BCAS1 defines a heterogeneous cell population in diffuse gliomas.

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.

Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification.

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.

Differential effect of vascularity between long- and short-term survivors with IDH1/2 wild-type glioblastoma.

INTRODUCTION: IDH1/2 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. PURPOSE: To 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 METHODS: Ninety-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). RESULTS: For 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. CONCLUSION: We 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.

Robust association between vascular habitats and patient prognosis in glioblastoma: An international multicenter study.

BACKGROUND: Glioblastoma (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). PURPOSE: To validate the association between hemodynamic markers from vascular habitats and overall survival (OS) in glioblastoma patients, considering the intercenter variability of acquisition protocols. STUDY TYPE: Multicenter retrospective study. POPULATION: In all, 184 glioblastoma patients from seven European centers participating in the NCT03439332 clinical study. FIELD STRENGTH/SEQUENCE: 1.5T (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. ASSESSMENT: We 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 TESTS: Uniparametric Cox regression; Kaplan-Meier test; Mann-Whitney test. RESULTS: The 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 CONCLUSION: The 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: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1478-1486.

Sunitinib rechallenge in advanced renal cell carcinoma: outcomes of a multicenter retrospective study.

PURPOSE: The aim of this multicenter study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who received sunitinib retreatment. METHODS: 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. RESULTS: 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. CONCLUSIONS: Sunitinib rechallenge is a feasible treatment option for selected patients with mRCC.

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review.

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.

Radium-223 international early access program: results from the Spanish subset.

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.

Erratum: Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study.

[This corrects the article DOI: 10.3892/ol.2017.5988.].

Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study.

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.

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification.

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.

Functional PTGS2 polymorphism-based models as novel predictive markers in metastatic renal cell carcinoma patients receiving first-line sunitinib.

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.

Geometrical Measures Obtained from Pretreatment Postcontrast T1 Weighted MRIs Predict Survival Benefits from Bevacizumab in Glioblastoma Patients.

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.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

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/m(2), 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.

Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma.

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with renal cell carcinoma.

Clear-cell renal cell carcinoma (RCC) is the most common kidney cancer. New treatment options of localized RCC recently incorporated include laparoscopic surgery, nephron-sparing surgery, ablative techniques and active surveillance. But 50 % of patients may develop disease recurrence attributable to subclinical metastases. In these cases, and considering the low benefits of chemotherapy, new targeted therapies such as tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have been developed as first- and second-line treatment. Both sunitinib and pazopanib are TKIs that constitute the first-line treatment option in patients with metastatic RCC. As second-line treatment, sequential therapy with a second TKI or a mTOR inhibitor is recommended. This review has collected together a series of recommendations issued by the Spanish Oncology Genitourinary Group with the aim of facilitating the treatment of these patients. Each recommendation is accompanied by the level of evidence and grade of recommendation on the basis of the available data.

Sunitinib administered prior to radiotherapy in patients with non-resectable glioblastoma: results of a phase II study.

Sunitinib is a tyrosine kinase inhibitor with direct anti-tumor and anti-angiogenesis activity targeting VEGFR 1-2, PDGFR α-ß, c-kit, bFGF, (CSF-1), FLT3 and RET. The present trial examined the activity of sunitinib in 12 patients with newly diagnosed, non-resectable glioblastoma. Patients (≤75 years of age with performance status [PS] ≥2 and minimental status [MMS] ≥25) were treated post-biopsy with sunitinib 37.5 mg daily for 8 weeks pre-radiotherapy, during radiotherapy (60 Gy, 6 weeks) and post-radiotherapy until disease progression. The primary endpoints were overall response rate (ORR; RANO criteria) after 8 weeks of sunitinib and patient tolerance. Secondary endpoints were percentage of patients free of neurological deterioration pre-radiotherapy, percentage of patients completing radiotherapy, progression-free survival (PFS), overall survival (OS), and 1-year survival. A Simon 2-stage design (12 →20) based on ORR was applied to calculate the number of patients needed to detect at least 10 % response with α error of 0.05 and ß error of 0.10. The trial was closed because it did not meet minimal activity criteria. ORR was 0 % with only 1/12 patients (8.3 %) achieving stable disease after sunitinib treatment. No patient showed reduction in gadolinium enhancement. The most frequent G3/4 toxicities were fatigue (24.9 %) and diarrhea (16.6 %); one patient died of a CNS hemorrhage; 10/12 patients (83.3 %) deteriorated neurologically before radiation therapy; median PFS was 7.7 weeks (95 % CI: 7.2-8.2); median OS was 12.8 weeks (95 % CI: 0.5-23.8 weeks); 1-year survival was 0 %. Sunitinib has no activity as monotherapy in glioblastoma, and further investigation of its efficacy in this setting is unwarranted.

A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma.

To determine the maximum tolerated dose of irinotecan administered every 2 weeks, in combination with a fixed and continuous administration of temozolomide, in patients with glioblastoma at first relapse. Patients received oral temozolomide at a fixed and continuous dose of 50 mg/m divided into three daily doses, except for a single 100 mg/m dose, administered before every irinotecan infusion. Irinotecan was given intravenously on days 8 and 22 of 28-day cycles. The starting dose of irinotecan was 100 mg/m, and this was escalated by increments of 15 mg/m in cohorts of 3-6 evaluable patients. Determination of the dose-limiting toxicity was based on toxicities recorded from day 1 of the first cycleto day 8 of the third cycle. Enzyme-inducing antiepileptic drugs were not allowed. Tumor response was assessed by MRI every 8 weeks. Twelve patients were enrolled in this phase I study. The three patients enrolled at dose level 1 and six of nine patients enrolled at dose level 2 were evaluable for toxicity. The maximum tolerated dose of irinotecan was 100 mg/m. The dose-limiting toxicities were hematologic and gastrointestinal. Nine patients were evaluable for response: one patient achieved a partial response, four patients remained stable, and four patients had disease progression. The combination of metronomic temozolomide and irinotecan every 2 weeks can be safely administered at the recommended doses; a phase II study with this combination was started and has completed accrual.

Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value.

AIM: Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. METHODS: Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification. RESULTS: Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001). After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th) percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004). CONCLUSION: Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma.

Circulating endothelial cells and microparticles as prognostic markers in advanced non-small cell lung cancer.

BACKGROUND: Circulating endothelial cells and microparticles have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We have investigated the prognostic value of circulating endothelial cells and microparticles in patients treated for advanced non-small cell lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood samples were obtained from 60 patients before first line, platinum-based chemotherapy +/- bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Circulating endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Phosphatidylserine-positive microparticles were evaluated by flow cytometry. Microparticle-mediated procoagulant activity was measured by the endogen thrombin generation assay. RESULTS: pre- and posttreatment levels of markers were higher in patients than in controls (p<0.0001). Elevated levels of microparticles were associated with longer survival. Elevated pretreatment levels of circulating endothelial cells were associated with shorter survival. CONCLUSIONS/SIGNIFICANCE: Circulating levels of microparticles and circulating endothelial cells correlate with prognosis, and could be useful as prognostic markers in patients with advanced non-small cell lung cancer.

SEOM guideline for the treatment of malignant glioma.

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients' treatment, with the best results obtained when the three of them can be used.