BackgroundNew biomarkers are needed to improve treatment selection in patients with metastatic clear cell renal cell carcinoma (CCRCC). This study aims to identify predictive biomarkers through the investigation of serum proteins related to angiogenesis and tumor immune escape, alongside metabolic patterns associated with clinical outcomes.MethodsWe conducted a prospective, multicenter study in patients with locally advanced or metastatic CCRCC receiving first-line sunitinib. Serum protein levels, including those related to angiogenesis and immune escape, were measured. Additionally, untargeted lipidomic and targeted metabolic analyses focused on tryptophan metabolism and amino acid profiles were performed. Routine blood test results were recorded, and correlations among all parameters were analyzed.ResultsThirty-eight patients from ten Spanish hospitals were included. Median progression-free survival (PFS) was 9.87 months, and median overall survival (OS) was 21.10 months. Multivariate analysis identified higher interleukin-6 (IL-6), arginase-1, and S100 calcium binding protein A9 (S100A9) concentrations as significant predictors of shorter OS. We defined three distinct risk groups based on the combined levels of S100A9 and IL-6: high levels of both proteins, high levels of either one protein, or low levels of both proteins confer a poor, intermediate and favorable prognosis, respectively. Metabolomic analysis revealed significant differences in the tryptophan-kynurenine pathway between patients with extreme PFS and OS phenotypes. Elevated levels of tryptophan metabolites were associated with poorer PFS, while alterations in amino acids and tryptophan metabolites correlated with OS extremes. Notably, significant correlations were observed between IL-6 levels and increased tryptophan metabolism.ConclusionsThis study underscores the prognostic value of specific proteins and metabolites in metastatic CCRCC, proposing potential biomarkers for patient stratification and treatment response prediction.

Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, BCAS1 role in diffuse glioma is still underexplored. This study analyzes the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovers the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy. Our results show that BCAS1+ cells exhibit stellate or spherical morphology with similar ultrastructural features. Stellate and spherical cells were detected as isolated cells in all studied gliomas. Nevertheless, only stellate cells were found to be proliferative and formed tightly packed nodules with a highly proliferative rate in oligodendrogliomas. Our findings provide a comprehensive characterization of the BCAS1+ cell population within diffuse gliomas. The observed proliferative capacity and distribution of BCAS1+ stellate cells, particularly in oligodendrogliomas, highlight BCAS1 as an interesting marker, warranting further investigation into its role in tumor malignancy.

IDH -wildtype glioblastoma and IDH -mutant astrocytoma are classified as different gliomas according to WHO 2021. IDH mutations are key at clinical level, since they are associated with patient prognosis and seem to be critical for treatment selection. Despite these evidences, current protocols do not include the full sequencing for all tumors. In this sense, non-invasive and automatically calculated MRI-based biomarkers can be helpful for the clinical practice. Our results show that perfusion markers obtained in an automated, repeatable, and non-invasive manner may be candidates for being surrogate predictive markers of IDH mutation status in astrocytomas grade 4.

Background The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. Methods Data from 73 tissue blocks belonging to 17 IDH- wildtype glioblastomas and 7 blocks from 2 IDH -mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts’ supervision, achieving an accuracy of 88.8% of overlay. Spearman’s correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH -mutant astrocytoma samples. Results Significant positive correlations were found between rCBV and microvessel area in the IDH -wildtype blocks ( p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it ( p < 0.0001). In addition, significant differences in rCBV were found between IDH -wildtype glioblastoma and IDH -mutant astrocytoma samples, being 2–2.5 times higher rCBV values in IDH -wildtype glioblastoma samples. Conclusions The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH -wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.

IntroductionIDH1/2 wt glioblastoma (GB) represents the most lethal tumour of the central nervous system. Tumour vascularity is associated with overall survival (OS), and the clinical relevance of vascular markers, such as rCBV, has already been validated. Nevertheless, molecular and clinical factors may have different influences on the beneficial effect of a favourable vascular signature.PurposeTo evaluate the association between the rCBV and OS of IDH1/2 wt GB patients for long‐term survivors (LTSs) and short‐term survivors (STSs). Given that initial high rCBV may affect the patient's OS in follow‐up stages, we will assess whether a moderate vascularity is beneficial for OS in both groups of patients.Materials and methodsNinety‐nine IDH1/2 wt GB patients were divided into LTSs (OS ≥ 400 days) and STSs (OS < 400 days). Mann‐Whitney and Fisher, uni‐ and multiparametric Cox, Aalen’s additive regression and Kaplan‐Meier tests were carried out. Tumour vascularity was represented by the mean rCBV of the high angiogenic tumour (HAT) habitat computed through the haemodynamic tissue signature methodology (available on the ONCOhabitats platform).ResultsFor LTSs, we found a significant association between a moderate value of rCBVmean and higher OS (uni‐ and multiparametric Cox and Aalen’s regression) (p = 0.0140, HR = 1.19; p = 0.0085, HR = 1.22) and significant stratification capability (p = 0.0343). For the STS group, no association between rCBVmean and survival was observed. Moreover, no significant differences (p > 0.05) in gender, age, resection status, chemoradiation, or MGMT methylation were observed between LTSs and STSs.ConclusionWe have found different prognostic and stratification effects of the vascular marker for the LTS and STS groups. We propose the use of rCBVmean at HAT as a vascular marker clinically relevant for LTSs with IDH1/2 wt GB and maybe as a potential target for randomized clinical trials focused on this group of patients.

