bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab use and central nervous system (CNS) hemorrhage.
Authors: LeTarte Nathalie , Bressler Linda R. , Villano John L. 
Published: March 2020

2073 Background: Bevacizumab is widely used and may cause life-threatening bleeding, usually at sites of disease involvement such as the CNS. We attempted to identify clinical characteristics associated with CNS hemorrhage in a broad population. Methods: We did a retrospective review of the FDA Medwatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Results: We searched the database for keywords bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke, and brain. 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1041 reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage was the most frequent event reported (n=39), followed by intracranial hemorrhage (n=20) and subarachnoid hemorrhage (n=18). Median age was 62 years; 54% of patients were female. Primary cancer was colorectal (42%), glioma (13%), and breast cancer (10%). Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. 54% of patients received myelosuppressive chemotherapy, and 30% had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. For 70 patients, information on CNS involvement was not reported. Death was reported as a complication of hemorrhage in 48% of patients. Nine patients with brain metastases died and CNS hemorrhage was the cause of death in seven. Six patients with glioma died, and CNS hemorrhage was the cause in three. One patient with brain metastases, and one patient with glioma also experienced a non-CNS bleed. Five patients in each group had received heparin, warfarin or NSAIDs. Low platelet counts were reported in 3 patients with CNS metastases and 2 patients with glioma. The most common factor associated with CNS hemorrhage was medication predisposing to bleeding, followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, was reported in 4 patients with brain metastases, and 2 patients with glioma. Conclusions: In this database, 154 of 1195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in more than half of the cases.
Tegwondo-CCNU: A novel combination of protracted, near-continuous temozolomide and CCNU with activity in recurrent malignant gliomas.
Authors: Strik Herwig Matthias , Rock Hans , Kallenberg Kai 
Published: March 2020

2079 Background: Recent data have been raising doubt if dose-dense temozolomide is more efficient against malignant gliomas than with conventional dosing. We report here updated results of combined near-continuous temozolomide, aimed at depleting anti-alkylating MGMT, with once weekly application of low-dose lomustine (CCNU) at first or second relapse of malignant gliomas. Methods: 25 consecutive patients with recurrent malignant gliomas (12 anaplastic gliomas WHO III, 13 glioblastomas or gliosarkomas WHO IV) were treated: 15 males (60%), 10 females (40%); mean age at start of chemotherapy was 52 (20-78) years; Eight patients were treated at first, 15 at second and two at third recurrence. All patients were pretreated with temozolomide. Four patients received fractionated, stereotactically guided re-irradiation (FSRT). The treatment regimen consisted of near-continuous temozolomide 50mg/m2 day 1‑5/7 and low-dose CCNU 40mg absolute dose day 6/7. In cases of bone-marrow depression, temozolomide was reduced in steps of 20mg total dose or – in more severe cases – chemotherapy was interrupted until normalization of blood counts. Results: In total, 89 cycles (months) of chemotherapy were applied. The combination was well tolerated in terms of nausea and fatigue. Blood counts usually decreased continuously, enabling a gradual dose adaptation. Hematological WHO grade 3+4 toxicity occurred in 5/25 patients (20%), two of them were symptomatic. Three patients had prolonged elevation of liver enzymes. Best responses after ≥ 3 months (23 patients) were: 2 complete and 1 partial remissions (13%, ), 13 stable diseases (57%), and 7 progressive diseases (30%). Progression-free survival at six months from start of chemotherapy of the 16 patients treated > 6 months or deceased (PFS 6) was 37%, median overall survival 6.3 months. Conclusions: Although some hematotoxicity was observed, the regimen presented here is well tolerated and safe if carefully controlled. The objective responses and considerable rate of stable diseases indicate that this combination is active in malignant gliomas after pretreatment with temozolomide alone. The results have to be controlled in a prospective trial.
The role of fluorescence-guided surgical resection in the combined treatment of malignant glioma.
Authors: Carapella Carmine Maria , Oppido Piero Andrea , Vidiri Antonello , Cattani Fabio , Telera Stefano Maria , Pompili Alfredo , Pace Andrea 
Published: March 2020

