Georgios Tsakonas

Cancers 2020, 12(12), 3707; https://doi.org/10.3390/cancers12123707 - 10 Dec 2020

Cited by 15 | Viewed by 2562

Abstract

There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic [...] Read more.

There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic driven NSCLC with BM who were treated with ICIs at two medical oncology institutes in Sweden and Greece from 2016 to 2019. IC efficacy was assessed in patients who had not received local treatment for BM less than three months prior to the initiation of ICIs and had adequate radiological evaluation. We screened 280 patients, of which 51 had BM. BM was an independent predictor for inferior PFS (HR = 2.27; 95% CI, 1.53–3.36) but not OS (HR = 1.58; 95% CI, 0.97–2.60) for the whole patient population. IC response assessment was done on 33 patients. IC objective response rate (ORR) was 24.2%. The presence of neurological symptoms related to BM did not affect IC ORR (p = 0.48). High PD-L1 levels from extracranial biopsies were not a predictive factor for IC ORR (p = 0.13). ICIs are active in NSCLC patients with BM regardless of the presence of neurological symptoms and can achieve durable IC disease stabilization in a subgroup of patients. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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16 pages, 1440 KiB

Open AccessArticle

Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy

by Anna Cho, Helena Untersteiner, Dorian Hirschmann, Abdallah Shaltout, Philipp Göbl, Christian Dorfer, Karl Rössler, Wolfgang Marik, Klaus Kirchbacher, Irene Kapfhammer, Sabine Zöchbauer-Müller, Brigitte Gatterbauer, Maximilian J. Hochmair and Josa M. Frischer

Cancers 2020, 12(12), 3668; https://doi.org/10.3390/cancers12123668 - 7 Dec 2020

Cited by 16 | Viewed by 2651

Abstract

The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the [...] Read more.

The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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8 pages, 361 KiB

Open AccessArticle

Comorbidity Burden and Presence of Multiple Intracranial Lesions Are Associated with Adverse Events after Surgical Treatment of Patients with Brain Metastases

by Matthias Schneider, Muriel Heimann, Christina Schaub, Lars Eichhorn, Anna-Laura Potthoff, Frank A. Giordano, Erdem Güresir, Yon-Dschun Ko, Jennifer Landsberg, Felix Lehmann, Alexander Radbruch, Katjana S. Schwab, Leonie Weinhold, Johannes Weller, Christian Wispel, Ulrich Herrlinger, Hartmut Vatter, Niklas Schäfer and Patrick Schuss

Cancers 2020, 12(11), 3209; https://doi.org/10.3390/cancers12113209 - 31 Oct 2020

Cited by 20 | Viewed by 2386

Abstract

Surgical resection is a key treatment modality for brain metastasis (BM). However, peri- and postoperative adverse events (PAEs) might be associated with a detrimental impact on postoperative outcome. We retrospectively analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions [...] Read more.

Surgical resection is a key treatment modality for brain metastasis (BM). However, peri- and postoperative adverse events (PAEs) might be associated with a detrimental impact on postoperative outcome. We retrospectively analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions (HACs) and specific cranial surgery-related complications (CSCs) as high-quality metric profiles for PAEs in patients who had undergone surgery for BM in our department between 2013 and 2018. The comorbidity burden was assessed by means of the Charlson comorbidity index (CCI). A multivariate analysis was performed to identify independent predictors for the development of PAEs after surgical resection of BM. In total, 33 patients (8.5%) suffered from PAEs after surgery for BM. Of those, 17 PSI, 5 HAC and 11 CSC events were identified. Multiple brain metastases (p = 0.02) and a higher comorbidity burden (CCI > 10; p = 0.003) were associated with PAEs. In-hospital mortality of patients suffering from a PAE was significantly higher than that of patients without a PAE (24% vs. 0.6%; p < 0.0001). Awareness of risk factors for postoperative complications enables future prevention and optimal response, particularly in vulnerable oncological patients. The present study identified the presence of multiple brain metastases and increased comorbidity burden associated with PAEs in patients suffering from BM. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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11 pages, 813 KiB

Open AccessArticle

Metabolic Parameters Influence Brain Infarction and Outcome after Resection of Brain Metastases

by Nicole Lange, Julia Urich, Melanie Barz, Kaywan Aftahy, Arthur Wagner, Lucia Albers, Stefanie Bette, Benedikt Wiestler, Martin Bretschneider, Bernhard Meyer and Jens Gempt

Cancers 2020, 12(5), 1127; https://doi.org/10.3390/cancers12051127 - 30 Apr 2020

Cited by 2 | Viewed by 2610

Abstract

Perioperative infarction in brain tumor surgery occurs in about 30–80% of cases and is strongly associated with poor patient outcomes and longer hospital stays. Risk factors contributing to postoperative brain infarction should be assessed. We retrospectively included all patients who underwent surgery for [...] Read more.

