bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of antiangiogenic resistance: Targeting the JAK/STAT3 pathway in glioblastoma.
Authors: De Groot John Frederick , Liang Ji , Kong Ling-Yuan , Wei Jun , Piao Yuji , Fuller Greg , Qiao Wei , Heimberger Amy B. 
Published: March 2020

2011 Background: Determining the mechanism of treatment failure of antiangiogenic therapies would provide insight into either potential combination approaches or salvage therapies. Methods: Tumor and monocyte expression of phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) was compared between recurrent glioblastoma patients treated with either conventional chemotherapy or bevacizumab (BEV), and secondarily validated in murine model systems of intracerebral glioma treated with either BEV or cediranib. The JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib was evaluated in immunocompetent mice bearing intracerebral GL261 xenografts to evaluate therapeutic synergy. Results: Human glioblastoma patients failing BEV have an increase in intratumoral p-STAT3- expression with a mean number of p-STAT3 expressing cells of 36.5 + 8.6% (n=7) compared to a mean of 20.2 + 4 % (n=5) in patients never receiving antiangiogenic therapy. In a separate cohort of recurrent glioblastoma patients, the up-regulation of p-STAT3 was detected in monocytes within 24 hours after initial BEV administration. In intracranial xenograft models, both BEV and cediranib extended median animal survival time, but during treatment failure BEV increased the mean percentage of p-STAT3-expressing cells to 24.6 + 6.4% (P=0.0011), and cediranib increased this to 16.2 + 1.8% (P=0.0125) relative to 9.0 + 4.4% in controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and infiltration of VEGF inhibitor-induced p-STAT3 macrophages. The combination reduced tumor volume by 80% compared to untreated controls, and by 65% compared to cediranib or AZD1480 treatment alone. Microvascular density and tumor de-differentiation were reduced, indicating that up-regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy. Conclusions: Cumulatively, these data suggest that a prominent mechanism of failure of anti-VEGF therapy in malignant glioma patients involves up-regulation of the STAT3 pathway, and resistance to antiangiogenic therapy can be modulated with inhibitors of the JAK/STAT pathway.
Modeling radiation dose to circulating lymphocytes during brain tumor treatment: Effects of target volume, dose rate, and treatment technique.
Authors: Yovino Susannah G. , Grossman Stuart A. , Kleinberg Lawrence , Ford Eric C 
Published: March 2020

2017 Background: Severe treatment-related lymphopenia (TRL) occurs in 40% of glioblastoma patients despite minimal radiation (RT) doses to bone marrow or nodal sites. In glioblastoma, TRL is associated with decreased survival. To explain the lymphopenia, we sought to estimate radiation doses received by circulating lymphocytes during partial brain RT. Methods: An in-house computer program linked to treatment planning software was used to calculate the mean radiation dose to circulating blood (DCB) and the fraction of blood receiving >0.5 Gy. The model also studied the impact of different target volumes (PTV), dose rates (DR), and delivery techniques (IMRT, 3D-CRT). Results: The mean DCB for a 60-Gy course (8-cm diameter PTV, dose rate 600 MU/minute) was 2.2 Gy. With this the entire blood pool receives a lymphotoxic dose of >0.5 Gy. DCB is correlated with fraction number, PTV size, and DR. Regardless of dose rate or delivery technique, the percent of circulating blood receiving >0.5 Gy approached 100% as the number of fractions increased. Changing dose rate had minimal effects on mean DCB (3.1Gy for 300 MU/min vs 2.2 Gy for 1200 MU/min). Smaller PTV size reduced the percent of blood receiving >0.5 Gy (15% for 2-cm diameter PTV vs 100% for 8-cm PTV). Conclusions: Standard RT for brain tumors delivers a lymphotoxic radiation dose to circulating blood. Altering dose rate may initially affect DCB, but advantages disappear over the course of 30 fractions. Marked reductions in target size appear to be the best way to avoid radiation injury to normal circulating lymphocytes. Other novel approaches are needed to limit radiation exposure to circulating lymphocytes given evidence associating lymphopenia with poorer outcomes in cancer patients.
Blood alterations preceding clinical manifestation of glioblastoma.
Authors: Ilhan-Mutlu Aysegul , Wagner Ludwig , Woehrer Adelheid , Susanne Jungwirth , Marosi Christine , Fischer Peter , Preusser Matthias 
Published: March 2020