2085 Background: Malignant glioma represents a relevant therapeutic issue and the value of extensive surgical resection remains debated; recent evidence suggests that radical removal is associated with better survival. An interesting tool for identifying tumor tissue and increasing the extent of surgery is represented by fluorescence-guided resection, taking advantage of metabolic and structural changes induced by a natural precursor of heme biosynthetic pathway, 5-amino-levulinic acid (ALA). Methods: The present experience is related to 32 patients affected by malignant glioma (18 newly diagnosed: 16 glioblastoma (GBM), 2 anaplastic oligodendroglioma; and 14 recurrent GBM) eligible for fluorescence-guided resection, operated on in our Institute since fall of 2009. All patients underwent preoperative and early postoperative MRI, showing contrast enhancing lesions. An oral dose of 20 mg 5-ALA /kg bw was administered to each patient. Microsurgical resection was performed by an operating microscope enabled to visualize the fluorescence. All the patients, as first line treatment, have been submitted to radiotherapy and chemotherapy; second and in some cases third line treatments were utilized in recurrent cases. The patients follow-up ranged from 2 years to 6 months. Results: In more than 90% of patients tumor tissue showed intraoperative red fluorescence; mainly in recurrent GBM, when MRI documented heterogeneous lesions with enhancing areas mixed with non enhancing gliotic scars, fluorescence-guided surgery allowed a better definition of active tumor, with net margins from perilesional “healthy” brain. Early postoperative MRI confirmed gross total resection without contrast enhancement in 80 % of patients. In the present experience the procedure did not determine any relevant additional neurological deficit. Considering overall survival of recurrent patients we obtained a median extension of at least 9.0 months (3 – 16+ months). Conclusions: Fluorescence-guided surgery improves tumor detection and allows extended resection of malignant glioma, without any relevant impact on neurological status, resulting helpful mainly in the recurrent setting with a consistent effect on overall survival.
Correlation of survival with tumor antigen expression in patients with newly diagnosed glioblastoma receiving a multi-epitope pulsed dendritic cell vaccine.
Authors: Phuphanich Surasak , Wheeler Christopher Jay , Rudnick Jeremy , Mazer Mia , Wang Hong Qiang , Nuno Miriam , Richardson Jaime , Fan Xuemo , Ji Jianfei , Chu Ray M , Bender James , Hawkins Elma S. , Patil Chirag , Black Keith L. , Yu John 
Published: March 2020

2087 Background: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1 and/or HLA-A2 positive glioblastoma (GBM) patients with gross total resection were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals in the axilla region after a standard treatment with concurrent temozolomide (TMZ) and radiation therapy for newly diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 ND-GBM and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33% responders. TAA expression by qRT-PCR showed all patient tumors expressed at least three TAA with 75% expressing all six. Correlations of increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and HER2 were observed. A decrease or absence of CD133 expression was seen in five patients who underwent a second resection. As of February 1, 2012, six of 16 ND-GBM patients showed no evidence of tumor recurrence (44-63 months). Median progressive free survival (PFS) in newly diagnosed patients was 16.9 months with a two-year PFS rate was 43.8% (95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumor.
The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM).
Authors: Friedman Henry S. , Desjardins Annick , Peters Katherine B. , Reardon David A. , Kirkpatrick John , Herndon James Emmett , Coan April D. , Bailey Leighann , Sampson John Howard , Friedman Allan H. , Vredenburgh James J 
Published: March 2020