ABSTRACTBackgroundThe microvascular proliferation (MVP) and the microvessel area (MVA) are known as diagnostic and prognostic biomarkers for glioblastoma; nevertheless, its measurement is costly, labor-intense, and invasive. MRI perfusion biomarkers such as such as relative cerebral blood volume (rCBV) may be a feasible alternative to predict MVP and estimate MVA.PurposeThis study aims to evaluate the detection capacity of MRI markers such as rCBV to detect local microvascular proliferation in IDH wild-type glioblastoma. In addition, we aim to analyze the association between rCBV values and the microvessel area in different regions of the tumor.Study typeRetrospective study.Population and subjectsData from 71 tissue blocks belonging to 17IDHwild-type glioblastoma patients were compiled from the Ivy GAP database.Field Strength/Sequence1.5T or 3.0T. Pregadolinium and postgadolinium-based contrast agent-enhanced T1-weighted MRI, T2- and FLAIR T2-weighted, and dynamic susceptibility contrast (DSC) T2* perfusion.AssessmentWe analyzed preoperative MRIs to establish the association between the maximum and mean relative cerebral blood volume (rCBVmaxand rCBVmean) with the presence/absence of microvascular proliferation and with the microvessel area for each tumor block.Statistical testsSpearman’s correlation and Mann-Whitney test.ResultsSignificant positive correlations were found between rCBV and MVA in the analyzed tumor blocks (p<0.001). Additionally, significant differences in rCBV were found between blocks with MVP and blocks without MVP (p<0.0001).Data conclusionThe rCBV is shown as significantly different in those tissue blocks with microvascular proliferation from those blocks without it, and it is significantly correlated with microvessels area. This method allows a local detection and definition of MVP and MVA in different regions of the glioblastoma since the first diagnostic stage and in a non-invasive way.

Purpose: To systematically review evidence regarding the association of multiparametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th, 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and highrisk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, α=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.

BackgroundGlioblastoma (GBM) is the most aggressive primary brain tumor, characterized by a heterogeneous and abnormal vascularity. Subtypes of vascular habitats within the tumor and edema can be distinguished: high angiogenic tumor (HAT), low angiogenic tumor (LAT), infiltrated peripheral edema (IPE), and vasogenic peripheral edema (VPE).PurposeTo validate the association between hemodynamic markers from vascular habitats and overall survival (OS) in glioblastoma patients, considering the intercenter variability of acquisition protocols.Study TypeMulticenter retrospective study.PopulationIn all, 184 glioblastoma patients from seven European centers participating in the NCT03439332 clinical study.Field Strength/Sequence1.5T (for 54 patients) or 3.0T (for 130 patients). Pregadolinium and postgadolinium‐based contrast agent‐enhanced T1‐weighted MRI, T2‐ and FLAIR T2‐weighted, and dynamic susceptibility contrast (DSC) T2* perfusion.AssessmentWe analyzed preoperative MRIs to establish the association between the maximum relative cerebral blood volume (rCBVmax) at each habitat with OS. Moreover, the stratification capabilities of the markers to divide patients into "vascular" groups were tested. The variability in the markers between individual centers was also assessed.Statistical TestsUniparametric Cox regression; Kaplan–Meier test; Mann–Whitney test.ResultsThe rCBVmax derived from the HAT, LAT, and IPE habitats were significantly associated with patient OS (P < 0.05; hazard ratio [HR]: 1.05, 1.11, 1.28, respectively). Moreover, these markers can stratify patients into "moderate‐" and "high‐vascular" groups (P < 0.05). The Mann–Whitney test did not find significant differences among most of the centers in markers (HAT: P = 0.02–0.685; LAT: P = 0.010–0.769; IPE: P = 0.093–0.939; VPE: P = 0.016–1.000).Data ConclusionThe rCBVmax calculated in HAT, LAT, and IPE habitats have been validated as clinically relevant prognostic biomarkers for glioblastoma patients in the pretreatment stage. This study demonstrates the robustness of the hemodynamic tissue signature (HTS) habitats to assess the GBM vascular heterogeneity and their association with patient prognosis independently of intercenter variability.Level of Evidence: 3Technical Efficacy Stage: 2J. Magn. Reson. Imaging 2020;51:1478–1486.

