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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 15367

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Dr. Kenichiro Kakutani

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Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650‑0017, Japan
Interests: metastasis reconstruction; spine surgery; rehabilitation
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Dr. Yutaro Kanda

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Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Interests: bone metastases; spinal metastases; spine tumor surgery; minimally invasive surgery; intervertebral disc degeneration
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Special Issue Information

Dear Colleagues,

The incidence and prevalence of bone metastases have been rising because cancer-carrying patients have a longer life expectancy owing to recent advances in treatment and diagnosis. Bone metastases can cause pathological fractures, spinal cord compression, and hypercalcemia, leading to serious symptoms including neurological dysfunction and intractable pain. The spine is the most common site of bone metastases, and these symptoms impair the health status and quality of life of patients, the addressal of which is the goal of multidisciplinary treatment for bone and spine metastases. However, there is still room for improvement in the treatment of bone and spine metastases. Further research on surgery, radiotherapy, and systemic treatment, including anti-tumor drugs, molecular targeted drugs, and bone‐modifying agents, is warranted. Additionally, it is extremely valuable to understand the biology of bone metastases and to develop new treatments with fewer and/or less-severe side effects. The goal of this Special Issue is to improve clinical outcomes and propose a new strategy for bone and spine metastases.

You may choose our Joint Special Issue in JCM.

Dr. Kenichiro Kakutani
Dr. Yutaro Kanda
Guest Editors

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Keywords

bone metastases
spinal metastases
stereotactic body radiotherapy
conventional radiotherapy
spine surgery
spondylectomy
minimally invasive surgery
particle-beam radiotherapy
systemic agents
microenvironment

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Published Papers (9 papers)

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22 pages, 3136 KiB

Open AccessArticle

GATA3-Driven ceRNA Network in Lung Adenocarcinoma Bone Metastasis Progression and Therapeutic Implications

by Yun Liu, Shihui Shen, Xudong Wang, Hansen Chen, Wenjie Ren, Haifeng Wei, Kun Li and Lei Li

Cancers 2025, 17(3), 559; https://doi.org/10.3390/cancers17030559 - 6 Feb 2025

Cited by 2 | Viewed by 1107

Abstract

Background/Objectives: Bone metastasis is a common and severe complication of lung adenocarcinoma (LUAD), impacting prognosis and treatment outcomes. Understanding the molecular mechanisms behind LUAD bone metastasis (LUADBM) is essential for developing new therapeutic strategies. The interactions between long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in the competing endogenous RNA (ceRNA) network are crucial in cancer progression and metastasis, but the regulatory mechanisms in LUADBM remain unclear. Methods: Microarray analysis was performed on clinical samples, followed by weighted gene co-expression network analysis (WGCNA) and construction of a ceRNA network. Molecular mechanisms were validated using colony formation assays, transwell migration assays, wound healing assays to assess cell migration, and osteoclastogenesis assays to evaluate osteoclast differentiation. Potential therapeutic drugs and their binding affinities were predicted using the CMap database and K_deep. The interaction between the small-molecule drug and its target protein was confirmed by surface plasmon resonance (SPR) and drug affinity responsive target stability (DARTS) assays. Mechanistic insights and therapeutic efficacy were further validated using patient-derived organoid (PDO) cultures, drug sensitivity assays, and in vivo drug treatments. Results: Our results identified the XLOC_006941/hsa-miR-543/NPRL3 axis as a key regulatory pathway in LUADBM. We also demonstrated that GATA3-driven Th2 cell infiltration creates an immunosuppressive microenvironment that promotes metastasis. Additionally, we confirmed that the inhibitor E7449 effectively targets NPRL3, and its combination with the IL4R-blocking antibody dupilumab resulted in improved therapeutic outcomes in LUADBM. Conclusions: These findings offer new insights into the molecular mechanisms of LUADBM and highlight potential therapeutic targets, including the XLOC_006941/miR-543/NPRL3 axis and GATA3-driven Th2 cell infiltration. The dual-target therapy combining E7449 with dupilumab shows promise for improving patient outcomes in LUADBM, warranting further clinical evaluation. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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12 pages, 1439 KiB

Open AccessArticle

Radiotherapy with 15 × 2.633 Gy vs. 20 × 2.0 Gy in Patients with Malignant Spinal Cord Compression and Favorable Survival Prognoses: A Secondary Analysis of the RAMSES-01 Trial

by Dirk Rades, Darejan Lomidze, Natalia Jankarashvili, Fernando Lopez Campos, Arturo Navarro-Martin, Barbara Segedin, Blaz Groselj, Christian Staackmann, Nathan Y. Yu and Jon Cacicedo

Cancers 2024, 16(20), 3436; https://doi.org/10.3390/cancers16203436 - 10 Oct 2024

