Cancers

The role played by MKK3 in human cancer is controversial. MKK3 is an evolutionarily conserved protein kinase that activates in response to a variety of stimuli. Phosphorylates, specifically the p38MAPK family proteins, contribute to the regulation of a plethora of cellular processes such as proliferation, differentiation, apoptosis, invasion, and cell migration. Genes in carcinogenesis are classified as oncogenes and tumor suppressors; however, a clear distinction is not always easily made as it depends on the cell context and tissue specificity. The aim of this study is the examination of the potential contribution of MKK3 in cancer through a systematic analysis of the recent literature. The overall results reveal a complex scenario of MKK3’s involvement in cancer. The oncogenic functions of MKK3 were univocally documented in several solid tumors, such as colorectal, prostate cancer, and melanoma, while its tumor-suppressing functions were described in glioblastoma and gastric cancer. Furthermore, a dual role of MKK3 as an oncogene as well as tumor a suppressor has been described in breast, cervical, ovarian, liver, esophageal, and lung cancer. However, overall, more evidence points to its role as an oncogene in these diseases. This review indicates that the oncogenic and tumor-suppressing roles of MKK3 are strictly dependent on the tumor type and further suggests that MKK3 could represent an efficient putative molecular target that requires contextualization within a specific tumor type in order to adequately evaluate its potential effectiveness in designing novel anticancer therapies.  Full article

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future. Full article

The capacity of contrast-enhanced ultrasound (CEUS) to detect microvessel perfusion has received much attention in cancer imaging since it can be used to evaluate the enhancement patterns of the lesions during all vascular phases in real time, with higher temporal resolution as compared other imaging modalities. A rich body of literature has demonstrated the potential usefulness of CEUS in the assessment of HCC in response to both locoregional and systemic therapies. It is useful to evaluate the efficacy of ablation immediately after treatment to provide guidance for the retreatment of residual unablated tumors. In patients treated with transarterial chemoembolization (TACE), CEUS showed a high degree of concordance with computed tomography and magnetic resonance for the differentiation of responders from non-responders. Dynamic CEUS (D-CEUS) has emerged as a promising tool for the depicting changes in tumor perfusion during anti-angiogenetic treatment that can be associated with tumor response and clinical outcome. This article provides a general review of the current literature regarding the usefulness of CEUS in monitoring HCC response to therapy, highlighting the role of the procedure in different stages of the disease. Full article

Due to the development of molecular diagnostic techniques, the latest research in the diagnosis of cancer diseases, including laryngeal cancer, has been focused on the occurrence of specific types of molecular patterns, including markers expressed on cells of the immune system (e.g., PD-1, PD-L1, and CTLA-4), which may be directly or indirectly involved in the development of neoplastic diseases. Laryngeal cancer is one of the diseases that is diagnosed more often in men than in women, and many factors are involved in its development, including environmental and lifestyle factors, viral infections (e.g., HPV, HHV-1, and EBV), and disorders of the immune system. In this study, we determined the level of PD-1 receptor expression on T and B lymphocytes and their relationships based on the classification of the grade and TNM scale, in turn based on blood, tumor, and lymph node samples from patients diagnosed with laryngeal cancer. In addition, we determined the presence of EBV genetic material in the tested biological materials as well as the degree of cancer advancement and its correlation with the level of PD-1 receptor expression. The results suggested that the level of PD-1 expression on T and B lymphocytes was significantly higher in the tumor samples as compared to the lymph node samples, and their comparison with the immunophenotype results from the blood samples provided statistically significant data on changes in the incidence of individual subpopulations of T and B lymphocytes and the level of PD-1 receptor expression. The analysis of the individual parameters of the TNM scale also showed significant changes between the PD-1 expression and the tested biological material in individual subgroups of the scale. We also found that the expression of PD-1 on the CD4+ T cells from the lymph node samples caused an almost 1.5-fold increase in the risk of death. In the analyses of the presence of EBV, the highest concentration was recorded in the tumor samples, then for the lymph node samples, and followed by the blood samples. Furthermore, we showed that the presence of EBV genetic material was positively correlated with the level of PD-1 expression in the tested biological materials. Full article