2090^ Background: The prognosis for newly-diagnosed GBM is dismal. The addition of temozolomide to radiation therapy improved the median overall survival (OS) to 14.6 months (mos). GBM’s have the highest levels of vascular endothelial growth factor (VEGF). Hypoxia inducing factor-1 alpha (HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit HIF-1 alpha. Methods: We performed a phase II trial in newly diagnosed GBM by adding bevacizumab and topotecan to standard therapy. 80 newly diagnosed GBM patients were enrolled between January 2010 and January 2011. Patients received standard radiation therapy and temozolomide. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks post-op. Two weeks after radiation therapy was completed, 12 monthly cycles of temozolomide at 150 mg/m2 /d days 1-5, oral topotecan at 1.5 mg/m2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m2 for patients on an EIAED days 2-6, and bevacizumab at 10 mg/kg on days 1 and 15. Results: The addition of bevacizumab to standard radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 completed radiation therapy. Four patients did not complete radiation, two with clinical decline, one each with a bone flap infection, and a pulmonary embolus. Fifteen patients came off study for toxicity, five with recurrent grade IV thrombocytopenia, three with grade III fatigue, two each with grade 2 CNS hemorrhage, and wound dehiscence requiring surgery and one each with GI perforation, pulmonary embolism and an aortic thrombus. Of the 80 patients, 56 have progressed and 37 have died. The median progression-free survival (PFS) and OS are 11.1 mos (95% CI: 9.4-13.6) and 17.2 mos (95% CI: 15.2) at a median follow-up of 18.4 months. The two year OS is 45.3%. Conclusions: The addition of bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab and oral topotecan is tolerable. The median PFS and OS are encouraging. The randomized phase III trials with bevacizumab for newly diagnosed GBM patients are essential.
CD40 ligand/interferon-γ matured DC immunization with gp100 antigen HLA class I A *0201 restricted peptides in patients with newly diagnosed metastatic melanoma.
Authors: Linette Gerald P. , Becker-Hapak Michelle , Huang Alexander , Alyasiry Amer , Chan Megan , Lie Wen-rong , Cornelius Lynn , Moley Jeffrey F. , Aft Rebecca , Tan Benjamin R. , Trinkaus Kathryn , Carreno Beatriz M 
Published: March 2020

2525 Background: CD40L/IFN-γ matured Dendritic Cells (DCs) produce IL-12 and are potent antigen-presenting cells for naïve resting T cells. We sought to determine the magnitude and kinetics of CD8+ T cell growth in patients receiving autologous CD40L/IFN-γ matured DC and identify biomarkers associated with clinical outcome. Methods: A phase I clinical trial (NCT00683670) incorporating CD40L/IFN-γ for the ex vivo maturation of autologous DCs pulsed with three well characterized gp100 melanoma antigen derived peptides (G154, G209-2M, G280-9V) was initiated with enrollment from 2008-11 at a single center. HLA-A*0201+ individuals with treatment naïve metastatic melanoma were immunized every 3 weeks by intravenous infusion for six doses after a single dose of cyclophosphamide (300 mg/m2 iv). CT imaging was performed at baseline, week 9 and 18 for clinical assessment using RECIST. Responding patients were eligible for maintenance doses every 2-4 months. PBMC were taken weekly for immune monitoring by tetramer analysis and functional assays. DC preparations were characterized to assess for biomarkers of response. Results: 10 patients were screened. Among the 7 treated patients, there were 3 confirmed responses (independently verified), including one durable CR >3 years and 2 PR. Three patients had rapid disease progression and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or more vaccine doses. No SAEs were noted. There was no correlation between tumor volume and response. Using pre-specified immune response criteria, 6 (86%) treated patients developed CD8+ T cell immunity to all three peptides as assessed by tetramer analysis. The vaccine-induced T cells from all 6 individuals were polyfunctional and killed gp100+, HLA-A2+ human melanoma targets in a standard 51Cr release assay. IL-12 production by DCs correlated with TTP (p=0.0198, likelihood ratio test) but not OS (p=0.08). Conclusions: Weekly immune monitoring reveals the rapid onset of CD8+ T cell immunity against gp100 among the responder patients. This is the first DC vaccine clinical trial in melanoma to demonstrate a correlation of IL-12 production and TTP.
Association of idiotype vaccine-induced T-cell response with improved survival and time-to-next treatment (TTNT) in untreated mantle cell lymphoma (MCL).
Authors: Dunleavy Kieron , Neelapu Sattva Swarup , Kwak Larry W. , Grant Cliona , Santos Carlos F. , Popa Mihaela A. , White Therese , Miller Barry , Jaffe Elaine S. , Steinberg Seth M. , Wilson Wyndham Hopkins 
Published: March 2020

