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Clinicians should address the different health needs of cancer survivors (CS). We investigated concerns about physical/psychosocial symptoms and quality of life (QoL) of CS enrolled in our survivorship program. Our primary aim is to describe the CS population and their quality of life, considering both physical and psychosocial issues, with the intent to identify some possible association with the most frequently observed variables.Adult patients, after ≥ 5 years from achieving complete hematologic or solid tumor remission, were included. The self-administered questionnaire used in the survey was based on the "Cancer Survivors Survey of Needs" (Mayo Clinic).We analyzed data from 191 CS. The median age was 63 years (53 years at diagnosis), and 70% of patients were females. A total of 93 patients (49%) reported a quality of life (QoL) score 2. The most common psychosocial symptom concerns were fear of relapse (53%), genetic counseling (43%), living with uncertainty (35%), defining a new sense of normal (31%), and managing stress (28%). Females are more at risk to develop the following concerns compared with males: pain (40% vs 21%), sleep disturbance (54% vs 30%), weight gain (42% vs 21%), osteoporosis (41% vs 11%), body changes (45% vs 13%), hair or skincare issues (42% vs 16%), hot flashes (40% vs 11%), fear of recurrence (74% vs 54%), and living with a sense of uncertainty (53% vs 29%). Younger patients reported a higher score ( 2) for physical and psychological concerns compared with older patients.In this study, differences in physical and psychological symptoms/stressors among women and younger patients were identified. Female and younger patients appear to report physical and psychosocial concerns more frequently than other subgroups of patients. These observations should be validated and deepened in larger, prospective studies and considered during the long-term follow-up of these subgroups of patients.

Purpose:Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas.Experimental design:We recruited two cohorts of newly diagnosed patients with glioma, one (n = 45) providing CSF collected in proximity of the tumor, the other (n = 39) CSF collected by lumbar puncture (LP). Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional and molecular diagnosis outcomes were compared.Results:We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from LP. Indeed, tumor DNA is mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of LP CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes.Conclusions:This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.

Supplementary Figures 1-4, Supplementary Tables S1-S13, Description of Supplementary Data 1-3, Supplementary Materials and Methods, Supplementary References.

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As the population of young cancer survivors is increasing and a trend toward postponing pregnancy later in life is reported, more efforts are focused toward understanding treatment-induced sequelae, in particular, the effects of cancer and/or treatment on fertility.Whereas the fertility risk of cytotoxic agents for both men and women is well recognized, the impact of molecular-targeted therapy (MTT) on fertility parameters, their teratogenic potential and pregnancy outcome/management in case of an accidental exposure are not established. We update available clinical data on the impact of new MTTs on fertility in both sexes, their potential teratogenic effects and the outcome of pregnancy during accidental exposure. Agents are categorized by class and the potential relevance of their target signaling pathways to gonadal maturation.The majority of MTTs have worrying preclinical data discouraging their use during pregnancy and reinforcing the idea that they can induce impairment in gonadal function. However, it does not mean that all MTTs result in permanent infertility and that they should be completely avoided during pregnancy. The current review provides a critical evaluation on the most commonly used MTTs, offering a possible guide for clinicians.

OBJECTIVE Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. METHODS Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. RESULTS Among 402 patients referred to the authors’ institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19–70 years). At admission, most patients had a Karnofsky Performance Scale score of 90–100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16–146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27–76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66–95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. CONCLUSIONS In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.

Background O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation Conclusions Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.

Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of P < .1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti-PD-1, anti-CSF-1R, anti-TGFβ, anti-cereblon), fifteen patients combination regimens (anti-PD-L1 + anti-CD38, anti-PD-1 + anti-CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than 6 years. Univariate analysis identified O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