Abstract Background Glioblastoma (GBM) is characterized by invasion, heterogeneity and high angiogenesis, conferring a poor prognosis. The aim of our study was to assess serum proteins related to these hallmarks with potential prognostic value in GBM. Methods Serum samples from GBM patients (N = 57 pts) were collected before Stupp regimen. We defined as “LT survivors” (LTS) those pts above 36-months survival, and as “ST survivors” (STS) those below 6-months survival. In the discovery cohort (N = 25 pts), 4 pts were identified in each group. A pooled analysis from serum samples of each group was performed by a protein profiling platform based on antibody array technology. Expressed proteins were assessed for differential expression between the two groups. In silico validation by using data obtained from French glioma study at R2 was performed. In situ expression levels from selected proteins involved in tumor progression (TP), cell proliferation (CP), invasion (Inv) and cell death (CD) that significantly correlate (p  Results A total of 1000 proteins were analyzed by the array. 214 proteins showed differences in fluorescence intensity more than 10-fold between LTS vs STS. Among them, SMAD4, SMAD5, TWEAK, VEGFR2, WISP1, FGF21, NEUROD1, SFRP3, SFPR4 and Bax were selected since obtained the highest differences in fluorescence intensity and correlated with differential OS outcomes in silico. ELISA validation demonstrated SFRP3 to be upregulated in the STS group (media expression (pg/ml) STS=1849;LTS=1039) (p = 0.018). No statistically significant differences were observed in the expression levels for the other proteins between LTS and STS. In validation cohort, median overall survival according to SFRP3 expression (low/high) was 19.7 months (CI 95% 10.7-28.61) vs 9.42 months (CI 95% 3.11-15.72) respectively, although did not reach statistical significance (p = 0.073). Conclusions Higher circulating SFRP3 level has been associated with STS in GBM. Overexpression of serum SFPR3 in GBM may be a surrogate indicator of poorer prognosis. Further studies are warranted. Legal entity responsible for the study The authors. Funding GEINO. Disclosure All authors have declared no conflicts of interest.

The aim of this multicenter study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who received sunitinib retreatment. Clinical data from patients treated with sunitinib rechallenge in nine Spanish centers were retrospectively analyzed. All patients received first-line sunitinib until progression or intolerance, followed by one or more successive drugs and rechallenge with sunitinib thereafter. Thirty-seven patients were included. At first-line treatment, objective response rate (ORR) was 69.4% and median progression-free survival (PFS) was 19.4 months. At rechallenge, ORR was 27.2% and 39.4% of patients obtained stabilization of disease. Median PFS was 6.2 months. Clinical benefit was obtained by 21 patients (75%) with > 6-month interval between sunitinib treatments and by 1 patient (20%) among those with ≤ 6-month interval (P = 0.016). Hemoglobin levels ≥ lower level of normal were associated with clinical benefit (P = 0.019) and with PFS (P = 0.004). Median overall survival from start of first-line sunitinib was 52.7 months. No new adverse events were observed at rechallenge. Sunitinib rechallenge is a feasible treatment option for selected patients with mRCC.