This systematic review and meta-analysis aims to evaluate the prognostic and clinicopathological significance of the aberrant expression of β-catenin (assessed through the immunohistochemical loss of membrane expression, cytoplasmic and nuclear expression) in oral squamous cell carcinoma (OSCC). We searched for primary-level studies published before October-2021 through PubMed, Embase, Web of Science, Scopus, and Google Scholar, with no limitation in regard to their publication date or language. We evaluated the methodological quality and risk of bias of the studies included using the QUIPS tool, carried out meta-analyses, explored heterogeneity and their sources across subgroups and meta-regression, and conducted sensitivity and small-study effects analyses. Forty-one studies (2746 patients) met inclusion criteria. The aberrant immunohistochemical expression of β-catenin was statistically associated with poor overall survival (HR = 1.77, 95% CI = 1.20–2.60, p = 0.004), disease-free survival (HR = 2.44, 95% CI = 1.10–5.50, p = 0.03), N+ status (OR = 2.39, 95% CI = 1.68–3.40, p < 0.001), higher clinical stage (OR = 2.40, 95% CI = 1.58–3.63, p < 0.001), higher tumour size (OR = 1.76, 95% CI = 1.23–2.53, p = 0.004), and moderately-poorly differentiated OSCC (OR = 1.57, 95% CI = 1.09–2.25, p = 0.02). The loss of β-catenin in the cell membrane showed the largest effect size in most of meta-analyses (singularly for poor overall survival [HR = 2.37, 95% CI = 1.55–3.62, p < 0.001], N+ status [OR = 3.44, 95% CI = 2.40–4.93, p < 0.001] and higher clinical stage [OR = 2.51, 95% CI = 1.17–5.35, p = 0.02]). In conclusion, our findings indicate that immunohistochemical assessment of the aberrant expression of β-catenin could be incorporated as an additional and complementary routine prognostic biomarker for the assessment of patients with OSCC. Full article

Background: Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For patients with advanced solid tumors, the integration of early palliative care (EPC) with standard oncologic care a few weeks after diagnosis has demonstrated several benefits. However, this model is underutilized in patients with hematologic malignancies. Methods: In this article, we analyze the palliative care (PC) needs of AML patients, examine the operational aspects of an integrated model, and review the evidence in favor of EPC integration in the AML course. Results: AML patients have a high burden of physical and psychological symptoms and high use of avoidant coping strategies. Emerging studies, including a phase III randomized controlled trial, have reported that EPC is feasible for inpatients and outpatients, improves quality of life (QoL), promotes adaptive coping, reduces psychological symptoms, and enhances the quality of end-of-life care. Conclusions: EPC should become the new standard of care for AML patients. However, this raises issues about the urgent development of adequate programs of education to increase timely access to PC. Full article

In head and neck squamous cell carcinoma (HNSCC) pathologic cervical lymph nodes (LN) remain important negative predictors. Current criteria for LN-classification in contrast-enhanced computed-tomography scans (contrast-CT) are shape-based; contrast-CT imagery allows extraction of additional quantitative data (“features”). The data-driven technique to extract, process, and analyze features from contrast-CTs is termed “radiomics”. Extracted features from contrast-CTs at various levels are typically redundant and correlated. Current sets of features for LN-classification are too complex for clinical application. Effective eliminative feature selection (EFS) is a crucial preprocessing step to reduce the complexity of sets identified. We aimed at exploring EFS-algorithms for their potential to identify sets of features, which were as small as feasible and yet retained as much accuracy as possible for LN-classification. In this retrospective cohort-study, which adhered to the STROBE guidelines, in total 252 LNs were classified as “non-pathologic” (n = 70), “pathologic” (n = 182) or “pathologic with extracapsular spread” (n = 52) by two experienced head-and-neck radiologists based on established criteria which served as a reference. The combination of sparse discriminant analysis and genetic optimization retained up to 90% of the classification accuracy with only 10% of the original numbers of features. From a clinical perspective, the selected features appeared plausible and potentially capable of correctly classifying LNs. Both the identified EFS-algorithm and the identified features need further exploration to assess their potential to prospectively classify LNs in HNSCC. Full article

