Exosomes (Exos) are nano-sized extracellular vesicles constitutively released by both prokaryotic and eukaryotic cells. Their role as inter-cellular messengers involved in both physiological and pathological processes has overwhelmingly come to light in the last decade, and their contribution to cancerogenesis and tumor metastasis is under intensive investigation. Here we review the most recent information concerning Exos in colorectal cancer (CRC) and focus on their effects on tumor microenvironment and the immune system, as well as unravel their role in the formation of the pre-metastatic niche and in drug resistance. Such a recent knowledge on Exos depicts their potential translations into the clinical arena, either as an alternative tool of “liquid biopsy” or novel therapeutic approaches for CRC. However, due to the limited data available from clinical trials, they need further validations before addressing their putative application in oncology.

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.

Renal cell carcinoma (RCC) is one of primary cancers that frequently metastasize to the brain. Brain metastasis derived from RCC has the propensity of intratumoral hemorrhage and relatively massive surrounding edema. Moreover, it confers a grim prognosis in a great percentage of cases with a median overall survical (mOS) around 10 months. The well-recognized prognostic factors for brain metastatic renal cell carcinoma (BMRCC) are Karnofsky Performance Status (KPS), the number of brain metastasis (BM), the presence of a sarcomatoid component and the presence of extracranial metastasis. Therapeutic strategies are multimodal and include surgical resection, radiotherapy, such as stereotactic radiosurgery due to the radioresistance of RCC and systemic strategies with tyrosin kinase inhibitors (TKI) or Immune checkpoint inhibitors (ICI) whose efficacy is not well-established in this setting of patients due to their exclusion from most clinical trials. To date, in case of positive prognostic factors and after performing local radical therapies, such as complete resection of BM or stereotactic radiosurgery (SRS), the outcome of these patients significantly improves, up to 33 months in some patients. As a consequence, tailored clinical trials designed for BMRCC are needed to define the correct treatment strategy even in this poor prognostic subgroup of patients.

The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood–brain barrier (BBB) or brain–tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. This review aims to provide an overview of the clinical and molecular factors involved in the selection of patients for local and/or systemic therapy, as well as the results of clinical trials on advanced BC. Moreover, insight on promising therapeutic options and potential directions of future therapeutic targets against BBB and microenvironment are discussed.

Patients with leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy. In the past, some randomized clinical trials have been conducted with heterogeneous inclusion criteria, diagnostic parameters, response evaluation and primary endpoints. Efforts to develop a standardized magnetic resonance imaging (MRI) assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid (CSF) are underway. This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC, in particular the role of MRI, CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease, as well as the most recent clinical trials on targeted therapies. Targeted therapy, such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors, represent a feasible treatment with encouraging results in terms of disease control and survival. For ineligible patients, immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance, although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.

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Background: Primary pulmonary enteric adenocarcinoma (PEAC) is a rare non-small cell lung cancer subtype sharing morphologic and immunohistochemical features with colorectal adenocarcinoma. Given the frequency of lung metastases in colorectal cancer, the differential diagnosis of PEAC according to routine morphological and immunohistochemical findings may be difficult. Genome sequence by next-generation sequencing has recently introduced new perspectives to better define the diagnosis and tumor sensitivity to treatments, while the rarity of this subtype of cancer still limits the current knowledge of its molecular features and provides no information to address patients to tailored therapies. Methods: We diagnosed a rare case of subcutaneous metastasis as a first symptom of a PEAC. Formalin-fixed paraffin-embedded samples of the primary tumor and subcutaneous metastases were examined by immunohistochemistry, and subsequently by targeted next-generation sequencing analysis. Results: Morphological and immunohistochemical findings suggested a rare case of metastatic pulmonary adenocarcinoma with enteric aspects. Next-generation sequencing analysis performed on both the primary tumor sample and the cutaneous lesion identified two pathogenic variants on CDKN2A and KRAS in both of them. However, the metastasis showed two additional pathogenic mutations located in SMAD4 and FLT3 genes. Conclusions: We describe for the first time an extensive molecular analysis on a rare case of PEAC with an unusual cutaneous metastasis. Our observation suggests that a specific pattern of mutations is harbored in this neoplasm, and that additional molecular studies may provide further information to identify prognostic and hopefully predictive genes of response to treatment.

Most commonly described as sporadic, pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare variant of invasive lung cancer recently established and recognised by the World Health Organization. This tumour is highly heterogeneous and shares several morphological features with pulmonary and colorectal adenocarcinomas. Our objective is to summarise current research on PAED, focusing on its immunohistochemical and molecular features as potential tools for differential diagnosis from colorectal cancer, as well as prognosis definition and therapeutic choice. PAED exhibits an ‘entero-like’ pathological morphology in more than half cases, expressing at least one of the typical immunohistochemical markers of enteric differentiation, namely CDX2, CK20 or MUC2. For this reason, this malignancy appears often indistinguishable from a colorectal cancer metastasis, making the differential diagnosis laborious. Although standard diagnostic criteria have not been established yet, in the past few years, a number of approaches have been addressed, aimed at defining specific immunohistochemical and molecular signatures. Based on previously published literature, we have collected and analysed molecular and immunohistochemical data on this rare neoplasm, and have described the state of the art on diagnostic criteria as well as major clinical and therapeutic implications. The analysis of data from 295 patients from 58 published articles allowed us to identify the most represented immunohistochemical and molecular markers, as well as major differences between Asian PAEDs and those diagnosed in European/North American countries. The innovative molecular approaches, exploring driver mutations or new gene alterations, could help to identify rare prognostic factors and guide future tailored therapeutic approaches to this rare neoplasm.