Cited by 1 | Viewed by 708

Abstract

Many patients with malignant spinal cord compression (MSCC) who are not candidates for neurosurgery receive radiotherapy alone. This study compared 15 × 2.633 Gy over three weeks to 20 × 2.0 Gy over four weeks in patients with favorable survival prognoses. The outcomes of 34 patients treated with 15 × 2.633 Gy (equivalent dose 41.6 Gy₁₀) in the RAMSES-01 trial were compared to 239 patients from an existing database receiving 20 × 2.0 Gy using propensity-score-adjusted Cox and logistic regression models. All patients had favorable survival prognoses. Endpoints included local progression-free survival (LPFS), improvement of motor function, post-treatment ambulatory status, and overall survival (OS). After propensity score adjustment, the 12-month rates of LPFS and OS were 98.1% (RAMSES-01 cohort) vs. 91.6% (p = 0.265) and 79.1% vs. 82.2% (p = 0.704), respectively. Regarding improvement of motor function, 15 × 2.633 Gy appeared superior (p = 0.073). No significant difference was observed regarding ambulatory status (p = 0.822). The three-week regimen for MSCC has similar outcomes and reduces treatment time when compared to a four-week regimen. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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16 pages, 1534 KiB

Open AccessArticle

Surgical Interventions Following Radiotherapy in Spinal Metastases with Intermediate Instability: A Risk Factor Analysis: The Korean Society of Spinal Tumor Multicenter Study (KSST 2022-02)

by Se-Jun Park, Jin Ho Kim, Yong Chan Ahn, Woong Sub Koom, Hwa Kyung Byun, Young-Hoon Kim, Sang-Il Kim, Dong-Ho Kang and on behalf of the Korean Society of Spinal Tumor

Cancers 2024, 16(14), 2554; https://doi.org/10.3390/cancers16142554 - 16 Jul 2024

Viewed by 1240

Abstract

Background: One important determinant in choosing a treatment modality is spinal instability. Clear management guidelines are suggested for stable and unstable spinal metastatic lesions, but lesions in the intermediate instability category (SINS [spinal instability neoplastic score] score of 7–12) remain a clinical dilemma. This study aims to analyze the risk factors necessitating surgical intervention after radiotherapy (RT) in patients with those lesions. Methods: A multicenter cohort of 469 patients with spinal metastases of intermediate instability who received radiotherapy (RT) as the initial treatment between 2019 and 2021 were retrospectively enrolled. All patients were neurologically intact at the time of RT. According to the performance of surgical intervention after RT, various clinical and radiographic risk factors for surgical intervention were compared between surgery and non-surgery groups using uni- and multivariate analyses. A recursive partitioning analysis (RPA) was performed using significant determinants identified in multivariate analysis. Results: The mean age at the time of RT was 59.9 years and there were 198 females. The lung was the most common primary site. During the mean follow-up duration of 18.2 months, surgical treatment was required in 79 (17.9%) of patients. The most common surgical method was decompressive laminectomy with stabilization (62.0%), followed by vertebrectomy with stabilization (22.8%) and stabilization only (15.2%). The mean SINS for the total cohort was 9.0. Multivariate regression analyses revealed that the primary tumor site of the lung, liver, and kidney, higher Bilsky grades of ESCC, lytic bone lesions, and higher EQD2₁₀ were significant risk factors for surgical intervention after RT. Among them, Bilsky grade, primary tumor type of the lung, liver, and kidney, and EQD2₁₀ were the most important determinants for expecting the probability of surgical intervention on RPA. Conclusions: Surgical intervention was performed in 17.9% of patients with intermediate instability after RT as the initial treatment. The primary tumor site of the lung, liver, and kidney, higher Bilsky grade of ESCC, and EQD210 were the most important determinants for expecting the probability of surgical intervention. Therefore, the optimal treatment strategy needs to be devised by carefully evaluating the risk of surgical intervention. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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12 pages, 2166 KiB

Open AccessArticle

Outcomes in Patients with Spinal Metastases Managed with Surgical Intervention

by Brendan Knapp, Ashwin Govindan, Shalin S. Patel, Kymberlie Pepin, Ningying Wu, Siddhartha Devarakonda and Jacob M. Buchowski