Cutaneous sweat gland tumors are a subset of adnexal neoplasms that derive or differentiate into the sweat apparatus. Their great diversity, rarity, and complex terminology make their pathological diagnosis challenging. Recent findings have revealed a wide spectrum of oncogenic drivers, several of which are of diagnostic interest for pathologists. Most of these molecular alterations are represented by gene fusions, which are shared with other homologous neoplasms occurring in organs containing exocrine glands, such as salivary and breast glands, which show similarities to the sweat apparatus. This review aims to provide a synthesis of the most recent immunohistochemical and molecular markers used for the diagnosis of sweat gland tumors and to highlight their relationship with similar tumors in other organs. It will cover adenoid cystic carcinoma (NFIB, MYB, and MYBL1 fusion), cutaneous mixed tumor (PLAG1 fusion), cylindroma and spiradenoma and their carcinomas thereof (NF-κB activation through CYLD inactivation or ALKP1 hotspot mutation), hidradenoma and hidradenocarcinoma (MAML2 fusion), myoepithelioma (EWSR1 and FUS fusion), poroma and porocarcinoma (YAP1, MAML2, and NUTM1 fusion), secretory carcinoma (ETV6, NTRK3 fusion), tubular adenoma and syringo-cystadenoma papilliferum (HRAS and BRAF activating mutations). Sweat gland tumors for which there are no known molecular abnormalities will also be briefly discussed, as well as potential future developments. Full article

Breast cancer (BC) is one of the common malignant tumors in women and affects 1.6 million new cases globally each year. Investigators have recently found that negative emotions (NEs) and their impacts have greatly influenced the incidence and risk of BC. The present study aims to provide an association between NEs and the incidence of BC with possible risk factors. A total of 9343 studies were screened; nine studies met all inclusion criteria that were considered for the meta-analysis. The qualitative studies were measured by the Newcastle-Ottawa Scale; the observational studies were included with relative risks (RR) and corresponding 95% confidence intervals (CI). Besides the NEs and BC, the possible risk factors were evaluated. We analyzed data from 129,621 women diagnosed with NEs of which 2080 women were diagnosed with BC and their follow-up year ranges were from 4–24 years. NEs were significantly (p < 0.0001) associated with a higher incidence of BC with RR = 1.59, 95% CI:1.15–2.19, with other high-risk factors including, geographical distribution, emotion types, standard diagnosis of NEs, and follow-up duration. This study suggests that NEs significantly increase the risk for the incidence of BC, which can be supportive of the prognosis of the disease. Full article

Epigenetic therapies remain a promising, but still not widely used, approach in the management of patients with cancer. To date, the efficacy and use of epigenetic therapies has been demonstrated primarily in the management of haematological malignancies, with limited supportive data in solid malignancies. The most studied epigenetic therapies in breast cancer are those that target DNA methylation and histone modification; however, none have been approved for routine clinical use. The majority of pre-clinical and clinical studies have focused on triple negative breast cancer (TNBC) and hormone-receptor positive breast cancer. Even though the use of epigenetic therapies alone in the treatment of breast cancer has not shown significant clinical benefit, these therapies show most promise in use in combinations with other treatments. With improving technologies available to study the epigenetic landscape in cancer, novel epigenetic alterations are increasingly being identified as potential biomarkers of response to conventional and epigenetic therapies. In this review, we describe epigenetic targets and potential epigenetic biomarkers in breast cancer, with a focus on clinical trials of epigenetic therapies. We describe alterations to the epigenetic landscape in breast cancer and in treatment resistance, highlighting mechanisms and potential targets for epigenetic therapies. We provide an updated review on epigenetic therapies in the pre-clinical and clinical setting in breast cancer, with a focus on potential real-world applications. Finally, we report on the potential value of epigenetic biomarkers in diagnosis, prognosis and prediction of response to therapy, to guide and inform the clinical management of breast cancer patients. Full article

