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High-grade gliomas, including anaplastic oligodendroglioma, represent the most common malignant neoplasms of the central nervous system in the adult. The standard treatment of anaplastic oligodendroglioma consists of maximum surgical resection, radiotherapy and subsequent chemotherapy. Despite multimodal treatment, theoretically, all cases can relapse. Immune checkpoint inhibitors (ICIs) as pembrolizumab demonstrated promising results in many types of tumors, particularly in the presence of mismatch repair deficiency (MMRd). However, no ICI benefit was demonstrated in high-grade glioma prospective studies, although no biomarker was analyzed. Here, we describe an interesting case of recurrent anaplastic oligodendroglioma with MMRd, reporting a prolonged disease stability during pembrolizumab treatment.

Medulloblastoma is an embryonal neuroepithelial tumor that affects mainly childhood and more rarely adults. Medulloblastoma occurring as multiple nodules at diagnosis is a rare and tricky presentation. Here, we describe the case of a previously healthy 47-year-old woman with multiple posterior fossa cerebellar tumors. Histological, immunohistochemical, and molecular analyses were performed to best characterize the two excised lesions. The histopathological analysis revealed different variants of medulloblastoma in the excised nodules, one being extensive nodularity, rare in adults, and the other desmoplastic/nodular with areas of anaplasia. Immunostains and molecular analysis classified both nodules as SHH medulloblastoma. Adult medulloblastoma is extremely rare. Important differences exist between adult medulloblastoma and medulloblastoma arising in children and infants. Such differences are in location, distribution of histological variants and of molecular subgroups, survival rates, and therapeutic options. An extensive morphological and molecular characterization of such rare tumors is necessary to choice the best-tailored therapy.

This article explores the Nordic denial of colonial involvement and complicity and the way it operates in welfare work with refugees in Denmark. Deploying a postcolonial welfare analytics that puts...

Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.

Objective: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. Methods: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. Results: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan–Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. Conclusion In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. Advances in knowledge Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

BackgroundAlthough gliomas are confined to the central nervous system, their negative influence over the immune system extends to peripheral circulation. The immune suppression exerted by myeloid cells can affect both response to therapy and disease outcome. We analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome.MethodsPeripheral blood was obtained from 134 low- and high-grade glioma patients. CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and four myeloid-derived suppressor cell (MDSC) subsets, were evaluated by flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters.ResultsChanges in myeloid parameters associated with immune suppression allowed to define a diagnostic score calculating the risk of being a glioma patient. The same parameters, together with age, permit to calculate the risk score in differentiating each glioma grade. A prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3, and ARG1 activity together with clinical parameters in predicting patient’s outcome.ConclusionsThis work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis, and outcome of glioblastoma patients lays the ground for their clinical use.

We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan–Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III–IV (n = 10) presented a shorter median OS than Group 2stages III–IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient’s clinical history and based on multidisciplinary management.

BACKGROUND Despite advances in surgical and first-line treatment, all glioblastoma pts relapse. The aim of this study is to evaluate the benefit of metronomic temozolomide (mTMZ) for recurrent glioblastoma. METHODS 120 pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis. RESULTS mFollow-up was 15.6ms, mAge 59ys (range 18-81), ECOG PS 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated in 66 of 105 (62%) evaluable pts, IDH mutated in 9 of 106 (8%). mNumber of prior lines of treatment was 2 (range 1-7); 41% of pts received mTMZ beyond the third line. mTime between last standard TMZ (sTMZ) cycle and mTMZ administration was 6ms (range 1-50); 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS 2.6ms (95% CI 2.3-2.8). On univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p= 0.03); mOS for pts with ECOG PS > or ≤ 2 was 2.3 and 6.0ms (p< 0.001). On multivariate analysis, MGMTmet status (HR= 2.3, 95% CI, p= 0.004) and ECOG PS (HR= 0.5, 95% CI, p= 0.017) remained significant for PFS; ECOG PS (HR= 0.4, 95% CI, p= 0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon. CONCLUSIONS Rechallenge with mTMZ can be a well tolerated treatment option for recurrent glioblastoma, even in heavily pretreated pts. Pts with MGMTmet and good ECOG PS might report the major benefit.

