The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant" for this intriguing group.

The TNM classification of malignant tumours is a mainstay tool in clinical practice and research for prognostic assessment of patients, treatment allocation and trial enrolment, as well as for epidemiological studies and data collection by cancer registries worldwide. Pathological TNM (pTNM) represents the pathological classification of a tumor, assigned after surgical resection or adequate sampling by biopsy, and periodical updates to the relative classification criteria are necessary to preserve its clinical relevance by integrating newly reported data. A structured approach has been put in place to fulfil this need and, based upon this process, the Eighth Edition of Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours has been published, introducing many significant changes, including novel classification criteria for specific tumour types. In this review, we aim to describe the major changes introduced in the pTNM classification criteria and to summarize the evidence supporting these changes.

BackgroundTERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.MethodsWe applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.ResultsTERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.ConclusionsTERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.Trial registration numberPROSPERO: CRD42018110566.

This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy.

The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.

Typical (TCs) and atypical carcinoids (ACs) are defined based on morphological criteria, and no grading system is currently accepted to further stratify these entities. The 2015 WHO classification restricts the Ki-67 role to biopsy or cytology samples, rather than for prognostic prediction. We aimed to investigate whether values and patterns of Ki-67 alone would allow for a clinically meaningful stratification of lung carcinoids, regardless of histological typing. Ki-67 proliferation index and pattern (homogeneous versus heterogeneous expression) were assessed in a cohort of 171 TCs and 68 ACs. Cases were subdivided into three Ki-67 ranges (<4/4–9/≥10%). Correlations with clinicopathological data, univariate and multivariate survival analyses were performed. The majority of cases (61.5%) belonged to the <4% Ki-67 range; 25.1 and 13.4% had a proliferation index of 4–9% and ≥10%, respectively. The <4% Ki-67 subgroup was significantly enriched for TCs (83%, p < 0.0001); ACs were more frequent in the subgroup showing Ki-67 ≥ 10% (75%, p < 0.0001). A heterogeneous Ki-67 pattern was preferentially seen in carcinoids with a Ki-67 ≥10% (38%, p < 0.02). Mean Ki-67 values ≥4 and ≥10% identified categories of poor prognosis both in terms of disease-free and overall survival (p = 0.003 and <0.0001). At multivariate analysis, the two thresholds did not retain statistical significance; however, a Ki-67 ≥ 10% identified a subgroup of dismal prognosis even within ACs (p = 0.03) at univariate analysis. Here, we describe a subgroup of lung carcinoids showing brisk proliferation activity within the necrosis and/or mitotic count-based categories. These patients were associated with specific clinicopathological characteristics, to some extent regardless of histological subtyping.

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6 % (95 % CI 29.3–55.2) and a median PFS of 5.2 months (95 % CI 3.8–6.6). The median OS was 9.1 months (95 % CI 7.3–10.3). Twenty-eight patients (52 %) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60 %). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76 %), while the diffuse non-enhancing progression accounted for 9.5 %. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22 %) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4 %) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.