We report preliminarily results of an international retrospective study (NCT03439332) analyzing the prognostic value of the early assessment of vascular architecture of glioblastoma (GBM). The initial cohort included 300 pts treated at 7 European hospitals. Multiparametric images were processed by Oncohabitats (www.oncohabitats.upv.es) to obtain the cerebral blood volume (CBV) and cerebral blood flow (CBF) from 4 automatically delimited regions of interest (ROIs): high angiogenic tumor (HAT), low angiogenic tumor (LAT), infiltrating peripherial edema (IPE), and vasogenic peripherial edema (VPE). Uniparametric Cox regression models and Kaplan-Meier analysis were developed to test prognostic and stratification capabilities of each biomarker. 115 pre-surgical MRIs passed quality controls and were included in the analysis. Median follow up was 12.9 months (m) (IQR: 9.2-17.6). 73 pts (63.5%) were male. 54 pts (47%) underwent total resection; 84 pts (73%) received adjuvant temozolomide. Median OS was 13.6 m (95%CI:12.1-15.2). Cox regression analysis yielded a significant correlation between OS and maximum rCBV and rCBF in HAT and LAT (Table), independent of the extent of resection. Median OS by Kaplan-Meier analysis in patients with high and low vascularity is shown in the Table. Our preliminarily results shows that patients with lower vascularity (rCBV or rCBF) in vascular habitats inside enhancing tumor region (HAT and LAT) is associated with higher OS, and could improve patient stratification. Our results are consistent with our pilot study [1], Validation in large multicentric studies is underway. COX REGRESSION ANALYSISKAPLAN-MEIER STRATIFICATION ANALYSISCOX REGRESSION ANALYSISKAPLAN-MEIER STRATIFICATION ANALYSISHAZARD RATIO95% CONFIDENCE INTERVALP-VALUE*NUMBER OF PATIENTSMEDIAN SURVIVAL (months)P-VALUErCBV máximumHigh Angiogenic Tumor10.339[1.09- 1.14]0.0202*[29 86][16.66 12.78]0.004***Low Angiogenic Tumor10.485[1.17- 1.31]0.0262*[29 86][17.10 12.78]0.002***Infiltrating Peripheral Edema0.9835[1.30- 1.71]0.1208[29 86][14.60 12.91]0.119Vasogenic Peripheral Edema0.7942[1.14- 1.63]0.6046[29 86][15.23 12.91]0.220rCBF máximumHigh Angiogenic Tumor0.9997[1.02- 1.03]0.1077[47 68][14.93 11.65]0.009**Low Angiogenic Tumor10.411[1.21- 1.40]0.0384*[29 86][15.56 12.75]0.016*InfiltratingPeripheral Edema0.8923[1.35- 2.04]0.2589[29 86][15.23 12.83]0.394Vasogenic Peripheral Edema0.6846[1.11- 1.81]0.7447[29 86][14.60 12.96]0.508Table: Results of Cox-regression and Kaplan-Meier analysis. (P VALUE*: False discovery rate corrected.)[1]: https://doi.org/10.1148/radiol.2017170845 Citation Format: María del Mar Álvarez-Torres, Fuensanta Bellvís–Bataller, Javier Juan–Albarracín, Elies Fuster–Garcia, David Lorente Estellés, Gaspar Reynes, Fernando Aparici-Robles, Carlos Botella, Jose Muñoz-Langa, Raquel Faubel, Sabina Asensio-Cuesta, Germán Adrían García–Ferrando, Cristina Auger, Alex Rovira, Jose Pineda, Jaime Font de Mora, Enrique Mollà-Olmos, Antonio José Revert-Ventura, Luaba Tshibanda, Didier Martin, Girolamo Crisi, Kyrre Eeg Emblem, Paulina Due-Tonnessen, Torstein R Meling, Juan M García-Gómez. Preliminarily results of the Oncohabitats Study: A multicentre validation of overall survival (OS) estimation of patients with glioblastoma (GBM) using vascular biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4258.

PurposeWe retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients.Patients and methodsWe compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy.ResultsOS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13weeks for the NA group and 4.2weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12weeks and the shortest by patients who started radiotherapy within 4weeks (12.3 vs 6.6months) (P=0.05). OS was 6.6months for patients who started radiotherapy before the optimal cutoff of 6.43weeks and 19.1months for those who started after this time (P=0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P=0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor.ConclusionIn our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with >= 50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

The present observational, multicenter, retrospective study investigated the efficacy and tolerability of lacosamide in controlling secondary epileptic seizures in patients with brain tumors in Spain. Data from the medical records of patients ≥18 years of age with brain tumors, who had received at least one dose of lacosamide for seizure management between July 2013 and November 2013, were collected. The primary and secondary objectives of the present study were to assess the effectiveness and tolerability of lacosamide. Data from 39 patients (mean age, 54.1 years; 66.7% male) were collected, where the two main reasons for initiation of lacosamide treatment were the lack of efficacy of other antiepileptic drugs (in 76.9% of patients) and the presence of adverse events (12.8%) associated with other antiepileptic drugs. At the initiation of treatment, patients received a mean lacosamide dose of 138.5±68.3 mg/day. At 6 months, lacosamide had significantly reduced the mean number of seizures from 26.4 (standard deviation [SD], 50.4) seizures for the 6 months prior to lacosamide initiation to a mean of 9.4 (SD, 22.8) seizures during the 6 months subsequent to lacosamide initiation; P<0.001. Lacosamide was generally well tolerated; of the 25 patients who had complete safety data available at a 6-month follow-up, 3 patients (12%) reported an adverse event, including dizziness, asthenia, instability and irritability. The present retrospective analysis suggested that lacosamide is an effective and well-tolerated treatment in patients experiencing seizures due to brain tumors. Additional prospective studies with a larger patient population and randomized trial design are warranted.

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk–benefit ratio of adjuvant treatment must be weighed for each individual.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 ( PTGS2 ) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management.

The original version of this article unfortunately contained a mistake. Figure 3 was incorrect.

Background. We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods. Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results. Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2% /65.3% /24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions. Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Background Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. Methods 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE ‘rim’ geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. Results Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. Conclusion Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m2, days 1–21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.