Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here, we dissect the heterogeneity in metastasis-associated astrocytes using single-cell RNA sequencing and report a population that blocks the antitumoral activity of infiltrating T cells. This protumoral activity is mediated by the secretion of tissue inhibitor of metalloproteinase-1 (TIMP1) from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of tissue inhibitor of metalloproteinase-1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications. Significance: This study presents a significant advancement in understanding immune modulation in brain tumors and offers new insights into the potential therapeutic interventions for brain metastases. See related commentary by Lorger and James, p. 11

MDM2 amplification represents the leading oncogenic pathway and diagnostic hallmark of liposarcoma, whose assessment is based on Fluorescence In Situ Hybridization (FISH) analysis. Despite its diagnostic relevance, no univocal interpretation criteria regarding FISH assessments of MDM2 amplification have been established so far, leading to several different approaches and potential diagnostic misinterpretations. This study aims to address the most common issues and proposes troubleshooting guidelines for MDM2 amplification assessments by FISH. We retrospectively retrieved 51 liposarcomas, 25 Lipomas, 5 Spindle Cell Lipoma/Pleomorphic Lipomas, and 2 Atypical Spindle Cell Lipomatous Tumors and the corresponding MDM2 FISH analysis. We observed MDM2 amplification in liposarcomas cases only (43 out of 51 cases) and identified three MDM2-amplified patterns (scattered (50% of cases), clustered (14% of cases), and mixed (36% of cases)) and two nonamplified patterns (low number of signals (82% of cases) and polysomic (18% of cases)). Based on these data and published evidence in the literature, we propose a set of criteria to guide MDM2 amplification analysis in liposarcoma. Kindled by the compelling importance of MDM2 assessments to improve diagnostic and therapeutic liposarcoma management, these suggestions could represent the first step to develop a univocal interpretation model and consensus guidelines.

The present review focuses on the function of the forkhead protein FOXA1 in breast cancer (BC) in relation to steroid hormone receptors. We explored the currently available analytic approaches for FOXA1 assessment both at gene and protein levels, comparing the differences between the available techniques used for its diagnostic assessment. In addition, we elaborated on data regarding the prognostic and predictive role of this marker in BC based on several studies that evaluated its expression in relation to the outcome and/or response to therapy. FOXA1, similar to the androgen receptor (AR), may have a dual role in BC according to hormonal status. In luminal cancers, its expression contributes to a better prognosis, while in triple-negative breast cancers (TNBC), it implies an adverse outcome. Consequently, we observed that FOXA1-positive expression in a neoadjuvant setting may predict a lack of response in luminal BC as opposed to TNBC, in which FOXA1 allegedly increases its chemosensitivity. In conclusion, considering its accessible and convenient identification by immunohistochemistry, its important impact on prognosis, and its suitability to identify patients with different responses to chemotherapy, we propose that FOXA1 could be tested in routine diagnostics as an additional prognostic and predictive marker in BC.

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.

Brain metastases (BMs) represent the most frequent metastatic event in the course of lung cancer patients, occurring in approximately 50% of patients with non-small-cell lung cancer (NSCLC) and in up to 70% in patients with small-cell lung cancer (SCLC). Thus far, many advances have been made in the diagnostic and therapeutic procedures, allowing improvements in the prognosis of these patients. The modern approach relies on the integration of several factors, such as accurate histological and molecular profiling, comprehensive assessment of clinical parameters and precise definition of the extent of intracranial and extracranial disease involvement. The combination of these factors is pivotal to guide the multidisciplinary discussion and to offer the most appropriate treatment to these patients based on a personalized approach. Focal radiotherapy (RT), in all its modalities (radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), adjuvant stereotactic radiotherapy (aSRT)), is the cornerstone of BM management, either alone or in combination with surgery and systemic therapies. We review the modern therapeutic strategies available to treat lung cancer patients with brain involvement. This includes an accurate review of the different technical solutions which can be exploited to provide a “state-of-art” focal RT and also a detailed description of the systemic agents available as effective alternatives to SRS/SRT when a targetable molecular driver is present. In addition to the validated treatment options, we also discuss the future perspective for focal RT, based on emerging clinical reports (e.g., SRS for patients with many BMs from NSCLC or SRS for BMs from SCLC), together with a presentation of innovative and promising findings in translational research and the combination of novel targeted agents with SRS/SRT.

Aims: The current criteria for surgical treatment after endoscopic resection of a pT1 colorectal carcinoma (CRC) are unsatisfactory because nodal involvement is rarely present. This study investigates the correlation between PD‐L1 expression and nodal metastasis in pT1 CRCs to enable its use for tailoring surgical treatment after endoscopic removal.Methods and results: Histopathological features of 81 surgically resected pT1 CRC, 19 metastatic and 62 non‐metastatic cases were assessed. PD‐L1 expression was evaluated by immunohistochemistry (clone 22C3) and independently assessed by two pathologists using tumour proportion score (TPS), combined positive score (CPS) and immune cell score (ICS). The correlation between PD‐L1 expression and nodal metastasis, the optimal cut‐off values, interobserver agreement and impact upon patients' surgical management were determined. PD‐L1 expression in terms of CPS and ICS independently correlated with lymph node metastasis (PD‐L1_CPS: OR = –2.5, 95% CI = −4.11 to −0.97, P = 0.008 and PD‐L1_ICS: OR = −1.85, 95% CI = −2.90 to −0.79, P = 0.004) and < 1.2 CPS and <1.3% ICS were identified as the optimal cut‐off values to discriminate between metastatic and non‐metastatic patients. In our cohort, the implementation of these cut‐off values would have avoided a significant rate of unnecessary surgeries in pN0 patients (PD‐L1_CPS = 43.2; PD‐L1_ICS = 51.9%). Ultimately, PD‐L1 evaluation showed good interpathologist concordance in absolute terms [PD‐L1_CPS interclass correlation coefficient (ICC) = 0.91; PD‐L1_ICS ICC = 0.793] and using the identified cut‐off values (PD‐L1_CPS ICC = 0.848; PD‐L1_ICS ICC = 0.756).Conclusions: Our study shows that PD‐L1 expression is an effective predictor of nodal status and could improve patient selection for surgery after endoscopic removal of pT1 CRCs.