(1) Background: We investigated the role of [11C]-methionine PET in a cohort of newly diagnosed glioblastoma multiforme (GBM) patients to evaluate whether it could modify the extent of surgical resection and improve radiation therapy volume delineation. (2) Methods: Newly diagnosed GBM patients, ages 18–70, with a Karnofsky performance scale (KPS) ≥ 70 with available MRI and [11C]-methionine PET were included. Patients were treated with different amounts of surgical resection followed by radio-chemotherapy. The role of [11C]-methionine PET in surgical and RT planning was analyzed. A threshold of SUVmax was searched. (3) Results: From August 2013 to April 2016, 93 patients were treated and included in this analysis. Residual tumor volume was detected in 63 cases on MRI and in 78 on [11C]-methionine PET, including 15 receiving gross total resection. The location of uptake was mainly observed in FLAIR abnormalities. [11C]-methionine uptake changed RT volume in 11% of patients. The presence of [11C]-methionine uptake in patients receiving GTR proved to influence survival (p = 0.029). The threshold of the SUVmax conditioning outcome was five. (4) Conclusions: [11C]-methionine PET allowed to detect areas at higher risk of recurrence located in FLAIR abnormalities in patients affected by GBM. A challenging issue is represented by integrating morphological and functional imaging to better define the extent of surgical resection to perform.

Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia, correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. We evaluated the prognostic relevance of TMT measured on brain MRIs acquired at diagnosis in patients affected by glioblastoma. We retrospectively enrolled 51 patients in our Institution affected by methylated MGMT promoter, IDH1–2 wild-type glioblastoma, who underwent complete surgical resection and subsequent radiotherapy with concomitant and maintenance temozolomide, from January 1, 2015, to April 30, 2017. The last clinical/radiological follow-up date was set to September 3, 2019. TMT was measured bilaterally on reformatted post-contrast 3D MPRAGE images, acquired on our 3-T scanner no more than 2 days before surgery. The median, 25th, and 75th percentile TMT values were identified and population was subdivided accordingly; afterwards, statistical analyses were performed to verify the association among overall survival (OS) and TMT, sex, age, and ECOG performance status. In our cohort, the median OS was 20 months (range 3–51). Patients with a TMT ≥ 8.4 mm (median value) did not show a statistically significant increase in OS (Cox regression model: HR 1.34, 95% CI 0.68–2.63, p = 0.403). Similarly, patients with a TMT ≥ 9.85 mm (fourth quartile) did not differ in OS compared to those with TMT ≤ 7 mm (first quartile). The statistical analyses confirmed a significant association among TMT and sex (p = 0.0186), but none for age (p = 0.642) and performance status (p = 0.3982). In our homogeneous cohort of patients with glioblastoma at diagnosis, TMT was not associated with prognosis, age, or ECOG performance status. • Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia and has been correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. • We appraised the correlation among TMT and survival, sex, age at surgery, and performance status, measured on brain MRIs of patients affected by glioblastoma at diagnosis. • TMT did not show any significant correlation with prognosis, age at surgery, or performance status, and its usefulness might be restricted only to patients with brain metastases and recurrent or treated glioblastoma.

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.

Glioma is the most common primary brain cancer, and half of patients present a diagnosis of glioblastoma (GBM), its most aggressive and lethal form. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have not resulted in major ameliorations in GBM survival outcome, which remains extremely poor. Recent immunotherapy improvements for other tumors, coupled with growing knowledge of the complex interactions between malignant glioma cells and the immune system, led to an exponential increase in glioma immunotherapy research. However, immunotherapeutic strategies in GBM have not yet reached their full potential, mainly due to the limited understanding of the strong immunosuppressive microenvironment (TME) characterizing this tumor. Glioma-associated macrophages and microglia (GAMs) are key drivers of the local immunosuppression promoting tumor progression and its resistance to immunomodulating therapeutic strategies. Together with other myeloid cells, such as dendritic cells and neutrophils, GAMs actively shape glioma TME, modulate anti-tumoral immune response and support angiogenesis, tumor cell invasion and proliferation. In this review, we discuss the role of myeloid cells in the complex TME of glioma and the available clinical data on therapeutic strategies focusing on approaches that affect myeloid cells activity in GBM.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65–year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.

Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. Methods: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled, they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. Results: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.

The proposal of a multi-scale, multi-generational and inter-temporal strategic governance in parks integrated management programs introduces a perspective of research where the national park identifies a complex system of relationships among the various dimensions (economy, mobility, environment, people, living, culture, governance) and different interpretative approaches, overcoming the administrative boundaries of each municipality and considering the territory as the expression of different scales and communities according to a dynamic vision. The paper, starting from the evolution of the governance's concept, focuses on the management of its complexity in the change processes oriented to the development strategies designed to support and strengthen local values, structured and tested in the National Park of Cilento, Vallo di Diano and Alburni (Italy).