Background Although gliomas are strictly confined to the central nervous system, their negative influence over the immune system can extend to peripheral circulation. The immune suppression exerted by myeloid cells is capable of affecting both response to therapy and disease outcome. Here we analyzed the expansion of several myeloid parameters in the blood of low- and high-grade gliomas and assessed their relevance as biomarkers of disease and clinical outcome. Methods Peripheral blood was obtained from 134 low- and high-grade glioma patients before surgery and treatment. Myeloid cell subsets such as total CD14+, CD14+/p-STAT3+, CD14+/PD-L1+, CD15+ cells and 4 myeloid derived suppressor cell (MDSC) subsets, were evaluated by multiparametric flow cytometry. Arginase-1 (ARG1) quantity and activity was determined in the plasma. Principal component analysis was performed to define correlations between myeloid markers. Multivariable logistic regression model was used to obtain a diagnostic score to discriminate glioma patients from healthy controls, and between each glioma grade. A glioblastoma prognostic model was determined by multiple Cox regression using clinical and myeloid parameters. Results In the blood of glioma patients, changes in myeloid parameters associated with immune suppression were identified and allowed us to define a diagnostic score calculating the risk of being a glioma patient, that included CD15+ cells, MDSC1, MDSC3, p-STAT3 and ARG1 activity. Of note, the same parameters, together with age, can also be used to calculate the risk score in differentiating each glioma grade. Finally, a prognostic model for glioblastoma patients stemmed out from a Cox multiple analysis, highlighting the role of MDSC, p-STAT3 and ARG1 activity together with clinical parameters in predicting the patient outcome. Conclusions This work emphasizes the role of systemic immune suppression carried out by myeloid cells in gliomas. The identification of biomarkers associated with immune landscape, diagnosis and outcome of glioblastoma patients lays the ground for their clinical use for stratification and follow up.

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%), 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

BACKGROUND Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use. MATERIAL AND METHODS Patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. RESULTS From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0–1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4–13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3–3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related. CONCLUSION We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.

BACKGROUND the current standard to treat meningiomas can include surgical resection and radiotherapy. Despite the high rate of relapse no systemic treatment is indicated. Few data are available regarding the effectiveness of bevacizumab (BEV) in this setting. We performed a retrospective analysis investigating the efficacy and safety of BEV in meningioma patients relapsed after receiving surgery and radiotherapy. Gene mutations were also collected. Material and METHODS we analyzed pts treated with off-label BEV from Jul 2019 to Feb 2022. Inclusion criteria were diagnosis of grade 2-3 meningioma, previous treatment with surgery and radiotherapy, no indication to further surgery or reirradiation, absence of contraindications to the use of BEV. Data were estrapolated from clinical records. RESULTS Median follow up was 13 months (3-30 range). 26 pts were enrolled. Median age was 68 ys (29-84); male pts were 16 (61%);61% (16 pts) with atypical meningioma, 38.5% (10 pts) with anaplastic meningioma; 27% (7 pts) underwent 2 or more surgeries; 58% had 2 or more RT treatments; 96.1% (25 pts) received < 2 previous lines of systemic treatment. 61% of patients (16 pts) had NGS analyses available; 62% (10 pts) had NF2 mutations (1 pt had a confirmed diagnosis of neurofibromatosis type 2), 23% (6 pts) CDKN2A/2B deletion, 11% (3 pts) PTEN mutation. OS rate was 82% and 62% at 6 and 12 months respectively; 6 months PFS rate was 83%. The DCR was 71% and the ORR was 19%. Median PFS and OS weren't reached. 19% (5 pts) experienced CTCAE grade 1 or 2 toxicity, mainly hypertension. CONCLUSION BEV showed very promising activity in recurrent grade 2-3 meningioma. The treatment was well tolerated. BEV should be considered an optimal therapeutic option in this setting of meningioma patients. The NGS results might be useful in identifying targetable mutations in case of further recurrence.

Oligodendroglioma is a subtype of diffuse glioma defined by a mutation in the isocitrate dehydrogenase (IDH) genes and a co-deletion of chromosome arms 1p and 19q. These tumors primarily occur in adult patients in their third and fourth decade of life and are universally fatal due to an inevitable recurrence that follows a treatment regimen of surgical resection and an optional combination of alkylating chemotherapy and/or radiation therapy. While initially slow growing, recurrent tumors exhibit increasingly aggressive phenotypes that become progressively more difficult to treat with conventional therapy. Currently, the molecular mechanisms and cellular phenotypes that drive this recurrence remain unknown. To understand these factors, we assembled a cohort of matched initial and recurrent oligodendroglioma samples from over 100 patients and performed whole-genome sequencing and whole-exome sequencing on each of them. To link these molecular profiles to cell state changes, we additionally performed bulk and single-nucleus RNA-sequencing on a subset of these tumor pairs. In nearly 40% of alkylating chemotherapy-treated patients, recurrent tumors presented with hypermutation that corresponded with an increase in neoplastic cell proliferation. Additionally, while individual somatic alterations specific to recurrence were relatively rare, we observed a subset of tumors that acquired deletions in the cell cycle regulator CDKN2A following treatment with radiotherapy. Acquisition of either of these features associated with shorter patient survival and higher grade at recurrence, implicating cell cycle dysregulation as a mechanism of treatment resistance and increased tumor severity. Together, these results indicate that oligodendrogliomas evolve in a treatment-specific manner following chemo- and radiation therapy and highlight key pathways that can be targeted to delay the onset of recurrence.

BACKGROUNDNGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. METHODS From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. RESULTS We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of newly diagnosed and recurrent GBM samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. CONCLUSIONNGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.

Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.

TPS2073 Background: The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. Methods: With these assumptions, we started a multicentric single arm Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol after radiochemotherapy combination. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 38 patients out of 41 patients planned have been enrolled. Clinical trial information: NCT04224441.

3139 Background: NGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. Methods: From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOneCDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. Results: We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. Incidence of actionable molecular alterations in newly diagnosed and relapsed GBM samples is described in the Table. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. Conclusions: NGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples. [Table: see text]

Background: Depatuxizumab Mafodotin (Depatux-M, ABT-414) is an antibody-drug conjugate consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The INTELLANCE 2/EORTC 1410 phase 2 trial produced interesting results for the combination regimen of Depatux-M and temozolomide in EGFR-amplified glioblastoma patients at first recurrence. For the first time worldwide, our work investigated the clinical outcome and safety of this combination in a real-life population. Materials and Methods: Patients were enrolled from seven AINO (Italian Association of Neuro-Oncology) Institutions. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, EGFR-amplified, one or more prior systemic therapies and ECOG PS ≤ 2. According to the original schedule, patients received Depatux-M 1.25 mg/kg every 2 weeks combined with temozolomide. The primary endpoints of the study were overall survival and safety. Results: A total of 36 patients were enrolled. The median age was 57 years, ECOG PS was 0–1 in 28 patients (88%), MGMT methylated status was found in 22 (64%), 15 patients (42%) received the combined treatment as second-line therapy. The median OS was 8.04 months (95% CI, 5.3–10.7), the 12 month-OS was 37%. On univariate and multivariate analyses, the MGMT methylation status was the only factor resulting significantly associated with survival. Grade 3 ocular toxicity occurred in 11% of patients, no grade 4 ocular toxicity was reported. No death was considered to be drug-related. Conclusions: The study reported the first “real world” experience of Depatux-M plus temozolomide in recurrent glioblastoma patients. Encouraging clinical benefits were demonstrated, even though most patients were treated beyond second-line therapy. Overall, the results are close to those reported in the previous phase 2 trial. Toxicity was moderate and manageable.

This study aimed to prospectively evaluate, on a long-term basis, corneal side effects secondary to compassionate administration of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in patients affected by EGFR-amplified recurrent glioblastoma. Fifteen patients with a median follow-up of 4.3 months after treatment discontinuation were enrolled. Each patient underwent full ophthalmologic examination including in vivo corneal confocal microscopy (CCM). No CTCAE grade 4 toxicity and four (27%) grade 3 toxicities were documented during treatment. Ocular symptoms (blurred vision, eye pain, photophobia) were experienced by all patients, reaching maximal severity after the second ABT-414 infusion, with persistence until treatment discontinuation. During treatment, CCM documented specific changes in the corneal epithelium and in the sub-basal nerve plexus layer fibers of all eyes. The median time of symptoms resolution after treatment discontinuation ranged from 38 days (eye pain) to 53 days (photophobia). The median time of signs resolution ranges from 14 days (corneal ulcer) to 38 days (superficial punctate epitheliopathy, corneal stroma edema and intraepithelial cysts). ABT-414 corneal side effects are detectable in all treated patients. Related symptoms are gradually experienced by all patients during treatment and although reversible, they are characterized by a relative prolonged persistence after treatment discontinuation.