2024 Background: Glioblastoma is the most common and aggressive primary brain tumour in adults. There is lack of knowledge on biochemical blood alterations prior to clinical diagnosis of glioblastoma. We had the rare opportunity to investigate selected blood markers from plasma samples taken 12, 42 and 72 months before tumor manifestation in a glioblastoma patient. This index patient was enrolled in the longitudinal population based Vienna Transdanube Aging Study (VITA), which prospectively collects blood plasma from 600 participants at baseline (age 75), 30 and 60 months thereafter. Methods: We determined plasma levels of S100B, neuropeptide Y (NPY), secretagogin (SCGN), microRNA-21, microRNA-let7, microRNA-128, and microRNA-342-3p in all three blood samples from our index patient and in consecutive blood samples from five male and five female controls from the VITA cohort. These proteins and microRNAs were previously shown to be relevant for the pathobiology of glioblastomas. None of the controls had a malignant or neurological disease. Protein markers were analysed using commercially available ELISAs and microRNAs were quantified using RT-qPCR. Results: Compared to baseline values, we found a significant increase of microRNA-21 (up to 4-fold) and microRNA-let7 (up to 7-fold) levels in the blood samples of our index patient, whereas control samples showed almost stable levels of these markers. There was no significant difference in S100B, NPY, SCGN, microRNA-128, and microRNA-342-3p plasma levels between the index patient and controls. Conclusions: Increases of microRNA-21 and microRNA-let7 plasma levels may be associated with pre-clinical development of glioblastoma.
Phase II trial of sunitinib malate and lomustine in patients with temozolomide refractory recurrent low-grade and anaplastic gliomas.
Authors: Duerinck Johnny , Du Four Stephanie , Van Binst An , Everaert Hendrik , Michotte Alex , D'haens Jean , Neyns Bart 
Published: March 2020

2050 Background: Recurrent low-grade and anaplastic gliomas eventually transform to a higher grade that is characterized by neo-angiogenesis. Sunitinib inhibits multiple tyrosine kinase receptors (including VEGFR, PDGFR and c-Kit) but has no meaningful activity as a mono-therapy for recurrent glioblastoma when given at a daily dose of 37,5 mg (Neyns et al. J Neurooncol. 2011). We investigated sunitinib in combination with lomustine (CCNU) for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent low-grade or anaplastic glioma. Methods: Pts received a daily dose of 25 mg sunitinib for 28 consecutive days followed by a 14 days treatment-free interval. CCNU was administered as a single dose (80 mg/m²) on day 14 of a 6w cycle. T1 ± Gd and T2/FLAIR weighted MRI images were obtained q6 wks. 18FET-PET was performed at baseline and reassessed in responding pts. Results: 13 pts were enrolled (mean age 40 [range 33-49]; M/F 8/5; KPS 80-90/70-60: 8/5 pts). All pts had PD following surgery, RT and TMZ. In 7 pts, treatment was initiated at 2nd recurrence, in 4 pts at 3rd recurrence and in 2 pts at the 4th recurrence. Most frequent AEs where fatigue (gr 2: n= 3; gr 3: n= 1), thrombopenia (gr 2: n= 1 gr 3: n= 3 gr4: n= 1), neutropenia (gr 2: n= 2; gr3: n= 2; gr4: n= 2) and lymphopenia (gr 2: n=1; gr 3: n=2; gr 4: n=1). In 5/13 pts CCNU had to be discontinued because of AEs. Treatment with sunitinib was continued in these cases without reoccurrence of AEs. BOR according to RANO criteria: 1 CR, 1 PR (not-confirmed) and 2 SD (DCR: 4/13= 31%). In the patient with CR, FET-PET indicated a complete metabolic response. After a mean FU of 7 mths (range 2 -19), 5 pts are alive. The 6-month PFS is 23% (3/13 pts); median PFS is 1,8 mths (95%CI 1.0 - 2,7). A durable disease control was obtained in 3 pts (TTP respectively 14.8, 11.8+ and 19.2+ mths). Conclusions: in this heavily pretreated population with recurrent low-grade and anaplastic glioma the combination of sunitinib and CCNU is associated with acceptable toxicity and offers a durable progression-free survival in a subgroup of pts. Molecular predictive factors identifying the sensitive population would be needed to justify further clinical investigation of this combination.
Management of primary intraocular lymphoma (PIOL): Results from the prospective German PIOL registry (PIOL-R).
Authors: Jahnke Kristoph , Pleyer Uwe , Herwig Martina , Guthoff Rainer , Lueke Matthias , Meyer-ter-Vehn Tobias , Willerding Gregor , Thiel Eckhard , Korfel Agnieszka 
Published: March 2020

2054 Background: Primary intraocular lymphoma (PIOL) is a very rare disorder, and the optimal treatment is yet to be defined. Here, we report clinical characteristics and outcome of patients with PIOL enrolled in the prospective German PIOL registry (PIOL-R). Methods: Patient data in this prospective, non-interventional multicenter study were compiled by standardized questionnaires sent to Ophthalmology and Hematology/Oncology centers in Germany. All histologically or cytologically confirmed immunocompetent PIOL patients were eligible. Results: Fifteen patients (8 female, median age 66 years, median Karnofsky performance status 90%) from 4 centers were included between August 2008 and January 2012. Median follow-up was 7 months. Median time from first occurrence of symptoms to PIOL diagnosis was 5 (range, 1-11) months. All PIOL were of diffuse large B-cell histology. Eight patients had concomitant (n=3), prior (n=2) and/or subsequent (n=4) parenchymal brain involvement. First-line treatment included methotrexate (MTX)-, rituximab- and/or ifosfamide-based systemic chemotherapy in 12 (including high-dose chemotherapy [HDCT] with autologous stem cell transplantation [ASCT] in 2), intraocular (i.o.) chemotherapy with MTX (n=2) and/or rituximab (n=6) in 7, and ocular radiation in one patient(s). Two patients received prophylactic intrathecal (i.th.) treatment with MTX and none had whole-brain irradiation. The PIOL remission rate was 100% (complete remission in 11/14 evaluable patients and partial remission in 3 patients). Four patients relapsed in the brain after 5, 6, 21 and 23 months and received salvage treatment with MTX and/or ifosfamide (n=3) and HDCT with ASCT (n=1). No ocular or systemic relapses were observed. Median progression-free survival was 23 (95% confidence interval, 19-26) months. All patients are alive. Conclusions: Although the awareness of PIOL and diagnostic possibilities have improved over the past 2 decades, time from symptom presentation to diagnosis seems to remain at previously reported levels. There appears to be a shift from local ocular treatments and radiation to systemic therapy as compared to anecdotal data with promising response and survival rates.
The association of pretreatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme (GBM).
Authors: Bambury Richard Martin , Teo MinYuen , Yusuf Anny , Murray Susan , Battley Jodie E , Drake Catherine , O'Dea Pauline , Bermingham Niamh , Keohane Catherine , O'Reilly Seamus , Power Derek Gerard , Moylan Eugene J. 
Published: March 2020

2062 Background: GBM is the most common and aggressive primary brain tumor. The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic inflammatory response and lymphopenia, both of which are poor prognostic factors in many malignancies. No published study has assessed the prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our regional referral centre with assessable complete blood count at first presentation (prior to corticosteroid therapy or surgery) were identified. Medical notes were reviewed to extract demographic and treatment data. Survival curves were estimated via Kaplan-Meier method and compared via log-rank method. Multivariate analysis was performed via Cox proportional hazards regression modelling. Results: A total of 86 patients were identified, of which 65(76%) were male. Median age at diagnosis was 58 years (range: 18–76). At the time of analysis all patients still alive had ≥ 2 years follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% completed the standard adjuvant Stupp protocol and 43% discontinued early due to disease progression or treatment toxicity. Median OS was 11.2 months in patients with NLR<4 and 7.5 months in patients with NLR>4 (HR 0.59, p=.04). Other significant prognostic factors based on univariate analysis were consistent with published data (Table). After correcting for known prognostic factors NLR remained a significant predictor of survival (Table). Conclusions: Recent advances in immunotherapy have highlighted the importance of the immune system in the treatment and prognosis of cancer patients. Many GBM patients are on corticosteroids for a significant proportion of their disease course which may abrogate the effects of host immunity on outcome. Nevertheless, we have shown that NLR at diagnosis is an independent predictor of survival in GBM patients. Investigation of therapies which harness the immune response are warranted in this disease. [Table: see text]
A preclinical study on the combined treatment of nimotuzumab and sirolimus in glioblastoma.
Authors: Tham Chee Kian , Lam Paula , See Siewju , Lai Siang Hui , Thomas John , Ng Wai Hoe 
Published: March 2020

2066 Background: The human epidermal growth factor receptor (EGFR) is an ideal therapeutic target for inhibiting glioblastoma (GBM) growth as the signaling pathway is highly dysregulated in GBM. However, trials so far with EGFR inhibitors have not shown clinically meaningful improvement in response rates and survival. One of the postulated mechanisms of resistance is the constitutive activation of the downstream, PI3K/AKT/mTOR pathway, independent of the upstream EGFR activation status. Hence, the dual blockage of the pathways with an anti-EGFR agent and mTOR inhibitor is postulated to have synergistic anti-tumour effects. We aim to investigate the anti-tumour effect of combined nimotuzumab (anti-EGFR monoclonal antibody) and sirolimus (mTOR inhibitor) in a GBM preclinical model. Methods: Primary human GBM cells were derived from surgical GBM specimens. The endogenous expressions of glial-fibrillary acidic proteins and EGFR were determined by IHC staining and Western Blot analysis. Cell viability assays were then carried out in these GBM cells and immortalized human normal astrocytes (iHNA) using a range of concentrations of nimotuzumab alone, sirolimus alone or combined treatment. Results: GBM cells treated with nimotuzumab showed a dose- dependent cell kill and the optimal concentration was determined to be 2 µg/ml. Treatment of the GBM cells with sirolimus showed that the drug was capable of inducing cell death at varying levels and the optimal level was determined to be 0.1 mM. Combined treatment with nimotuzumab (2µg/ml) and rapamycin (0.1 mM) showed a dose dependent cell kill in GBM cells which was not observed in iNHA cells. The combined treatment resulted in only 10% of residual gliomas at 24 h post treatment. Single treatment with rapamycin has no cytotoxic effect whereas treatment with nimotuzumab alone exerts a cytotoxicity effect of 33%. Taken together, we observed an additive effect of cell kill when rapamycin is used together with nimotuzumab in human glioma cells. Conclusions: In this study, combined treatment of nimotuzumab and sirolimus resulted in a greater cytocidal effects in GBM cells than either agent alone. We will further examine this combination regimen in a subsequent phase I clinical trial.
Bevacizumab failure in glioblastomas.
Authors: Tabatabai Ghazaleh , Felsberg Joerg , Sabel Michael , Hofer Silvia , Westphal Manfred , Weller Michael , Reifenberger Guido 
Published: March 2020

2067 Background: Bevacizumab has been approved for the treatment of recurrent glioblastoma in various countries. The phase III registration trial assessing the addition of bevacizumab to standard chemoradiotherapy in newly diagnosed glioblastomas has completed recruitment. Salvage treatment of glioblastoma patients after bevacizumab failure, however, is commonly not successful. In the present study, we aimed at characterizing histological and molecular characteristics associated with glioma recurrence after bevacizumab. Methods: Paired tissue samples from primary and recurrent tumors obtained from 12 patients with glioblastoma (n=11) or anaplastic astrocytoma (n=1) before and after bevacizumab treatment, and 14 non-bevacizumab-treated patients as a reference group, were analyzed for histological features as well as molecular markers. Clinical records and magnetic resonance images were reviewed. Results: Histologically, recurrent tumors after bevacizumab showed more commonly a decreased blood vessel density and reduced glomeroloid microvascular proliferations when compared to recurrent tumors after conventional radiochemotherapy. In contrast, tumor cellularity and proliferation rate were similar. Distant relapse was more common in bevacizumab-treated patients. Molecular genetic studies of the respective tissue specimens are currently under way. Conclusions: Histological and molecular analyses of tumor tissue samples from glioma patients before and after bevacizumab treatment, combined with thorough clinical and radiological correlates, may provide hints for therapy escape mechanisms that can then be validated in preclinical models.
Effect of electrochemotherapy with IV bleomycin on complete response in a preclinical brain tumor study.
Authors: Agerholm-Larsen Birgit , Iversen Helle K. , Moller Jakob M. , Ibsen Per , Jensen Kurt S. , Linnert Mette , Gehl Julie 
Published: March 2020

2069 Background: Electrochemotherapy (ECT) describes enhanced chemotherapeutic drug uptake after cell membranes have been made transiently permeable due to application of an electric field to the tumor. ECT is routinely used to treat skin metastases, with high response rates after once-only treatment. We have developed an electrode for use in the brain, both a rodent model and an electrode for clinical use. The aim of the present study was to evaluate ECT using intravenous (iv) bleomycin in a rat brain tumor model. Methods: Sprague Dawley male rats (7-11 week old) were inoculated with rat glial cell derived tumor cells (N32) through a burr hole in the skull. When tumors appeared on MRI, animals were allocated to ECT (iv bleomycin and local electric pulses), iv bleomycin only, iv bleomycin with placement of electrodes (no pulses), or no treatment. Bleomycin was injected iv in the tail vein (600µL, 3 IU/µL) and electrode deployment was made through the burr hole into the brain tissue. Electrochemotherapy parameters were 32 pulses, 100V, 100µs, 1Hz. Tumor size was determined based on contrast enhanced area from MR scans. Kaplan-Meyer events were defined as termination due to extensive tumor progression prior to end of the three independent experiments performed. Immuno-histo-pathology was performed after termination to verify MRI findings. Results: In 88% of the animals (14 of 16) treated with electrochemotherapy we found complete response (no tumor), validated by MRI and immuno-histo-pathology, whereas bleomycin only, bleomycin and electrodes, and no treatment showed progression in 11 out of 13 control animals. A Kaplan-Meier plot showed a pronounced improved survival for the ECT group as compared to controls within 3 weeks from treatment (p<0.001). Treatment was well tolerated. Conclusions: The present data suggest that electrochemotherapy with iv injection of bleomycin is a new promising treatment for brain tumors. In a clinical study using iv bleomycin and electrochemotherapy for brain metastases ( www.clinicaltrials.gov , ID:NCT01322100) the first patient has just been treated successfully with ECT, indicating feasibility of the approach in the clinical setting.
Prospective follow-up of a cohort of 112 patients with leptomeningeal metastases of breast cancer recruited from 2007 to 2011: Prognostic factors.
Authors: Zairi Fahed , Kotecki Nuria , Rodrigues Isabelle , Baranzelli Marie-Christine , Andre Charles , Dubois François , Devos Patrick , Faivre-Pierret Matthieu , Assaker Richard , Bonneterre Jacques , Le Rhun Emilie 
Published: March 2020

2070 Background: Around 5% of patients with breast cancers (BC) will develop leptomeningeal metastasis (LM). The incidence may increase. Methods: We reported the description and outcome of 112 consecutive BC patients diagnosed with LM in our institution from 2007 to 2011. Correlations between characteristics and overall survival (OS) were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox model). Results: BC were invasive ductal carcinoma in 69.7%. Estrogen and progesterone receptors were detected in respectively 61.6 and 44.6%. HER2 expression was observed in 26%. 23% were triple negative. Median time between BC diagnosis and LM diagnosis was 44 months. At LM diagnosis, median age was 54 and median Performance Status (PS) was 2. CSF cytology and cerebrospinal MRI were positive in respectively 72,5% and 87%. 103 (92%) LM patients received IT liposomal cytarabine as 1st line of treatment (ventricular device in 47%). IT therapy could be associated with systemic treatment in 58% of the cases and cerebral radiotherapy for LM in 14% of the cases. Clinical response after 1st line treatment was observed in 57%, CSF response in 30,5%, MRI response in 62,5%. 24 patients received a 2nd line of IT thiotepa, 6 a 3rd line of IT methotrexate. The more significant prognostic factors (p<0,0001) were initial PS, associated systemic treatment and triple negative BC status. Other significant predictors of OS were thiotepa as 2nd line treatment (p=0,0004), intracranial hypertension at LM diagnosis (p=0,019), associated cerebral radiotherapy (p=0,02), progesterone receptor status (p=0,04). Median OS of the 103 treated patients was 3,8 months (4,75 months for 0-2 PS and 1,6 months for 3-4 PS patients). Conclusions: Median OS was consistent those of other recent cohorts of BC LM. Our results confirm the role of a very early diagnosis, before the degradation of the general status. The association with systemic treatment or cerebral radiotherapy is indicated when possible.