BACKGROUND: Different immunotherapeutic strategies are currently under clinical evaluation in the context of neuroncology. However, a critical barrier to an effective antitumor immunity is still represented by the wide array of immunosuppressive forces exhibited by malignant gliomas (MGs). The present study aims to perform a comprehensive analysis of infiltrating and circulating leukocyte subsets (lymphocytes, macrophages, dendritic cells, neutrophils) in patients with MGs, identifying the immunological profile of the different histo-molecular subtypes, exploring the functional changes during and after anticancer therapies. Here we report first preliminary data on infiltrating and circulating neutrophils. MATERIALS AND METHODS: Patients with a clinical-radiological diagnosis of malignant diffuse glioma referring to the NeuroOncological Surgery Unit of the Humanitas Research Hospital between January 2017 and March 2018 were prospectively enrolled in the study. Fresh tumor tissue specimens were collected the day of surgery; peripheral blood samples (PBS) were collected at baseline and then prospectively every two months during active anticancer treatments and then every six months during follow-up. The analysis of the frequency as well as phenotypic and functional characterization of tumor associated neutrophils (TANs) and of circulating neutrophils were performed by flow cytometry. Data were correlated with histology and the molecular markers isocitrate dehydrogenase (IDH) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. RESULTS: As per May 2018, 26 out of 84 patients (MG specimens and PBS) plus PBS of 4 healthy donors were analyzed. 12 had IDH wt GBM (n=7 MGMT methylated; n=5 MGMT unmethylated), 5 IDH mut GBM (n=5 MGMT unmethylated), 4 IDH mut anaplastic astrocytoma (n=3 MGMT methylated; n=1 MGMT undetermined), 4 IDH mut anaplastic oligodendrogliomas (n=4 MGMT methylated). TANs represented 5% (SD= 2,67%) of all CD45+ tumor disaggregated single cell suspensions. No statistically significative differences were found comparing the percentage of TANs (CD45(+)CD11b(+)CD66b(+)CD16(+)) among different histo-molecular subgroups. However, an increased percentage of activated TANs (CD62L(neg)CD16(high)) were found in samples from IDH wt GBM patients with methylated MGMT promoter compared to unmethylated ones (p=0,005). Increased percentages of activated neutrophils were found in PBS from IDH wt GBM patients compared to healthy donors (p=0,005). CONCLUSIONS: An increased number of activated TANs are present in MGMT methylated IDH wt GBM patients compared to unmethylated. IDH wt GBM patients seem to have higher percentages of circulating activated neutrophils compared to healthy donors. Correlation between different subpopulations of TANs, treatment response and clinical outcome will be presented at the meeting.

BACKGROUND: Immune-checkpoint inhibitors (ICI) represent a new interesting approach in oncology. The presence of DNA MMRd would seem to be a predictor of ICI efficacy. We analyzed MMRd frequency in glioma PTS and its correlation with clinical, histological and molecular characteristics. MATERIAL AND METHODS: From July 2017 to May 2018, we prospectively analyzed histologically confirmed glioma PTS for the presence of MMRd by immunohistochemistry (IHC): MSH2, MSH6, PMS2, MLH1. Clinical, histological and molecular characteristics (MGMT methylation and IDH mutational status, PD-L1 expression) were recorded. Chi-square test was used for analyzing their correlations with MMRd. RESULTS: 167 PTS were enrolled: 78% glioblastoma (GBM), 14% anaplastic astrocytoma (AA), 1% ependymoma, 2% anaplastic oligodendroglioma (OD) and 5% LGG. The analyses were assessed on tissue samples of first (82% of the cases), second surgery (18%). All PTS performing a second surgery received radiotherapy and temozolomide as first-line therapy. 134 PTS were analyzed for IDH status: 99 were IDH wt; 117 for MGMT status: 68 were methylated.27 PTS (16%) showed MMRd by IHC (MSH2 in 48%, MSH6 in 55.6%, PMS2 in 18.5% and MLH1 in 14.8%): 33% of AA, 14% of GBM, 33% of OD and 0% of LGG (p=0.2). MMRd was found in 13% and 32% on first and second surgery samples (p=0.03). PD-L1 expression analysis was performed in 60 cases: no expression was showed in 58% of cases, ≥ 1% and 50% in 10%. MMRd was not correlated with PD-L1 expression (p=0.3). MMRd was found in 10% and 29% of IDHwt and IDHmut gliomas(p=0.008); MMRd was showed in 10% and 21% of PTS with unmet and metMGMT (p=0.1). Among MMRd tumors, 7 were also investigated by molecular analysis (PCR) of mononucleotide markers: in only 1 PT (14%) was confirmed MMRd in agreement with IHC analysis (p=0.1.). CONCLUSION: We showed a small group of glioma PTS have MMRd by IHC, expecially at second surgery. Correlation was observed between IHC MMRd and IDH mutational status. No association was demonstrated between IHC MMRd and histology, MGMT status, PD-L1 expression or molecular analysis of MMRd. A prospective study analyzing ICI efficacy in MMRd PTS should be warranted.

