Achievements of international rare cancers networks and consortia in the neuro-oncology field.

PURPOSE OF REVIEW: In this review, we investigated the role of European oncological networks on management and care of patients with central nervous system (CNS) malignancies. RECENT FINDINGS: Within this universe of tumors, malignancies of the central nervous system (CNS) malignancies represent a challenge because of several reasons such as biological complexity, the need of dedicated experienced physicians (surgeons, pathologists, radiologists and neuro-oncologists) and tertiary healthcare providers. Limits to the development of effective and innovative care are represented by the rarity of these tumors and their extreme heterogeneity in terms of clinical presentation, course of the disease, genetic assessments and site of presentation. The oncological networks are societies or associations, which make possible to connect patients, scientists, doctors and researchers together allowing to obtain several improvements. SUMMARY: Oncological networks can cooperate to increase accrual rate and speed in clinical trials, share data about CNS malignancy management and improve knowledge toward this class of tumors within patients and health operators promoting equity and high standard of care.

The role of adjuvant chemotherapy in patients with H3K27 altered diffuse midline gliomas: a multicentric retrospective study.

PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.

Immune-checkpoint inhibitors in pituitary malignancies.

To date, there are no standardized systemic treatment options for patients with metastatic pituitary carcinoma progressed to chemo and radiation therapy. Immune-checkpoint inhibitors (ICIs) have been successfully assessed in other solid malignancies and could be a concrete hope for these patients. We performed a critical review of the literature aimed to evaluate studies assessing ICIs in pituitary malignancies. We also conducted research about published translational data assessing immune-contexture in these malignancies. Some preliminary reports reported a successful administration of pembrolizumab or the combination between nivolumab and ipilimumab in patients with metastatic ACTH-secreting pituitary carcinomas. Translational data suggest that adenomas secreting growth hormone and ACTH have a suppressed immune-microenvironment, which could be more likely to benefit from ICIs. Immune-checkpoint inhibitors can be an effective treatment in patients with pituitary carcinoma and maybe also recurrent adenoma. Tumors secreting growth hormone and ACTH are more likely to benefit from ICIs due to a different immune-microenvironment.

Machine learning in neuro-oncology: toward novel development fields.

PURPOSE: Artificial Intelligence (AI) involves several and different techniques able to elaborate a large amount of data responding to a specific planned outcome. There are several possible applications of this technology in neuro-oncology. METHODS: We reviewed, according to PRISMA guidelines, available studies adopting AI in different fields of neuro-oncology including neuro-radiology, pathology, surgery, radiation therapy, and systemic treatments. RESULTS: Neuro-radiology presented the major number of studies assessing AI. However, this technology is being successfully tested also in other operative settings including surgery and radiation therapy. In this context, AI shows to significantly reduce resources and costs maintaining an elevated qualitative standard. Pathological diagnosis and development of novel systemic treatments are other two fields in which AI showed promising preliminary data. CONCLUSION: It is likely that AI will be quickly included in some aspects of daily clinical practice. Possible applications of these techniques are impressive and cover all aspects of neuro-oncology.

Liquid Biopsy in Glioblastoma Management: From Current Research to Future Perspectives.

Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Arising from neuroepithelial glial cells, GBM is characterized by invasive behavior, extensive angiogenesis, and genetic heterogeneity that contributes to poor prognosis and treatment failure. Currently, there are several molecular biomarkers available to aid in diagnosis, prognosis, and predicting treatment outcomes; however, all require the biopsy of tumor tissue. Nevertheless, a tissue sample from a single location has its own limitations, including the risk related to the procedure and the difficulty of obtaining longitudinal samples to monitor treatment response and to fully capture the intratumoral heterogeneity of GBM. To date, there are no biomarkers in blood or cerebrospinal fluid for detection, follow-up, or prognostication of GBM. Liquid biopsy offers an attractive and minimally invasive solution to support different stages of GBM management, assess the molecular biology of the tumor, identify early recurrence and longitudinal genomic evolution, predict both prognosis and potential resistance to chemotherapy or radiotherapy, and allow patient selection for targeted therapies. The aim of this review is to describe the current knowledge regarding the application of liquid biopsy in glioblastoma, highlighting both benefits and obstacles to translation into clinical care. IMPLICATIONS FOR PRACTICE: To translate liquid biopsy into clinical practice, further prospective studies are required with larger cohorts to increase specificity and sensitivity. With the ever-growing interest in RNA nanotechnology, microRNAs may have a therapeutic role in brain tumors.

Predictive markers of immune response in glioblastoma: hopes and facts.

Immune-checkpoint inhibitors (ICI) represent a concrete hope for patients with advanced solid tumors. Indeed, patients responding to these agents may experience a long-lasting response. Recently, results of interventional clinical trials investigated the role of ICIs in patients with glioblastoma. Results of these studies suggested that only a small percentage of these patients could benefit from these agents. Research of predictive markers assumes a critical importance to adequately select patients likely to benefit from ICIs. Molecular and clinical variables associated to tumors and patients have been evaluated as potential predictive markers. Main aim of the current work is to summarize and critically evaluate current knowledge in this field.

Cabozantinib-related cardiotoxicity: a prospective analysis in a real-world cohort of metastatic renal cell carcinoma patients.