Cancers 2024, 16(2), 438; https://doi.org/10.3390/cancers16020438 - 19 Jan 2024

Cited by 6 | Viewed by 1969

Abstract

Background: Spinal metastases are a significant cause of morbidity in patients with advanced cancer, and management often requires surgical intervention. Although prior studies have identified factors that influence outcomes with surgery, the ability of these factors to predict outcomes remains unclear in the era of contemporary therapies, and there is a need to better identify patients who are likely to benefit from surgery. Methods: We performed a single-center, retrospective analysis to evaluate risk factors for poor outcomes in patients with spinal metastases treated with surgery. The primary outcome was mortality at 180 days. Results: A total of 128 patients were identified. Age ≥ 65 years at surgery (p = 0.0316), presence of extraspinal metastases (p = 0.0110), and ECOG performance scores >1 (p = 0.0397) were associated with mortality at 180 days on multivariate analysis. These factors and BMI ≤ 30 mg/kg² (p = 0.0008) were also associated with worse overall survival. Conclusions: Age > 65, extraspinal metastases, and performance status scores >1 are factors associated with mortality at 180 days in patients with spinal metastases treated with surgery. Patients with these factors and BMI ≤ 30 mg/kg² had worse overall survival. Our results support multidisciplinary discussions regarding the benefits and risks associated with surgery in patients with these risk factors. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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19 pages, 3866 KiB

Open AccessArticle

A Novel Metastatic Estrogen Receptor-Expressing Breast Cancer Model with Antiestrogen Responsiveness

by Kendall L. Langsten, Lihong Shi, Adam S. Wilson, Salvatore Lumia, Brian Westwood, Alexandra M. Skeen, Maria T. Xie, Victoria E. Surratt, JoLyn Turner, Carl D. Langefeld, Ravi Singh, Katherine L. Cook and Bethany A. Kerr

Cancers 2023, 15(24), 5773; https://doi.org/10.3390/cancers15245773 - 9 Dec 2023

Cited by 1 | Viewed by 2104

Abstract

Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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15 pages, 1800 KiB

Open AccessArticle

Efficacy of Total En Bloc Spondylectomy versus Stereotactic Ablative Radiotherapy for Single Spinal Metastasis

by Dong-Ho Kang, Wooseok Lee, Bong-Soon Chang, Hyoungmin Kim, Sam Yeol Chang, Seong Hwa Hong, Jin Ho Kim and Hee Jung Son

Cancers 2023, 15(23), 5518; https://doi.org/10.3390/cancers15235518 - 22 Nov 2023

Cited by 2 | Viewed by 1487

Abstract

To compare total en bloc spondylectomy (TES) with stereotactic ablative radiotherapy (SABR) for single spinal metastasis, we undertook a single center retrospective study. We identified patients who had undergone TES or SABR for a single spinal metastasis between 2000 and 2019. Medical records and images were reviewed for patient and tumor characteristics, and oncologic outcomes. Patients who received TES were matched to those who received SABR to compare local control and survival. A total of 89 patients were identified, of whom 20 and 69 received TES and SABR, respectively. A total of 38 matched patients were analyzed (19 TES and 19 SABR). The median follow-up period was 54.4 (TES) and 26.1 months (SABR) for matched patients. Two-year progression-free survival (PFS) and overall survival (OS) rates were 66.7% and 72.2% in the TES and 38.9% and 50.7% in the SABR group, respectively. At the final follow-up of the matched cohorts, no significant differences were noted in OS (p = 0.554), PFS (p = 0.345) or local progression (p = 0.133). The rate of major complications was higher in the TES than in the SABR group (21.1% vs. 10.5%, p = 0.660). These findings suggest that SABR leads to fewer complications compared to TES, while TES exhibits better mid-term control of metastatic tumors. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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18 pages, 2639 KiB

Open AccessSystematic Review

Evaluating the Accuracy and Efficiency of Imaging Modalities in Guiding Ablation for Metastatic Spinal Column Tumors: A Systematic Review

by Siran Aslan, Mohammad Walid Al-Smadi, Murtadha Qais Al-Khafaji, András Gati, Mustafa Qais Al-Khafaji, Réka Viola, Yousif Qais Al-Khafaji, Ákos Viola, Thaer Alnofal and Árpád Viola

Cancers 2024, 16(23), 3946; https://doi.org/10.3390/cancers16233946 - 25 Nov 2024