Simple Summary Diffuse low-grade gliomas (LGG) are relatively uncommon primary brain cancers. In recent years, the molecular, diagnostic, and therapeutic approaches have evolved. IDH (isocitrate dehydrogenase) mutations can affect the great majority of these tumors with distinct genetic and clinical characteristics, carrying a more favorable prognosis compared with wild-type IDH. In patients with LGG, the most common manifestation is seizure and new neuroradiological tools are available to improve the diagnostic and therapeutic pathways. Surgical intervention is performed with the goal of maximum safe resection; postoperative chemoradiotherapy showed benefits in selected patients. New treatments based on molecular profiling, new small molecule and immunotherapy approaches could improve survival and quality of life. In this review, in order to identify the optimal clinical management of patients with LGG, we discuss the relevant biological and clinical characteristics, new therapeutic approaches, and future research directions for these tumors. Abstract Diffuse low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors arising from supporting glial cells and usually affecting young adults. Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors. Optimal post-operative management of LGG is still controversial, though radiation therapy and chemotherapy remain the optimal treatments after surgical resection in selected patients. In this review, we report the most important and recent research on clinical and molecular features, new neuroradiological techniques, the different therapeutic modalities, and new opportunities for personalized targeted therapy and supportive care.

Purpose: Brain tumor-related epilepsy (BTRE) is frequent in patients affected with glioma. Most patients have refractory seizures and require polytherapy. Promising treatment options derive from the development of novel anti-epileptic drugs (AEDs), like Eslicarbazepine (ESL), whose role in BTRE has not yet been explored. Our aim was to report a retrospective cohort of patients affected by BTRE treated with ESL as an adjunctive therapy and to discuss the potential role of this third-generation AED in this clinical context.Methods: We analyzed a single-center, retrospectively collected cohort of patients affected by glioma and BTRE, treated with ESL as an adjunctive therapy.Results: Analysis included 5 males and 3 females with age ranging from 37 to 75 years (mean = 55.5). Mean baseline Karnofsky performance status was 87.5 (range 70-100). Patients were affected by diffuse astrocytoma (3), low grade oligodendroglioma (2), anaplastic glioma (2) and glioblastoma (1). Mean follow-up was 19 months (range 6-59). Mean dose at the last follow-up was 950 mg daily. Mean weekly seizures in the month before initiation of ESL numbered 17.6 (range 0.25-50). At the last follow-up, mean weekly seizures were 2.2 (range 0-10), i.e. significantly lower than baseline (p = 0.03). The mean reduction of seizures achieved after introduction of ESL was 65%, with 6/8 patients (75%) showing a reduction of more than 50%. Two patients (25%) were seizure free.Conclusions: This single-center experience suggests that ESL may be a well-tolerated, efficacious option as an add-on drug in the treatment of BTRE.

This chapter addresses the legitimacy of public authorities to interfere in parenting when migrant parents are framed as a target group. The empirical data consist of three parenting programs devel ...

The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 28 patients out of 41 patients planned have been enrolled, without relevant toxicity.

INTRODUCTION Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use. MATERIAL AND METHODS Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. RESULTS 54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. CONCLUSIONS We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.

Background: Treatment of elderly glioblastoma patients (EGP) is a challenge in neuro-oncology. The comprehensive geriatric assessment (CGA) is currently used to assess geriatric oncological patients with other types of tumors. We performed a large retrospective study to analyze its predictive role in EGP. Methods: Patients aged &ge, 65 years with histologically confirmed diagnosis of glioblastoma were enrolled. CGA included the following tests: the Cumulative Illness Rating Scale-Comorbidity and Severity Index, Activities of Daily Living, Instrumental Activities of Daily Living, the Mini Mental State Examination, and the Geriatric Depression Scale. Based on CGA results, each patient was categorized as fit, vulnerable, or frail. Results: We enrolled 113 patients. According to the CGA scores, 35% of patients were categorized as &ldquo, fit&rdquo, 30% as &ldquo, vulnerable&rdquo, and 35% as &ldquo, frail&rdquo, patients. Median overall survival was 16.5, 12.1, and 10.3 months in fit, vulnerable, and frail patients (p = 0.1), respectively. On multivariate analysis, the CGA score resulted an independent predictor of survival, indeed, vulnerable and frail patients had a hazard ratio of 1.5 and 2.2, respectively, compared to fit patients (p = 0.04). No association between CGA and progression-free survival (PFS) was demonstrated. Conclusions: The CGA score proved to be a significant predictor of mortality in EGP, and it could be a useful treatment decision tool.

BACKGROUND REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. MATERIAL AND METHODS HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P=0.01 (2-sided). RESULTS Of 119 randomized pts, 117 partecipated in the HRQoL evaluation, and 114 had a baseline assessment (n=56 REG; n=58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD=28.6) vs 7.6 (SD=16.0); p=0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively;p=0.02). CONCLUSION In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.