Glioblastoma is the most common and lethal malignant brain tumor in adults, with a very poor prognosis of less than two years despite surgical resection followed by radiotherapy and chemotherapy. To date, targeted agents and antiangiogenic therapy have failed to show survival benefits and novel treatment approaches are urgently needed. Immune checkpoint inhibitors have recently revolutionized the landscape of cancer immunotherapy achieving regulatory approvals for a number of other 'historically' resistant cancers. These exciting successes have generated great interest in investigating if these agents could be such effective also in brain tumors field. Moreover, the traditional dogma that considers the central nervous system (CNS) as an immune-privileged site lacking the potential for immunosurveillance has been challenged as it has become clear that the CNS is immunoactive. Critical barriers to an effective antitumor immunity in brain tumor patients are still represented by the peculiar CNS immunological milieu and the numerous systemic and local immunosuppressive forces exhibited by malignant gliomas to avoid immune recognition and cellular death. This review describes the current status of checkpoint modulation as treatment for malignant gliomas. We start illustrating the compelling molecular and immunological rationale, than we show striking preclinical evidence of activity and discuss available data from prospective clinical trials. Furthermore, we explore the role of predictive biomarkers of responsiveness to checkpoint blockade in the context of gliomas, along with the development of combinatorial and potentially synergistic approaches with other established anti-cancer treatments or complementary immunotherapeutic modalities.

Background ieCTs historically excluded HGG patients (pts) due to unavailability of serial bioptic sampling, use of corticosteroids, concerns on activity of immunotherapy in central nervous system, and rapid clinical deterioration. Methods Data of all recurrent HGG pts enrolled into ieCTs at the Humanitas Cancer Center Phase I Unit between 2014 and 2019 were retrospectively reviewed. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard therapies (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A huge series of clinical and laboratory variables with an established prognostic relevance for solid tumors pts treated into ieCTs were studied through univariate analysis. Results Only 5 out 23 ieCTs allowed inclusion of HGG pts. The experimental cohort (EC) consisted of 25 pts (M/F: 16/9; median age: 50 years): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1-6). The median number of prior systemic therapies was 1 (range 1-2). 12 pts (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-s, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% in both EC (1 CR + 2 PR + 7 SD) and CC (1 PR + 9 SD). 4 pts (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up (FU) of 14 months PFS-6 were 35% and 16% (p = 0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p = 0.004). With limitations due to small sample size, short FU and few events recorded, none of the parameters analyzed resulted prognostic. Conclusions Survival of our HGG pts treated into ieCTs compared favorably with a matched CC. Inclusion of HGGs pts into ieCTs should be encouraged. Clinical selection factors predicting which pts may benefit most still lack. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Simonelli: Advisory / Consultancy: AbbVie. A. Santoro: Advisory / Consultancy: BRISTOL-MYERS-SQUIBB; Advisory / Consultancy: SERVIER; Advisory / Consultancy: GILEAD; Advisory / Consultancy: EISAI; Advisory / Consultancy: BAYER; Advisory / Consultancy: MERCK SHARP & DOHME; Speaker Bureau / Expert testimony: TAKEDA; Speaker Bureau / Expert testimony: BRISTOL-MYERS-SQUIBB; Speaker Bureau / Expert testimony: ROCHE; Speaker Bureau / Expert testimony: ABBVIE; Speaker Bureau / Expert testimony: AMGEN; Speaker Bureau / Expert testimony: CELGENE; Speaker Bureau / Expert testimony: SERVIER; Speaker Bureau / Expert testimony: GILEAD; Speaker Bureau / Expert testimony: ASTRAZENECA; Speaker Bureau / Expert testimony: PFIZER; Speaker Bureau / Expert testimony: ARQULE; Speaker Bureau / Expert testimony: LILLY; Speaker Bureau / Expert testimony: SANDOZ; Advisory / Consultancy: PFIZER. All other authors have declared no conflicts of interest.