Perioperative infarction in brain tumor surgery occurs in about 30–80% of cases and is strongly associated with poor patient outcomes and longer hospital stays. Risk factors contributing to postoperative brain infarction should be assessed. We retrospectively included all patients who underwent surgery for brain metastases between January 2015 and December 2017. Hemodynamic parameters were analyzed and then correlated to postoperative infarct volume and overall survival. Of 249 patients who underwent biopsy or resection of brain metastases during that time, we included 234 consecutive patients in this study. In total, 172/249 patients showed ischemic changes in postoperative magnet resonance imaging (MRI) (73%). Independent risk factors for postoperative brain infarction were perioperative blood loss (rho 0.189, p = 0.00587), blood glucose concentration (rho 0.206, p = 0.00358), blood lactate concentration (rho 0.176; p = 0.0136) and cumulative time of reduced PaCO₂ (rho −0.142; p = 0.0445). Predictors for reduced overall survival were blood lactate (p = 0.007) and blood glucose levels (p = 0.032). Other hemodynamic parameters influenced neither infarct volume, nor overall survival. Intraoperative elevated lactate and glucose levels are independently associated with postoperative brain infarction in surgery of brain metastases. Furthermore, they might predict reduced overall survival after surgery. Blood loss during surgery also leads to more cerebral ischemic changes. Close perioperative monitoring of metabolism might reduce those complications. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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Review

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24 pages, 573 KiB

Open AccessReview

Breast Cancer Brain Metastasis—Overview of Disease State, Treatment Options and Future Perspectives

by Chikashi Watase, Sho Shiino, Tatsunori Shimoi, Emi Noguchi, Tomoya Kaneda, Yusuke Yamamoto, Kan Yonemori, Shin Takayama and Akihiko Suto

Cancers 2021, 13(5), 1078; https://doi.org/10.3390/cancers13051078 - 3 Mar 2021

Cited by 38 | Viewed by 7003

Abstract

Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major [...] Read more.

Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood–brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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22 pages, 664 KiB

Open AccessReview

Brain Metastases from Uterine Cervical and Endometrial Cancer

by Mayumi Kobayashi Kato, Yasuhito Tanase, Masaya Uno, Mitsuya Ishikawa and Tomoyasu Kato

Cancers 2021, 13(3), 519; https://doi.org/10.3390/cancers13030519 - 29 Jan 2021

Cited by 13 | Viewed by 6467

Abstract

Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and [...] Read more.

Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of BMs from CC and uterine endometrial carcinoma EC. For patients with CC, early-stage disease and poorly differentiated carcinoma lead to BMs, and elderly age, poor performance status, and multiple BMs are listed as poor prognostic factors. Advanced-stage disease and high-grade carcinoma are high-risk factors for BMs from EC, and multiple metastases and extracranial metastases, or unimodal therapies, are possibly factors indicating poor prognosis. There is no “most effective” therapy that has gained consensus for the treatment of BMs. Treatment decisions are based on clinical status, number of the metastases, tumor size, and metastases at distant organs. Surgical resection followed by adjuvant radiotherapy appears to be the best treatment approach to date. Stereotactic ablative radiation therapy has been increasingly associated with good outcomes in preserving cognitive functions. Despite treatment, patients died within 1 year after the BM diagnosis. BMs from uterine cancer remain quite rare, and the current evidence is limited; thus, further studies are needed. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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17 pages, 292 KiB

Open AccessReview

Current Multimodality Treatments against Brain Metastases from Renal Cell Carcinoma

by Yoshiyuki Matsui

Cancers 2020, 12(10), 2875; https://doi.org/10.3390/cancers12102875 - 6 Oct 2020

Cited by 18 | Viewed by 2693

Abstract

In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients’ [...] Read more.

In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients’ survival. The pivotal clinical trials of those agents usually excluded patients with brain metastasis. The incidence of brain metastasis has been increasing in the actual clinical setting because of longer control of extra-cranial disease. Brain metastasis subgroup data from the prospective and retrospective series have been gradually accumulated about the risk classification of brain metastasis and the efficacy and safety of those new agents for brain metastasis. While the local treatment against brain metastasis includes neurosurgery, stereotactic radiosurgery, and conventional whole brain radiation therapy, the technology of stereotactic radiosurgery has been especially advanced, and the combination with systemic therapy such as molecular target therapy and immune checkpoint inhibitor is considered promising. This review summarizes recent progression of multimodality treatment of brain metastasis of renal cell carcinoma from literature data and explores the future direction of the treatment. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

22 pages, 1281 KiB

Open AccessReview

Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis

by Fulvio Borella, Luca Bertero, Antonio Morrone, Alessandro Gambella, Marialuisa Bovetti, Stefano Cosma, Andrea Carosso, Dionyssios Katsaros, Silvia Gemmiti, Mario Preti, Giorgio Valabrega, Giulia Scotto, Paola Cassoni and Chiara Benedetto

Cancers 2020, 12(8), 2156; https://doi.org/10.3390/cancers12082156 - 4 Aug 2020

Cited by 34 | Viewed by 5464

Abstract

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an [...] Read more.

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (<1 year) remains largely disappointing. Hopefully, novel therapeutic avenues are being explored, like PARP inhibitors and immunotherapy, based on our improved knowledge regarding tumor biology, but further investigation is warranted. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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Other

Jump to: Research, Review

21 pages, 2484 KiB

Open AccessSystematic Review

Brain Metastases from Colorectal Cancer: A Systematic Review of the Literature and Meta-Analysis to Establish a Guideline for Daily Treatment

by Sophie Müller, Franziska Köhler, Anne Hendricks, Carolin Kastner, Kevin Börner, Johannes Diers, Johan F. Lock, Bernhard Petritsch, Christoph-Thomas Germer and Armin Wiegering

Cancers 2021, 13(4), 900; https://doi.org/10.3390/cancers13040900 - 21 Feb 2021

Cited by 27 | Viewed by 3758

Abstract

Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) [...] Read more.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words “brain”, “metastas*”, “tumor”, “colorectal”, “cancer”, and “malignancy”. In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment. Full article

(This article belongs to the Special Issue Brain Metastases (Secondary Brain Tumor))

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