Background: The aim of this study was to prospectively analyse, for the first time worldwide by in vivo clinical confocal microscopy (CCM), corneal side effects secondary to the use of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in a cohort of patients affected by EGFR-amplified recurrent glioblastoma. Methods: Each enrolled patient underwent full ophthalmologic examination including in vivo CCM of the cornea. Each patient was examined at baseline and every 2 weeks during treatment as long as patient conditions allowed it. Results: A total of 10 patients were consecutively enrolled. Median follow-up was 5 months. No Common Terminology Criteria for Adverse Events Version 4.0 grade 4 toxicity was documented. Two (20%) grade 3 toxicities were documented at week 8. CCM examination detected in all eyes multiple and diffuse hyperreflective white round spots in the corneal basal epithelial layers (100%), progressive subbasal nerve plexus layer fibres fragmentation followed by full disappearance (100%) and appearance of round cystic structures in the corneal epithelium (100%). All CCM documented side effects reached the peak of prevalence and severity after a median of 3 infusions. After treatment discontinuation, the reversibility of corneal side effects was documented at CCM after a median of 4 weeks. Conclusion: ABT-414 toxicity is not only directed to the corneal epithelium, but also to corneal nerves. Side effects are detectable in all treated patients and CCM documents early corneal epithelium and subbasal nerve plexus toxicity, with subsequent progressive restoration after treatment discontinuation. Ocular side effects due to ABT-414 can be manageable.

Background: Neoplastic pericardial effusion (NPE) is a life-threatening condition that can worsen clinical outcome in cancer patients. The optimal management of NPE has yet to be defined because randomized studies are lacking. Objective: We report a retrospective monoinstitutional experience describing characteristics, management and prognostic factors in NPE patients. Design: We reviewed clinical, pathological, and echocardiographic features, therapeutic strategies, and outcome in NPE patients referred to our institute from August 2011 to December 2017. Measurements: Twenty-nine patients with NPE from solid tumors have been identified: 21 lung, 5 breast, and 3 other cancer patients. Results: Median age was 62 years. Most of the patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (69%) and a symptomatic NPE (69%). In 52% of patients NPE was detected at first diagnosis of metastatic disease, and in 20% of patients pericardium was the only site of metastases. Most of the patients (62%) received systemic therapy, 28% received combined locoregional and systemic therapy, and 10% received locoregional therapy alone. Median overall survival (OS) from NPE diagnosis was 3.9 months. Patients with PS ≥2 had worse OS than patients with better PS

e14024 Background: Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use. Methods: The clinical data of patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively into clinical records and were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0-1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related. Conclusions: We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.

This article revisits the state-immigrant nexus by exploring the making of immigrant schoolchildren and their families as precarious elements in the population management of the Danish welfare nation-state. The emphasis is on how immigrant schoolchildren and their families have become a problem, and what forms of knowledge, differentiations, technologies and rationalities emerge from the efforts made to understand and solve the problem(s) since their appearance on Danish territory from the 1970s and onwards. The article explores a diverse set of historical-empirical national and local government documents advancing a polyhedron of intelligibility by which the authors discover how problem-solving complexes responsive to immigrant schoolchildren and their families change and overlay each other in a diachronic perspective. The argument presented is that the problem-solving complexes reflect the ambiguous (re)crafting of the Danish welfare nation-state faced with intensified South-North/East-West labour immigration, UN-mandated refugee distribution and global economic restructuring. This article explores the making of immigrant families as precarious elements in the governing of the population's welfare within the Danish welfare nation-state since the 1970s. The emphasis is on how immigrant families became a problem of welfare governing, and what knowledge practices and welfare technologies emerged as problem-solving responses. The article analyses a diverse set of national and local administrative documents advancing a polyhedron of intelligibility by which the authors discover how problem-solving complexes responsive to immigrant families change and sediment, and ultimately, weave the fabric of a Danish welfare nation-state faced with non-Western immigration after the economic boom in the late 1960s.

Modern welfare states emerged as a response to the social question and were crafted through the educationalisation of society engendering a need for a variety of professionals who could take care of citizens of concern. This article revisits the social question in a post-1970 Danish context of a growing non-western immigrant and refugee population and increasing professional attention paid to the presence of immigrant schoolchildren as a new social problem. In particular, the article takes as its point of departure the educationalisation of this new social problem, often referred to in terms of “integration”. Hence, it examines the dispositions and capacities of teachers imagined to handle immigrant schoolchildren as objects of educational and societal concern. Moreover, it explores how these entangled processes of educational problematisations and teacher professionalisation embedded in visions of good citizens and a good society, ultimately fed into the crafting of a post-1970 Danish welfare nat...