Cited by 2 | Viewed by 1082

Abstract

Background/Objectives: Spinal metastases are a frequent and serious complication in cancer patients, often causing severe pain, instability, and neurological deficits. Thermal ablation techniques such as radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation (CA) have emerged as minimally invasive treatments. These techniques rely on precise imaging guidance to effectively target lesions while minimizing complications. This systematic review aims to compare the efficacy of different imaging modalities—computed tomography (CT), magnetic resonance imaging (MRI), fluoroscopy, and mixed techniques—in guiding thermal ablation for spinal metastases, focusing on success rates and complications. Methods: A systematic literature search was conducted across PubMed, OVID, Google Scholar, and Web of Science databases, yielding 3733 studies. After screening, 51 studies met the eligibility criteria. Data on success rates, tumor recurrence, complications, and patient outcomes were extracted. Success was defined as no procedure-related mortality, tumor recurrence or expansion, or nerve injury. This systematic review followed PRISMA guidelines and was registered with PROSPERO (ID: CRD42024567174). Results: CT-guided thermal ablation demonstrated high success rates, especially with RFA (75% complete success). Although less frequently employed, MRI guidance showed lower complication rates and improved soft-tissue contrast. Fluoroscopy-guided procedures were effective but had a higher incidence of nerve injury and incomplete tumor control. Mixed imaging techniques, such as CBCT-MRI fusion, showed potential for reducing complications and improving targeting accuracy. Conclusions: CT remains the most reliable imaging modality for guiding thermal ablation in spinal metastases, while MRI provides enhanced safety in complex cases. Fluoroscopy, although effective for real-time guidance, presents limitations in soft-tissue contrast. Mixed imaging techniques like CBCT-MRI fusion offer promising solutions by combining the advantages of both CT and MRI, warranting further exploration in future studies. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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18 pages, 2076 KiB

Open AccessSystematic Review

The Impact of Adjunct Medical Therapy on Survival after Spine Metastasis: A Systematic Review and Pooled Data Analysis

by Lilly Groszman, Jonathan A. Hubermann, Paul Kooner, Nawaf Alamiri, Anthony Bozzo and Ahmed Aoude

Cancers 2024, 16(7), 1425; https://doi.org/10.3390/cancers16071425 - 7 Apr 2024

Cited by 1 | Viewed by 2251

Abstract

Targeted therapy has greatly improved the outlook for patients with spinal metastatic cancers. Scoring systems like the Tokuhashi or Tomita scores are commonly used to predict prognosis and inform surgical decisions, but they are outdated and fail to consider recent advancements. We aimed to investigate the current state of the literature and treatment options pertaining to advancements in targeted therapy compared to other forms of medical management for metastatic spinal tumors. This study represents the first comprehensive systematic review that encompasses the most common primary cancers that metastasize to the spine and evaluates the median overall survival (mOS) across five different medical treatment modalities as well as surgical intervention. Additionally, our study analyzes the tumor receptor status in conjunction with these treatments. A PubMed search was conducted, and according to the PRISMA guidelines, 28 articles out of 1834 met the inclusion criteria. The pooled data analysis highlighted the superior efficacy of targeted therapy, evidenced by a significant improvement in the mOS and lower hazard ratios in patients with lung and breast cancers who received targeted therapy compared to those who did not. Our study provides valuable insights into the recent advancements in the medical management of metastatic spinal tumors. Future indications include incorporating this literature into personalized treatment approaches for metastatic spinal tumors. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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14 pages, 685 KiB

Open AccessSystematic Review

Leiomyogenic Tumor of the Spine: A Systematic Review

by Abdurrahman F. Kharbat, Kishore Balasubramanian, Kiran Sankarappan, Ryan D. Morgan, Khawaja M. Hassan, Paolo Palmisciano, Panayiotis E. Pelargos, Michael Chukwu, Othman Bin Alamer, Ali S. Haider, Tarek Y. El Ahmadieh and John F. Burke

Cancers 2024, 16(4), 748; https://doi.org/10.3390/cancers16040748 - 10 Feb 2024

Cited by 1 | Viewed by 2445

Abstract

The study cohort consisted of 83 patients with a mean age of 49.55 (SD 13.72) with a female preponderance (60 patients). Here, 32.14% of patients had primary LTS; the remaining were metastases. Clinical presentation included nonspecific back pain (57.83%), weakness (21.69%) and radicular pain (18.07%). History of uterine neoplasia was found in 33.73% of patients. LTS preferentially affected the thoracic spine (51.81%), followed by the lumbar (21.67%) spine. MRI alone was the most common imaging modality (33.33%); in other cases, it was used with CT (22.92%) or X-ray (16.67%); 19.23% of patients had Resection/Fixation, 15.38% had Total en bloc spondylectomy, and 10.26% had Corpectomy. A minority of patients had laminectomy and decompression. Among those with resection, 45.83% had a gross total resection, 29.17% had a subtotal resection, and 16.67% had a near total resection. Immunohistochemistry demonstrated positivity for actin (43.37%), desmin (31.33%), and Ki67 (25.30). At a follow-up of 19.3 months, 61.97% of patients were alive; 26.25% of 80 patients received no additional treatment, 23.75% received combination radiotherapy and chemotherapy, only chemotherapy was given to 20%, and radiotherapy was given to 17.5%. Few (2.5%) had further resection. For an average of 12.50 months, 42.31% had no symptoms, while others had residual (19.23%), other metastasis (15.38%), and pain (7.69%). On follow-up of 29 patients, most (68.97%) had resolved symptoms; 61.97% of the 71 patients followed were alive. Full article

(This article belongs to the Special Issue Bone and Spine Metastases)

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