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2083
Background: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). However, tumor recurrence inevitably occurs. Methods: We treated 63 ...recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m
2
) every 2 weeks, and investigated IL-12, IL-13, IL-17, FGF basic, G-CSF, MIP-1b, PDGF-beta, plasma levels before starting treatment and every 8 weeks by Bioplex. Ten age- and sex-matched healthy controls were used for comparison. Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%, respectively. OS at 6 months was 60%. Toxicity was mild. Baseline higher amounts of IL-13 (48±174 pg/ml vs 3.44±0.9 pg/ml, p=0.0001) and lower amounts of MIP-1b (35.3±20.9 pg/ml vs 67.2±18.8 pg/ml, p=0.0002), PDGF-beta (1585.5±1585 pg/ml vs 7098±1585 pg/ml, p=0.0001) and VEGF (27±39.8 pg/ml vs 54.5±32 pg/ml, p=0.001) were detected in patients than in healthy controls. In a cohort of 15 non-responders (patients who progressed 8 weeks after treatment onset), baseline IL-8 (15.7±10.8 pg/ml vs 10.9±9.4 pg/ml, p=0.03) and G-CSF (113.3±54 pg/ml vs 84.9±59.2 pg/ml, p=0.03) were significantly higher than in patients responding to treatment. In the same cohort no significant reduction of VEGF and other cytokines was observed after 8 weeks of treatment, while a decrease of plasma VEGF was observed in the remaining patients (26±32 pg/ml vs 13.3±28.5 pg/ml, p=0.001). Furthermore, in a cohort of 22 long-term responders (patients who progressed after more than 18 weeks of treatment), levels of VEGF decreased after 8 weeks of treatment when compared to baseline, whereas no difference was observed in baseline levels (23.9±22.6 pg/ml vs 9.8±9.4 pg/ml, p=0.001). Conclusions: Data suggest that high levels of IL-8 and G-CSF at baseline associated with a lack of VEGF decrease after 8 weeks of treatment identify patients who are resistant to bevacizumab. This hypothesis should be tested in a large number of patients.
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2074
Background: Angiogenesis is a requirement for progression of glioblastoma (GBM) and vascular endothelial growth factor (VEGF) is a mediator of neo-angiogenesis in this tumor. ...Bevacizumab (Bev), an antibody directed to VEGF, was recently used to treat GBM. However in vivo modifications induced by treatment are still not clearly understood. Aim of this study is to analyze tumor changes induced by Irinotecan (Ir) and Bev, using two different methodologies: relative CBV variation (rCBV) and Difference Perfusion Maps (DPMs). Methods: 42 recurrent GBM patients underwent Bev (10 mg/kg) and Ir (125 or 340 mg/m
2
) treatment every 2 weeks and were followed up with a radiological protocol, including Dynamic Susceptibility Contrast MRI every 8 weeks. Radiological responses were assessed based on RANO criteria (Wen et al, 2012). Two methods were used to assess perfusion changes. In method A, relative CBV variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. In method B, relative CBV variations with respect to baseline values were calculated into the evolving tumour region by means of a voxel-by-voxel difference. DPMs were created showing where rCBV significantly increased, decreased or remained unchanged. Results: After a median follow-up of 33.5 months median overall survival (OS) was 35.0 weeks and median progression free survival (PFS) was 20.0 weeks. Method A showed a significant decrease of rCBV for patients with stable disease or partial response after 8 weeks of treatment (p = 0.01) while progressing patients maintained elevated levels of rCBV (p = 0.38). Method B, based on DPMs, showed that patients presenting rCBV increase higher than 25° percentile (corresponding to rCBV increase higher than 18% of tumor volume) had a significantly longer PFS (p = 0.045) and OS (p = 0.016). Conclusions: Using DPM we observed that early increase in global perfusion is related to better survival. This may suggest that Bev, when effective, reduces blood-brain barrier permeability with a higher contrast retention in vessels. If confirmed by further studies this measure could be useful in identifying responders to Bev.
Abstract
Purpose: Bevacizumab, an anti-VEGF antibody, has shown significant activity in high grade gliomas (HGG). Previous studies emphasized the need for predictive markers of response. Experimental ...Design: We treated 63 recurrent HGG patients with poor prognostic factors with bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m2) every 2 weeks, and investigated the predictive potential of circulating endothelial cells (CECs) and their progenitors (CEPs). Results: After a median follow-up of 27 weeks, median OS and PFS were 33 and 18 weeks, respectively. PFS at 6 and 12 months were 32% and 12%. OS at 6 months was 60%. No complete response but fourteen partial responses according to RANO criteria were observed. Toxicity and side effects were mild. Patients with distant intracerebral disease or leptomeningeal dissemination at baseline MRI had shorter PFS (p=0.002; p=0.01) and OS (p=0.005; p=0.03). Baseline CEP over 32.8 cells/ml (1st quartile) or CD45dimCD34+CD133+ hematopoietic committed progenitors over 27 cells/ml (1st quartile) were associated with an increased PFS (p=0.01; p=0.001, respectively). Baseline CD109+ CECs over 47.5 cells/ml (2nd quartile) were associated with longer PFS and OS (p= 0.001; p=0.02). Patients who progressed after 18 weeks of therapy or more (n=22) had baseline levels of CD109+ CECs and CD45dimCD34+VEGFR2+ cells significantly higher than others (p=0.008; p=0.04, respectively). At progression no significant change in CEC and CEP was detected. Conclusions: The data point to baseline CD109+ CECs, CEP and CD45dimCD34+CD133+ hematopoietic committed progenitors as promising markers for the selection of patients who could benefit from bevacizumab in the treatment of HGG.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1383. doi:1538-7445.AM2012-1383
Abstract
Recurrent glioblastoma (GB) are highly aggressive tumors allowing 6-8 month survival. Here we evaluated the possible benefits of immunotherapy with mature dendritic cells (DC) loaded with ...autologous tumor lysate in 15 patients with recurrent GB. After a median follow-up of 8 months median progression free survival (PFS) was 4.4 months and median overall survival (OS) 8.0 months. Patients with small tumors at first vaccination (< 20 cc; n = 8) had significantly longer PFS and OS than others: 6.0 vs 3.0 months (p = 0.01) and 16.5 vs 7.0 months (p = 0.003), respectively. Patients were analysed for CD8+ T cells, CD56+ NK cells and other relevant immunological parameters in peripheral blood before and after immunization, defining a vaccination/baseline ratio (V/B ratio). Increased V/B ratio of NK but not CD8+ T cells was significantly associated to longer PFS and OS. Patients showing NK cell responses had higher levels of IFN-γ and E4BP4, the NK cell transcription factor. Furthermore, NK V/B ratio was inversely correlated with TGF-β2 and VEGF V/B ratio. The results suggest that tumor-loaded DC may increase survival of recurrent GB after effective tumor debulking and emphasize the role of NK cell responses in this therapeutic setting.
Citation Format: Serena Pellegatta, Marica Eoli, Simona Frigerio, Carlo Antozzi, Maria Grazia Bruzzone, Gabriele Cantini, Sara Nava, Elena Anghileri, Lucia Cuppini, Valeria Cuccarini, Emilio Ciusani, Marta Dossena, Bianca Pollo, Renato Mantegazza, Eugenio A. Parati, Gaetano Finocchiaro. NK cell response and tumor debulking are associated to prolonged survival in recurrent glioblastoma treated by dendritic cells loaded with autologous tumor lysate. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2013-2839
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
ITF2357 (Italfarmaco, Italia) is a novel hydroxamic acid-based HDAC inhibitor (HDACi) that has shown reduced toxicity in phase I studies. We have investigated the cytotoxic and anti-proliferative ...activities of ITF2357 in multiple myeloma (MM) and acute myelogenous leukaemia cells (AML). ITF2357 had a strong cytotoxic activity in 8/9 MM and 6/6 AML cell lines, with a mean IC50 of about 0.2 μM, a concentration largely attained following oral administration of safe doses of ITF2357 to healthy individuals. In contrast SAHA, the prototypic hydroxamic HDACi, showed an IC50 of about 1 μM or above in all cases. The cytotoxic activity of ITF2357 was due to induction of apoptosis, as documented by detection of annexin V and cleaved caspase 3. The ITF2357 induced hyperacetylation of histones in cell lines resistant or sensitive to the cytoytoxic activity of the drug is under investigation in order to further define its mechanism of action. ITF2357 had also more potent cytotoxic activity compared to SAHA against freshly isolated CD138+ purified MM cells and AML samples, with an IC50 of about 0.1 μM in 3/3 MM and 13/15 AML cases. Sensitive AML cases included five cases of FAB M1, five M2 and three M4. Three of the sensitive cases carried a t(8;21) translocation, 2 an inv(16), 6 had a normal and 2 a complex karyotype. Furthermore four of the sensitive AML also carried a flt3 internal tandem duplication and 3 a type A mutation in the nucleophosmin 1 gene (NPM1). The 2 more resistant AML cases (one M1 and one M5, both with normal karyotype) showed nonetheless a response to the drug with an IC50 of about 0.5 μM. We have also developed a culture system to grow freshly isolated AML cells for at least 3 weeks in vitro on human mesenchymal cells (MSC). Interestingly, ITF2357 was cytotoxic for primary AML cells stimulated to grow in optimal conditions on MSCs, at the same dose as in standard short term cultures. In contrast ITF2357 was not cytotoxic for MSCs even at the 1 μM concentration. The strong cytotoxic activity of ITF2357 on MM and AML has provided the framework for ongoing phase I studies of ITF2357 in these malignancies.
Pulmonary embolism (PE) is a frequent complication in COVID19 hospitalized patients. Inflammatory storm and endothelial dysfunction due to the virus seem to be the two major risk factors for PE. ...Consequently, PE related to COVID19 could be consider as triggered by a transient inflammatory acute phase and treated for no longer than 3 months. However, few data are available on management of anticoagulation and risk of venous thromboembolic (VTE) recurrences in these patients and guidelines are still undefined.
Aim of the present study is to evaluate the long-term follow-up of a cohort of covid-19 patients with PE.
We conducted a retrospective multicenter study in four Italian hospitals between March 1st, 2020, and May 31st, 2021 in patients who experienced a PE during hospitalization for a COVID-19 pneumonia, excluding patients who died during hospitalization. Baseline characteristics were collected and patients were grouped according to duration of anticoagulant treatment (< 3 months or > 3 months). The primary outcome was incidence of VTE recurrence while secondary outcome was the composite of deaths, major hemorrhages and VTE recurrence during follow-up.
106 patients with PE were discharged, of these 95 (89.6 %) had follow up longer than 3 months (seven patients were lost to follow up and four died within three months). The median follow-up was 13 months (IQR 1–19). Overall, 23 % of subjects (22/95) were treated for 3 months or less and 76.8 % (73/95) received anticoagulation for >3 months. Of patients in the short treatment group, 4.5 % died, compared with 5.5 % of those in the longer treatment group (p = NS); no difference was shown in risk of VTE recurrence (0 % vs 4.1 %, p = NS), major bleeding (4.5 % vs 4.1 %, p = NS) or in composite outcome (9.1 % vs 11 %, p = NS). No difference was found between the two treatment groups for composite outcome using the Kaplan-Meier analysis (Log Rank Test p = 0.387).
In our retrospective multi-center cohort, prolongation of duration of anticoagulation seems not to affect risk of VTE recurrences, deaths and bleeding after a PE related to COVID-19.
•PE during hospitalization for COVID-19 seems to be provoked by SARS-COV2 infection.•3 months of anticoagulation in these patients seem to be safe and efficacious.•Extended anticoagulation in these patients does not improve outcomes.
Objective: Hypertension and hyper-cholesterolaemia is a dangerous combination frequently found in clinical practice. Despite a wide range of medications available for these both conditions, a large ...proportion of treated patients remain uncontrolled. We aimed to evaluate the cost-effectiveness treatment of a polypill in high-risk hypertensive and hyper-cholesterolemic subjects. Design and method: 46 subjects (mean age 67.4 ± 11.5 years, 69.6% men) treated a with free-combination (FCT) of statins (atorvastatin 63.1%, simvastatin 19.6%, rosuvastatin 8.7%, other 8.6%), renin-angiotensin-system blockers (ramipril 37.1%, perindopril 28.2%, enalapril 11%, zofenopril 4.4%, candesartan 6.5%, valsartan, losartan and telmisartan 4.3%) and calcium-channel blockers (amlodipine 61%, lacidipine and lercanidipine 15.2%, manidipine 6.6%), were switched to once-daily therapy with a polypill containing atorvastatin/perindopril/amlodipine at different doses. The monthly cost for treating patients with FCT and polypill was estimated using pharmacy dispensing records. Blood pressure (BP) and low-density cholesterol (LDL-C) targets values to reach were < 130/80mmHg and < 70 mg/dL, respectively. Categorical variables, were compared using Pearson’s chi-squared test. The change of systolic BP (SBP), diastolic BP (DBP), LDL-C levels and the costs of treatments were compared from baseline to the follow-up (FW, 3.5 ± 1.5 months) by the analysis of variance for repeated measures using the Fisher’s (F) test. Results: From baseline to the FW, polypill significantly decrease SBP (141.3 ± 10.1 vs. 133.9 ± 10.5, F = 33.8, p < 0.0001), DBP (81.8 ± 5.3 vs. 77.8 ± 4.1, F = 9.3, p < 0.004) and LDL-C values (99.3 ± 31.5 vs. 70.9 ± 18.5, F = 60.6, p < 0.0001), respectively. The BP and LDL-C targets significantly increased from 24.1 to 56.5% (p < 0.05) and 21.7 to 63.1% (p < 0.05), respectively. The average cost of polypill is lower than the FCT one (13.5 ± 0.7 vs. 23.2 ± 5.3 €, p < 0.0001, difference -9.8 ± 5.2 €). No adverse event was observed during the polypill treatment. Conclusions: In high-risk hypertensive and hyper-cholesterolemic subjects, the polypill treatment is cost-effective. National and regional epidemiological data show a prevalence of high-risk hypertensives of about 12%. In perspective, in the local public health-unit 5 Polesana, which gathers about 235 thousand inhabitants, using polypill compared to the FCT could result in annual cost savings of about 3.2 million € (Figure). However, for definite conclusions, further studies including a wider number of subjects in this setting are needed.
Abstract Background The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. Methods In an Italian cohort, we ...investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4 mm of incompressibility of the proximal veins. Results RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48–0.81) after three months, and 0.17 (95% CI; 0.11–0.26) after six months. Conclusions In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT.
Introduction
Inhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The phase ...IIIb Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain.
Methods
This was a randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥ 4 on numerical rating scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3 mL or SAT intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4–6). The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane–SAT) was less than 1 and less than 0, respectively.
Results
Between 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference − 5.94 mm; 95% CI − 8.83, − 3.06 mm), moderate pain (− 5.97 mm; 95% CI − 9.55, − 2.39 mm) and severe pain (− 5.54 mm; 95% CI − 10.49, − 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated “Excellent”, “Very Good” or “Good” by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients.
Conclusion
Methoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option.
Trial registration
Trial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018.
Funding
Mundipharma Pharmaceuticals S.r.l.
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