Le piu recenti interpretazioni del modello di creazione del valore dei beni ed individuazione delle strutture di governance che aiutano i processi di integrazione tra innovazione nel manifatturiero e nei servizi pur considerando le possibili implicazioni scaturenti dalla diversa natura delle innovazioni, non si soffermano sul caso in cui l’innovazione scaturisca da azioni (individuali e/o collettive) di tipo cognitivo-relazionale. L’articolo intende colmare questo vuoto argomentando, con l’ausilio di un caso studio, un modello interpretativo basato su ipotesi dinamiche di circolarita del processo innovativo e la criticita del riconoscimento nello stesso processo dell’alternanza tra capabilities- competences. Il caso studio su un impianto pilota di de-manufacturing al centro di un’ipotesi di fabbrica circolare contribuisce ad individuare alcune interessanti implicazioni di policy.

The emergence of the knowledge economy has resulted in a new definition of regional policy milieu. Under the current EU policy framework the concepts of region and city are the result of an inductive, exploratory cognitive process. Interpreting, assessing and designing successful territorial milieux constitute a methodological challenge for analysts. This paper discusses the methodological capacity of a hybrid theoretical approach to discovery and design of smart specialization. Analysis of strategic network formation (why the network takes a particular form) demonstrates the competitive positioning of specific homogeneous communities within the global value chain and can be considered central to the regional policy milieu. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabella normale"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;}

Background Pem, an immune checkpoint inhibitor, has been demonstrated to be active in various neoplasms with MMRd. No data exist about its efficacy in MMRd glioma patients. Methods MMRd HGG patients relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency was defined as presence of a weak (wMMRd) or absent (aMMRd) signal on immunohistochemistry for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed gliomas, dexamethasone ≤4 mg. Pem was administered at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. CTCAE v4.0 was used for toxicity assessment. Results Among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p = 0.03, OR = 3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p = 0.9), PFS was 1.8 ms and 3.1 ms (p = 0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p = 0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p = 0.04). Grade ≥3 adverse events were reported in 8% of PTS. Conclusions A subgroup of recurrent MMRd HGG patients might benefit from Pem, especially those with anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Selecting which pts may benefit from ieCTs is challenging. Few prognostic indexes have been proposed so far and none qualifying as a predictor of response. The Gustave Roussy Immune Score (GRImS) identifies two prognostic categories based on three objective variables (albumin ULN=1; NLR>6=1). Methods We retrospectively reviewed data of all pts enrolled into ieCTs at the Humanitas Cancer Center Phase I Unit between 2014 and 2019. A large series of demographic and clinical variables were correlated with overall survival (OS) and objective response rate (ORR) through univariate and multivariate analysis (UVA; MVA). Laboratory parameters were calculated either as baseline values and as dynamic six-weeks (6wks) changes. Finally, we explored the performance of the GRImS in our cohort. Results A total of 111 pts (M/F:63/48; median age: 62) with advanced solid tumors treated into ieCTs have been selected. The most frequent histologies were hepatocellular carcinoma (34%), lung carcinoma (22%), glioblastomas (13%). With a median follow-up (FU) of 14.3 months (mos), the OS was 12.9 mos, and the ORR 12.6%. In the UVA ECOG PS 1) (14.3 mos vs 7.3 mos; p = 0.029), but not predictive. Conclusions We assessed the prognostic accuracy of GRImS in our ieCTs cohort. With limitations due to small sample size, short FU and few events recorded we identified additional static and dynamic variables with a potential prognostic and predictive relevance to be further explored in larger series and to be eventually included in new scores. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Simonelli: Advisory / Consultancy: AbbVie. A. Santoro: Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Servier; Advisory / Consultancy: Gilead; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Bristol-Myers-Squibb; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Abbvie; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Servier; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Arqule; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: SANDOZ. All other authors have declared no conflicts of interest.

