Therapeutic approach in glioblastoma multiforme with primitive neuroectodermal tumor components: case report and review of the literature

Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma that is treated with first-line therapy, using surgical resection followed by local radiotherapy and concomitant/adjuvant temozolomide (TMZ) treatment. GBM is characterised by a high local recurrence rate and a low response to therapy. Primitive neuroectodermal tumour (PNET) of the brain revealed a low local recurrence rate; however, it also exhibited a high risk of cerebrospinal fluid (CSF) dissemination. PNET is treated with surgery followed by craniospinal irradiation (CSI) and platinum-based chemotherapy in order to prevent CSF dissemination. GBM with PNET-like components (GBM/PNET) is an emerging variant of GBM, characterised by a PNET-like clinical behaviour with an increased risk of CSF dissemination; it also may benefit from platinum-based chemotherapy upfront or following failure of GBM therapy. The results presented regarding the management of GBM/PNET are based on case reports or case series, so a standard therapeutic approach for GBM/PNET is not defined, constituing a challenging diagnostic and therapeutic dilemma. In this report, a case of a recurrent GBM/PNET treated with surgical resection and radiochemotherapy as Stupp protocol, and successive platinum-based chemotherapy due to the development of leptomeningeal dissemintation and an extracranial metastasis, is discussed. A review of the main papers regarding this rare GBM variant and its therapeutic approach are also reported. In conclusion, GBM/PNET should be treated with a multimodal approach including surgery, chemoradiotherapy, and/or the early introduction of CSI and platinum-based chemotherapy upfront or at recurrence

Challenges and Knowledge Gaps with Immune Checkpoint Inhibitors Monotherapy in the Management of Patients with Non-Small-Cell Lung Cancer: a Survey of Oncologist Perceptions

Background: Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians' opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. Methods: A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. Results: Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. Conclusions: This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.info:eu-repo/semantics/publishedVersio

Clinical and treatment features associated with improved 5-year survival rate in ALK-positive lung cancer treated with ALK-TKIs

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Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer

OBJECTIVES: Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients aged 6565. As NSCLC is often diagnosed in patients aged 6570, real-world data about efficacy and safety of immunotherapy (IO) in elderly patients are essential. MATERIALS AND METHODS: We retrospectively collected data about all patients with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. The patients were stratified for age as follows: <70 year-old, 70-79 year-old, 6580 year-old. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model. RESULTS: We reviewed 290 cases, with a median age of 67 (range: 29-89). Patients aged<70, 70-79 and 6580 year-old were 180, 94 and 16, respectively. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (p 0.9470). Median Progression Free Survival (PFS) and Overall Survival (OS) did not differ according to age (p 0.2020 and 0.9144, respectively). Toxicity was comparable across subgroups (p 0.6493). The only variables influencing outcome were performance status (PS) (p\u2009<\u20090.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p\u2009<\u20090.0001 for both PFS and OS). CONCLUSION: Advanced age was not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerged even among the eldest pts. To our opinion, ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out

Immunotherapy has dramatically changed the therapeutic scenario in treatment na\uefve advanced non-small celllung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells 65 50%, the combination of pembrolizumab or atezolizumab and platinum-basedchemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamousand non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition hasshown promising results in treatment na\uefve patients with high tumor mutational burden (TMB). Of note, thepresence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has littlebenefit from immunotherapy combinations and for whom the best treatment option may still be platinum-basedchemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity inEGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns inboth EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumabin combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment optionupon progression to first line tyrosine kinase inhibitors

IL-18 receptor marks functional CD8+ T cells in non-small cell lung cancer

IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen-or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8(+) T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet(+)Eomes(+)), than by the majority of those with the dysfunctional phenotype T-bet(+)Eomes(+) generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFN gamma production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8(+) T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches

EPSILoN score: Validation cohort of a prognostic score in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy

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Predictive score using clinical and blood biomarkers in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy

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Exploring the role of respiratory microbiome in lung cancer: A systematic review

Giving the potential contribute in cancer initiation and progression, lung microbiota represents a promising topic in cancer research, although still unexplored. We performed a systematic literature search to identify clinical studies evaluating lung microbiota composition, its correlation with lung cancer patients’ clinico-pathological features and prognosis. Of the identified 370 studies, 21 were eligible and included. Although studies were heterogeneous, lung cancer resulted to be enriched in peculiar microbial communities, with differences in composition and diversity according to clinico-pathological parameters. Few studies explored how lung microbiota influences cancer outcome. In light of these findings and borrowing the suggestions coming from gut microbiota, we speculate that respiratory microbiome may influence pathogenesis, progression and outcome of lung cancer. Taking advantage of the experience of chronical lung diseases, prospective studies should be designed to evaluate lung microbiota changes throughout any phase of lung cancer course, particularly with the advent of immunotherapy as pivotal treatment

SMO mutations confer poor prognosis in malignant pleural mesothelioma

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway. Methods: We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher's test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models. Results: Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in BAP1, NF2, TP53, SMO and PTCH1 with no significant differences between the groups except for SMO. SMO, a member of the Hh pathway, was mutated only in NS (15.6%) and only SMO mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI: 2.32-8.18, P<0.0001) and multivariate (HR =9.2, 95% CI: 3.0-28.4, P=0.0001) analysis. All SMO mutated patients expressed high protein levels. Conclusions: SMO mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial