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  • 1
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    Actionable molecular alterations in newly diagnosed and recurrent IDH1/2 wild-type glioblastoma patients and therapeutic implications: a large mono-institutional experience using extensive next-generation sequencing analysis
    Elsevier BV ; 2023
    In:  European Journal of Cancer Vol. 191 ( 2023-09), p. 112959-
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 191 ( 2023-09), p. 112959-
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2023.112959
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 2
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    Next-generation sequencing (NGS) for identifying actionable molecular alterations in patients with newly diagnosed and recurrent IDHwt-glioblastoma (GBM): A large mono-institutional experience.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3139-3139
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3139-3139
    Abstract: 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]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3139
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Defining the prognostic role of MGMT methylation value by pyrosequencing assay in glioblastoma patients: A large Italian multicenter study.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 2539-2539
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 2539-2539
    Abstract: 2539 Background: MGMT methylation (MGMTmet) status represents an important prognostic factor for glioblastoma (GBM) patients (PTS). Quantitative pyrosequencing approach has proven to be feasible for MGMTmet testing but its value is still unclear. We performed a large, multicentre, retrospective study to identify the association between MGMTmet values and clinical outcome. Methods: from 9 Italian neuro-oncology centres, we collected consecutive GBM PTS with assessment of MGMTmet by pyrosequencing approach evaluating CpG islands from 75 to 84. Other inclusion criteria were: histological diagnosis of GBM, ECOG PS ≤2, therapy with RT+TMZ. Kaplan-Meier method was used to estimate the survival curves, time-dependent ROC curve for defining the optimal cut-off value of mean percentage of MGMTmet in terms of 2y-OS, Cox regression for multivariable analysis, and restricted cubic spline to investigate the non-linear association between methylation values and OS. Results: 681 PTS were enrolled; median age was 60 ys; ECOG PS was 0 in 292 PTS, 1 in 306 PTS, 2 in 83 PTS; 391 PTS (58%) had a complete resection. 8% of PTS received a second surgery. IDH was mutated in 6%. 2y-OS was 31.6%, median OS was 17.4 ms. Median MGMTmet was 3.5% (IQR 0-22%). ROC curve identified a cutoff of 15% of MGMTmet in terms of 2y-OS (sens 78%, spec 57%, AUC = 0.67). 2y-OS was 19.7% and 53.7% for PTS with MGMTmet 〈 and ≥15%, respectively (p 〈 0.0001). At multivariable analysis, MGMTmet 〈 15% was associated with impaired survival (HR 2.7, 95% CI 2.1-3.4; p 〈 0.00001), adjusting for age, KPS, type of surgery and second surgery. A non-linear association between MGMT methylation and survival was identified (non-linear term: p 〈 0.0001), with lower values of MGMT methylation associated with lower survival; indeed, estimated median OS was lowest (14 months, 2ys-OS: 17.4%) with MGMTmet of 4%, 21ms (2yr-OS: 40.9%) with MGMTmet of 20%, 27ms (2yr-OS: 40.9%) when MGMTmet was 40%, then leveled around 30ms (2yr-OS: 54.5-59.8%) when MGMTmet was 〉 40%. Conclusions: this study represents one of the largest trials analyzing MGMTmet by pyrosequencing approach. Lower values of MGMTmet were associated with impaired survival and the relationship was non-linear. Noteworthy, we identified a strong prognostic value of MGMTmet which could be used as stratification factor in prospective clinical trials
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.2539
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Depatuxizumab mafodotin (Depatux-M) plus temozolomide (TMZ) in recurrent glioblastoma patients: Real-world experience from a multicenter study of Italian Association of Neuro-Oncology (AINO).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 2544-2544
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 2544-2544
    Abstract: 2544 Background: Precision medicine is a promising tool in oncology. Depatux-M is a new antibody-drug conjugate, consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The Intellance2/EORTC 1410 phase II trial, showed interesting results for Depatux-M and TMZ combination in EGFR-amplified glioblastoma (GBM) patients (PTS) at first recurrence after RT and TMZ. In our study, we investigated clinical outcome and safety of this combination used in recurrent GBM PTS as “compassionate use”. Methods: In this prospective observational study, PTS were enrolled from 7 centres of AINO. Major inclusion criteria were: histologically confirmed diagnosis of GBM, 1 or more prior systemic therapies, ECOG PS ≤ 2 and EGFR-amplified (analyzed by FISH). According to original schedule, patients received Depatux-M 1.25 mg/kg every two weeks combined with TMZ until disease progression or unacceptable toxicity. 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 October 2018 to June 2019, we enrolled 36 PTS: median age was 57, ECOG PS 0-1 in 88% of PTS, MGMTmet in 64%, 42% received the treatment as second-line therapy and 27% underwent further chemotherapy at progression. At the time of analysis, 13 PTS (36%) had died and 27 PTS (75%) had progressed. Median OS was 8.7ms (95%CI not available), 6ms OS was 68%; median PFS was 2.3ms (95% CI 1.8 – 2.8), 6ms PFS was 37%. All PTS were evaluable for response: disease control rate was 47%: stable disease was reported in 36% and partial response in 11% of PTS. Drug-related adverse events led to dose reductions of Depatux-M in 17% of PTS, in 28% was delayed and in 8% was permanently discontinued. The most frequent grade 3-4 adverse events were ocular toxicity in 67% and haematological toxicity in 17% of PTS; no death was considered drug-related. Conclusions: We report the first “real world” experience of Depatux-M plus TMZ in recurrent GBM. We showed encouraging clinical benefit, despite most patients were treated beyond the second-line of therapy. Overall the results are closed to those reported in previous phase II trial. Although toxicity was higher than expected, it was manageable and only a small group of patients discontinued the treatment due to serious adverse events
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.2544
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Phase II multicentric Italian trial on repositioning of the antipsychotic drug chlorpromazine and its combination with temozolomide in patients with MGMT unmethylated glioblastoma: The RACTAC trial.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS2073-TPS2073
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS2073-TPS2073
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS2073
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Regorafenib in recurrent glioblastoma patients: A large real-life experience.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e14024-e14024
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e14024-e14024
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e14024
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Brief Report: Successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: An Italian multicenter study
    Wiley ; 2012
    In:  Arthritis & Rheumatism Vol. 64, No. 6 ( 2012-06), p. 1970-1977
    Details
    In: Arthritis & Rheumatism, Wiley, Vol. 64, No. 6 ( 2012-06), p. 1970-1977
    Type of Medium: Online Resource
    ISSN: 0004-3591
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v64.6
    DOI: 10.1002/art.34350
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 2754614-7
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  • 8
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    Pembrolizumab (Pem) in recurrent high-grade glioma (HGG) patients (PTS) with mismatch repair deficiency (MMRd): An observational study.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 2043-2043
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 2043-2043
    Abstract: 2043 Background: Pem, an immune checkpoint inhibitor, demonstrated to be active in various neoplasms with MMRd. No data exists about its efficacy in MMRd glioma PTS. Methods: MMRd HGG relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMRd was defined as presence of a weak (wMMRd) or absent (aMMRd) signal for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed glioma, dexamethasone ≤4 mg. Pem was administrated at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. Results: among 167 glioma PTS, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases , MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd, respectively. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04), respectively. Grade ≥3 adverse events were reported in 8% of PTS. Conclusions: a subgroup of recurrent MMRd HGG might benefit from Pem, especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. The enrollment and analyses for identifying additional molecular predictive factors are ongoing.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.2043
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 9
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    PET/MR in recurrent glioblastoma patients treated with regorafenib: [ 18 F]FET and DWI-ADC for response assessment and survival prediction
    British Institute of Radiology ; 2022
    In:  The British Journal of Radiology Vol. 95, No. 1129 ( 2022-01-01)
    Details
    In: The British Journal of Radiology, British Institute of Radiology, Vol. 95, No. 1129 ( 2022-01-01)
    Abstract: 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- 18 F-fluoroethyl)-L-tyrosine positron emission tomography ([ 18 F]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 [ 18 F]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 [ 18 F]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. [ 18 F]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, [ 18 F]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 [ 18 F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.
    Type of Medium: Online Resource
    ISSN: 0007-1285 , 1748-880X
    URL: Article
    DOI: 10.1259/bjr.20211018
    RVK:
    XA 34700
    Language: English
    Publisher: British Institute of Radiology
    Publication Date: 2022
    detail.hit.zdb_id: 1468548-6
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