BACKGROUND Pem, an immune checkpoint inhibitor, demonstrated to be activein various neoplasms with MMRd. No data exists about its efficacy in MMRdglioma patients. MATERIAL AND METHODS MMRd HGG relapsed after receiving RT and CT weretreated with Pem. MMR status was analyzed by immunohistochemistry,including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency wasdefined as presence of a weak (wMMRd) or absent (aMMRd) signal atimmunohistochemistry for at least one MMR protein. Other inclusion criteriawere: ECOG PS 0–2, histologically confirmed gliomas, dexamethasone ≤4 mg.Pem was administrated at 200 mg every 3 weeks until progression disease orunacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeksaccording to the RANO criteria. OS and PFS were evaluated by Kaplan-Meiercurves. CTCAE v4.0 was used for toxicity. RESULTS among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, allPTS had microsatellite stability. Tumor histologies included 5 anaplasticastrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1deficiency in 2 cases. Median number of prior line of chemotherapy was 1 (range 1–5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showedprogressive disease (PD). PTS with anaplastic gliomas showed a statisticallysignificant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6(deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1–13.8), PFS 2.4 ms (95% CI 1.8–2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6–10.2) and 1.8 ms (95% CI 0.2–3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04). Grade ≥3 adverse eventswere reported in 8% of PTS. CONCLUSION a subgroup of recurrent MMRd HGG might benefit from Pem,especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing.

e13512 Background: Patients with HGGs have historically been excluded from ieCTs due to unavailability of serial bioptic sampling, frequent need of corticosteroids, concerns on activity of immunotherapy in central nervous system, and rapid clinical deterioration. Methods: We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2018. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for age, line of treatment, MGMT methylation and IDH mutational status, was selected for comparison. Clinical parameters including use of steroids, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein, were correlated with survival through an univariate analysis. Results: 5 among 21 ieCTs allowed inclusion of HGG patients. 20 patients were enrolled in our experimental cohort (EC); 17 (85%) glioblastoma, 3 (15%) anaplastic astrocytoma. Median age was 53 years (range 30-71); 12 patients (60%) were men, 8 (40%) women; 13 pts (65%) required steroid therapy, with a median dexamethasone dose of 2 mg (range 1-6). The median number of prior systemic therapies was 1 (range 1-2). 11 patients (55%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 9 (45%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 45% (1 CR + 2 PR + 6 SD) and 30% (1 RP +5 SD), in EC and CC, respectively. 4 patients (20%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 22 months PFS-6 and OS-6 were 53% and 11% (p < .0001), 80% and 42% (p < 0.0001) in EC and CC, respectively. In our small series, none of clinical factors resulted prognostic. Conclusions: Survival outcomes of our HGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical selection factors remains crucial.

2043 Background: Pem, an immune checkpoint inhibitor, demonstrated to be active in various neoplasms with MMRd. No data exists about its efficacy in MMRd glioma PTS. Methods: MMRd HGG relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMRd was defined as presence of a weak (wMMRd) or absent (aMMRd) signal for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed glioma, dexamethasone ≤4 mg. Pem was administrated at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. Results: among 167 glioma PTS, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases , MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd, respectively. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04), respectively. Grade ≥3 adverse events were reported in 8% of PTS. Conclusions: a subgroup of recurrent MMRd HGG might benefit from Pem, especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. The enrollment and analyses for identifying additional molecular predictive factors are ongoing.

Le difficoltà dell'economista stanno che sono diventati obsoleti i suoi strumenti: legge di Okun, ancora insegnata," se il PIL aumenta dell'1% anche l'occupazione aumenta dell'1%, ma anche se l'aumento è del 5 anche l'occupazione aumenta del 5. La rivoluzione digitale e la globalizzazione hanno rivoluzionato il ciclo della produzione e le nuove tecnologie sono labour saving e capital saving. La variabile investimento si lega all'organizzazione innovativa e questo richiede una rivoluzione del sociale e delle istituzioni, rompendo il legame tra creazione di valore manifatturiero ed occupazione. Il secondo paradigma si chiama moltiplicatore Keynesiano e dice che se aumenta la spesa pubblica aumentano gli investimenti e l'occupazione, gruppi politici ed istituzioni del mercato hanno allargato il concetto portando inflazione e debito a redistribuire finanza ai nuovi monopolisti del potere. Il risparmio rimane la variabile morale da coltivare, mentre l'indebitamento di comunità deve essere più evidente, da tempo io parlo di finanza di città e di welfare di popolazione per allargare la prospettiva di una chiara trasparenza nell'uso della finanza e del prestito per l'investimento. Il terzo paradigma riguarda l'idea che l'abbassamento del salario di ingresso serva a fare occupazione, i casi di caporalato dimostrano che questo principio di flessibilità adorato dagli economisti liberali uccidono la dignità del lavoro, il salario minimo legato ad un servizio di comunità o di formazione è strada nuova per ridare al lavoro ed alla pausa creativa la loro dignità di appartenenza, ma non basta occorrono nuovi investimenti sul potenziale territoriale o di sistema /scientifico, culturale, manifatturiero etc.) Le azioni di risveglio citate da Aldo Bonomi a proposito dell'elogio del Margine vanno in una direzione giusta se la rete delle comunità provvisorie di nuova urbanità o nuovo umanesimo guadagnano soggettività politica ed ispirano una nuova politica economica della città e dell'altra città, a civiltà plurale.