AIMS: Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib-related cardiotoxicity in mRCC patients. METHODS: We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echocardiogram and plasma biomarkers assay were assessed at baseline, 3 and 6 months after cabozantinib initiation. RESULTS: The study population included 22 mRCC patients. At baseline, 9.1% had a reduced left ventricular ejection fraction (LVEF), but none had a left ventricular systolic dysfunction. Patients with baseline reduced LVEF did not show further significant LVEF modification after 3 months. After 6 months, only 1 had an LVEF decline >10% compared to baseline, resulting in LV systolic dysfunction. At baseline, 64.7% and 27.3% of patients had elevated precursor brain natriuretic peptide (proBNP) and high-sensitivity troponin I (hsTnI), respectively. Among patients with basal normal proBNP and hsTnI, none had elevated values at 3 and 6 months. No correlation was found between basal elevated proBNP and basal reduced LVEF (P = .29), and between elevated proBNP and reduced LVEF after 6 months (P = .37). Similarly, we found no correlations between elevated hsTnI and reduced LVEF or elevated proBNP at baseline (P = .47; P = .38), at 3 (P = .059; P = .45) and after 6 months (P = .72; P = 1.0). CONCLUSIONS: This prospective study revealed a modest risk of developing left ventricular systolic dysfunction related to cabozantinib. A lack of correlation between elevated cardiac biomarkers and reduced LVEF at different time-points was detected. Assessments of the cardiac function should be reserved at the occurrence of clinical symptoms.

BAP1 in solid tumors.

One of the most attractive cancer-related genes under investigation is BAP1. Reasons of this growing interest are related to the wide spectrum of pathways directly or indirectly modulated by this gene and shared by several solid tumors. Programmed cell-death, cell metabolisms, immune cells development, ferroptosis and defects in DNA damage response are only some of the multitude of processes depending on BAP1. Loss of this gene seems to occur in different times of tumor history. Moreover, times of BAP1 loss strongly diverge among primary tumors suggesting the presence of several and different triggering factors. Regardless of when it happens, BAP1 loss usually results in prognosis worsening and in the acquisition of more aggressive clinical features by cancer cells.

Clinical management of a pituitary gland metastasis from clear cell renal cell carcinoma.

In very few years, several treatments have significantly improved the prognosis of patients with metastatic renal cell carcinoma (RCC). Despite this, the clinical outcomes of specific subgroups of patients including those with central nervous metastases still remain poor. In this population, a very infrequent and poorly described site of metastases is the pituitary gland. Because of the important endocrinal function and the anatomic site of this specific organ, clinical management of this complication requires several additional precautions compared with other central nervous metastases. Here, we describe a case of a single pituitary metastasis from clear cell RCC in a patient who showed a surprising progression-free survival and overall survival to sunitinib first-line treatment. Because of the uncommon clinical course of the disease of our patient and the atypical site of metastases, we want also to underline the importance of further investigation of molecular pathways associated with a favorable prognosis in patients with metastatic clear cell RCC.

A case of complete response to nivolumab after long-term progression-free survival with tyrosine kinase inhibitor.

Nivolumab is an effective and tolerable treatment for metastatic renal cell carcinoma, showing longer median overall survival than everolimus and achieving a good percentage of objective response, stable disease, and prolonged responses. However, very few cases have been reported in the literature of a complete response to nivolumab in the metastatic pretreated setting. Here, we report a case of complete response to nivolumab in II line following sunitinib in a metastatic clear cell renal cell carcinoma with favorable risk according to the IMDC criteria. This is also an interesting case on the use of immunotherapy following a long period of antiangiogenetic therapy, underlining the importance of the sequence of treatment to achieve the best possible outcome in terms of prolonged overall survival, progression-free survival, and objective response.

Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug-drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a 'real' population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control.

TP53 mutations and survival in patients with histologically defined Glioblastoma, IDH-wildtype.

BACKGROUND: Mutations of the TP53 oncosuppressor gene are frequent events in patients with malignant tumors including IDH-wildtype GBM (GBM IDH wt). However, the effective impact of TP53 mutations on prognosis has been poorly evaluated. METHODS: We performed a retrospective study investigating the impact of TP53 mutations on patients with GBM IDH wt. Only patients with PS=0-1, treated with temozolomide concurrent with and adjuvant to radiotherapy, and younger than 70 years assessed with NGS were included in the analysis. RESULTS: 97 GBM IDH wt have been selected. The median follow-up was 34.5 months (95 %CI, 30.6 - NA). Overall, 20 patients (19.4 %) presented a TP53 mutation. There were no significant differences in terms of TERT mutation (75 % vs 79.2 %) between TP53 mutated and TP53 wild-type (wt) patients. We detected 6 TP53 mutations not previously described within GBM IDH wt patients. The overall survival (OS) did not significantly differ between TP53 mutated and wt patients (HR 0.69, 95 %CI 0.37-1.27, p = 0.24). Considering only patients with an OS longer than 36 months (n = 10), the presence of a TP53 mutation was significantly associated with prolonged survival (45.6 months vs Not Reached, p = 0.037). CONCLUSION: The presence of a TP53 mutation does not appear to be correlated with overall survival in this patient cohort. While there is an association with survival for patients with an OS of 36 months or longer, the number of patients is low and there is no available evidence correlating TP53 mutations to long-term survivors.

Olfactory neuroblastoma: diagnosis, management, and current treatment options.

Olfactory neuroblastoma (ONB) is a rare neoplasm originating from the olfactory neuroepithelium representing 3-6% of tumors of the sinonasal tract. ONB require multi-disciplinary care. Historically, the gold standard surgical procedure for ONB has been open craniofacial resection. In the last years, endoscopic endonasal approaches have been largely introduced with lower complication rates, shorter hospital stay, and similar clinical outcome. Radiotherapy plays an important role in the management of ONB, however there are not generally accepted recommendations for its application. Although there is agreement that multimodal therapy is needed, the optimal use of chemotherapy is still unknown. The rarity of the disease, makes difficult to draw definitive conclusions about the role of systemic treatment in induction and concomitant setting.