Objective interpretation of FC results may still be hampered by limited technical standardization. The EuroFlow consortium conducted a series of experiments to determine the impact of different variables on the relative distribution and the median fluorescence intensity (MFI) of markers stained on different cell populations, from both healthy donors and patients’ samples with distinct hematological malignancies. The use of different anticoagulants; the time interval between sample collection, preparation, and acquisition; pH of washing buffers; and the use of cell surface membrane-only (SM) vs. cell surface plus intracytoplasmic (SM+CY) staining protocols, were evaluated. Our results showed that only monocytes were represented at higher percentages in EDTA- vs. heparin-anticoagulated samples. Application of SM or SM+CY protocols resulted in slight differences in the percentage of neutrophils and debris determined only with particular antibody combinations. In turn, storage of samples for 24 h at RT was associated with greater percentage of debris and cell doublets when the plasma cell disorder panel was used. Furthermore, 24 h storage of stained cells at RT was selectively detrimental for MFI levels of CD19 and CD45 on mature B- and T-cells (but not on leukemic blasts, clonal B- and plasma cells, neutrophils, and NK cells). The obtained results showed that the variables evaluated might need to be tailored for sample and cell type(s) as well as to the specific markers compared; however, defining of well-balanced boundaries for storage time, staining-to-acquisition delay, and pH of washing buffer would be a valid recommendation for most applications and circumstances described herein. Full article

Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common malignancy worldwide, with approximately 25–40% of the diagnosed patients older than 70 years. HNSCC patients are often frail and frequently have multiple comorbidities due to their unhealthy lifestyle, and evidence suggests that older patients may receive less aggressive and suboptimal treatment than younger patients with the same disease status. The aim of this review is to depict and summarize the evidence regarding the different strategies that can be used in the clinical management of elderly HNSCC patients. Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. This paper contains a narrative report and a critical discussion of clinical approaches in the context of elderly HNSCC. Full article

Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival. Full article

Background: Our purpose was to investigate the potential of high-resolution, high b-value computed DWI (cDWI) in pancreatic ductal adenocarcinoma (PDAC) detection. Materials and Methods: We retrospectively enrolled 44 patients with confirmed PDAC. Respiratory-triggered, diffusion-weighted, single-shot echo-planar imaging (ss-EPI) with both conventional (i.e., full field-of-view, 3 × 3 × 4 mm voxel size, b = 0, 50, 300, 600 s/mm²) and high-resolution (i.e., reduced field-of-view, 2.5 × 2.5 × 3 mm voxel size, b = 0, 50, 300, 600, 1000 s/mm²) imaging was performed for suspected PDAC. cDWI datasets at b = 1000 s/mm² were generated for the conventional and high-resolution datasets. Three radiologists were asked to subjectively rate (on a Likert scale of 1–4) the following metrics: image quality, lesion detection and delineation, and lesion-to-pancreas intensity relation. Furthermore, the following quantitative image parameters were assessed: apparent signal-to-noise ratio (aSNR), contrast-to-noise ratio (aCNR), and lesion-to-pancreas contrast ratio (CR). Results: High-resolution, high b-value computed DWI (r-cDWI1000) enabled significant improvement in lesion detection and a higher incidence of a high lesion-to-pancreas intensity relation (type 1, clear hyperintense) compared to conventional high b-value computed and high-resolution high b-value acquired DWI (f-cDWI1000 and r-aDWI1000, respectively). Image quality was rated inferior in the r-cDWI1000 datasets compared to r-aDWI1000. Furthermore, the aCNR and CR were higher in the r-cDWI1000 datasets than in f-cDWI1000 and r-aDWI1000. Conclusion: High-resolution, high b-value computed DWI provides significantly better visualization of PDAC compared to the conventional high b-value computed and high-resolution high b-value images acquired by DWI. Full article