Il Parco dei monti lattari è ancora una istituzione debole, anche in considerazione della breve vita amministrativa. Il piano socioeconomico nella sua prima edizione diventa occasione per delineare un strategia di governance che punti fortemente a consolidare un nuova percezione del perché un parco regionale possa diventare cerniera istituzionale tra aree urbane ed area a forte vocazione naturalistica e paesaggistica. Un piano può essere visto come un algoritmo capace di rimettere coerenza tra diversi livelli istituzionali e diversi stakeholders che concorrono a definire una nuova identità territoriale che si fa riconoscere per la sua nuova capacità di concorrere ai temi dello sviluppo ed a quelli dello sviluppo sostenibile in particolare.

I laboratori di apprendimento o di ricerca e sviluppo della città del Quarto Paesaggio - territorio identificabile con il Parco Nazionale del Cilento - sono un esempio diffuso della possibilità di fare manutenzione al concetto di città, fino a viverla come rete di reti. In questa visione, lo sguardo comprende un saper vedere nuovo, raramente presente nella pianificazione territoriale e paesaggistica. Ciò è attribuibile ai modelli di pianificazione maggioritari (pianificazione forte o gerarchica), che si basano su modelli di apprendimento oramai messi in discussione dai crescenti insuccessi della pianificazione moderna, sia in termini di efficacia che di efficienza: de-costruire e ri-costruire allargando il contributo delle altre discipline, sono le pratiche necessarie per parlare di nuova pianificazione. Il nuovo modello mette in campo una nuova sensibilità per dare fattibilità al processo-progetto: quella la pianificazione debole.

8579Background: Angiogenesis has an important role in thymic epithelial tumours (TETs); VEGF, PDGF and PDGFRα are overexpressed in TETs, and VEGF expression and microvessel density are associated w...

This paper describes an approach to analyze big data in order to better understand the spatial, temporal and demographic properties of cultural heritage users. Based on a famous case study: Pompeii - but applicable to a much broader and varied case studies.

Le più recenti interpretazioni del modello di creazione del valore dei beni ed individuazione delle strutture di governance che aiutano i processi di integrazione tra innovazione nel manifatturiero e nei servizi pur considerando le possibili implicazioni scaturenti dalla diversa natura delle innovazioni, non si soffermano sul caso in cui l'innovazione scaturisca da azioni (individuali e/o collettive) di tipo cognitivo-relazionale. L'articolo intende colmare questo vuoto argomentando, con l'ausilio di un caso studio, un modello interpretativo basato su ipotesi dinamiche di circolarità del processo innovativo e la criticità del riconoscimento nello stesso processo dell'alternanza tra capabilities-competences. Il caso studio su un impianto pilota di de-manufacturing al centro di un'ipotesi di fabbrica circolare contribuisce ad individuare alcune interessanti implicazioni di policy.

Lo scenario che è stato presentato allarga la visione sui temi della mobilità in termini di efficacia ed efficienza delle politiche sulle infrastrutture di trasporto in campo e consente di elaborare nuove proposte strategiche in grado di ricucire il ritardo accumulato in termini di integrazione con le politiche regionali, le uniche in grado di rammendare i tessuti socie economici connessi al tema dei vantaggi competitivi localizzati dei sistemi territoriali diffusi in termini di attività economiche. Oltre al tema della revisione dei saperi per interpretare le dinamiche associabili al tema della mobilità occorre un vero e proprio salto in termini di ecologia della mente per cogliere le nuove connessioni tra politiche dei trasporti ed una più allargata politica per le città ed i tessuti territoriali connessi.