Background and aims: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk. Methods: We retrieved nationwide data from Sweden’s 28 pathology departments on all adults (age 20–79) with pathology-confirmed GBD diagnosed in 1965–2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. Results: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08–1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41–2.27) for adenoma, and 2.07 (95% CI = 1.52–2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10–15 years after start of follow-up. Conclusions: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11–16 years after GBD diagnosis. Full article

In breast cancer, the promising efficacy of farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical Phase II–III trials. The objective of this study was to explore the clinical relevance of farnesyltransferase β-subunit (FNTB) single nucleotide promoter polymorphisms (FNTB-173 6G > 5G (rs3215788), -609 G > C (rs11623866) and -179 T > A (rs192403314)) in early breast cancer. FNTB genotyping was performed by pyrosequencing in 797 patients from a prospective multicentre observational PiA trial (NCT 01592825). In the total cohort, the FNTB-173 6G > 5G polymorphism was an independent predictor of RFI (HR = 0.568; 95% CI = 0.339–0.949, p = 0.031), OS (HR = 0.629; 95% CI = 0.403–0.980, p = 0.040) and BCSS (HR = 0.433; 95% CI = 0.213–0.882; p = 0.021), whereas the FNTB-609 G > C polymorphism was an independent predictor of RFI (HR = 0.453; 95% CI = 0.226–0.910, p = 0.026) and BCSS (HR = 0.227; 95% CI = 0.075–0.687, p = 0.009). Subtype analysis revealed the independent prognostic relevance of FNTB promoter polymorphisms, particularly in TNBC but not in luminal or HER2-positive intrinsic subtypes. Finally, we used electrophoretic mobility shift assays (EMSAs) to confirm in vitro that the polymorphism FNTB-173 6G > 5G resulted in the differential binding of nuclear proteins from five different breast cancer cell lines. This is the first study on breast cancer suggesting that FNTB promoter polymorphisms (i) are independent prognostic biomarkers, particularly in patients with early TNBC, and (ii) could modulate FNTB’s transcriptional activity. Full article

Adrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials. Full article

The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL’s functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL’s role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases. Full article

Background: Stereotactic radiosurgery (SRS) is a well-established treatment modality for brain metastases (BM). Given the manifold implications of metastatic cancer on the body, affected patients have an increased risk of comorbidities, such as atrial fibrillation (AF) and venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep-vein thrombosis (DVT). These may require therapeutic anticoagulant therapy (ACT). Limited data are available on the risk of intracranial hemorrhage (ICH) after SRS for patients with BM who are receiving ACT. This bi-institutional analysis aimed to describe the bleeding risk for this patient subgroup. Methods: Patients with ACT at the time of single-fraction SRS for BM from two institutions were eligible for analysis. The cumulative incidence of ICH with death as a competing event was assessed during follow-up with magnetic resonance imaging or computed tomography. Results: Forty-one patients with 97 BM were included in the analyses. The median follow-up was 8.2 months (range: 1.7–77.5 months). The median and mean BM volumes were 0.47 and 1.19 cubic centimeters, respectively. The most common reasons for ACT were PE (41%), AF (34%), and DVT (7%). The ACT was mostly performed utilizing phenprocoumon (37%), novel oral anticoagulants (32%), or low-molecular-weight heparin (20%). Nine BM from a group of five patients with ICH after SRS were identified: none of them caused neurological or any other deficits. The 6-, 12-, and 18-month cumulative bleeding incidences per metastasis were 2.1%, 12.4%, and 12.4%, respectively. The metastases with previous bleeding events and those originating from malignant melanomas were found to more frequently demonstrate ICH after SRS (p = 0.02, p = 0.01). No surgical or medical intervention was necessary for ICH management, and no observed death was associated with an ICH. Conclusion: Patients receiving an ACT and single-fraction SRS for small- to medium-sized BM did not seem to have a clinically relevant risk of ICH. Previous bleeding and metastases originating from a malignant melanoma may favor bleeding events after SRS. Further studies are needed to validate our reported findings. Full article