2528 Background: Murine models show Id-vaccines induce antitumor responses, possibly through Th1/Tc1 cytokines. We report an 11-year follow-up of Id-vaccine following DA-EPOCH-Rituximab in 26 untreated MCL patients. Methods: DA-EPOCH-R was administered q3 weeks × 6, followed 12 weeks later by 5 cycles of Id-vaccine. Id protein was made by hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH) and administered with GM-CSF. Pre- and post-vaccine immune responses (IR) were tested in parallel: anti-Id and anti-KLH humoral responses (ELISA); anti-KLH cellular responses (intracellular cytokine assay); and anti-tumor cellular responses (cytokine induction, IFNγ ELISPOT). Results: Characteristics: median age 57 (r 22-73), blastoid variant 15%, and MIPI (low-65%; intermediate-16%; high-19%). With 122 mo median follow-up (r 111-132), the median PFS is 24 mo and OS is 104 mo. MIPI was associated with OS (p=0.0002); median OS: low (not reached), intermediate (84 mo) and high (44 mo). We found no association between OS and anti-KLH IR, anti-Id humoral response, IFNγ ELISPOT, or antitumor TNFα or IFNγ responses. Normalized antitumor T-cell GM-CSF response (median <4.3 vs. >4.3) was associated with OS of 79 mo vs. not reached, respectively (p=0.015 (unadj.) and p=0.045 (adj.)). MIPI (p=0.02) and GM-CSF (p=0.057) were independently associated with OS. TTNT (based on disease activity), correlated with antitumor GM-CSF response (p=0.018) but not MIPI and was independent of MIPI (GM-CSF; p=0.041). Correlation of pre-and post-treatment GM-CSF production suggested a priming effect. Tumor proliferation by GEP did not correlate with OS (n=14). Conclusions: Antitumor GM-CSF response was significantly associated with OS and TTNT, suggesting antitumor cellular immune response significantly delayed tumor growth. Antitumor GM-CSF response may serve as a surrogate biomarker for vaccine efficacy. Our results are consistent with recent data that T-cell GM-CSF production is required for breaking tolerance against self-antigens. Id vaccines may prolong survival of MCL following rituximab-based chemotherapy and should be further evaluated.
Feasibility and safety of sequential research-related tumor core biopsies in clinical trials with anti-angiogenic and targeted therapies.
Authors: Lee Jung-min , Hays John L. , Noonan Anne M. , Squires Jennifer , Annunziata Christina M. , Wood Bradford J , Yu Minshu , Houston Nicole D. , Azad Nilofer Saba , Kohn Elise C. 
Published: March 2020

2545 Background: There has been increasing interest in serial/paired research biopsies (bx) in studies of molecularly targeted therapies. Definition of optimal target tissue and patient characteristics for safe and feasible research tumor bx in the era of anti-angiogenic and targeted therapies is needed. Methods: IRB-approved review of retrospective clinical data including patient demographics, pre-and post-procedure and recovery notes, and radiographic bx images. The cohort consisted of 142 pts scheduled for serial bx enrolled in phase 1 (5) and phase 2 (1) studies. Tumor core bx were obtained percutaneously under local anesthesia using a 16 or 18g needles under US or CT visualization by interventional radiologists. Results: Paired tumor core bx were collected in 96 pts (68%) and baseline only in 42 pts (32%). Bx were aborted in 4 pts due to cystic mass (3) and safety (1). 132 pts were female and 10 pts were male, median age 56 yrs (27-78), median BMI 25.8 (14.4-46.2), ECOG PS 0-2, and normal end-organ function. All pts had recurrent metastatic cancers (gynecologic 121, breast 6, sarcoma 5, melanoma 4, colon 2, adrenal 1, mesothelioma 1, RCC 1, papillary thyroid ca 1). 67 pts (51%) were on bevacizumab (bev)-based therapy at the time of their 2nd/3rd bx (bev + sorafenib; bev + dasatinib); others received gefitinib (27), imatinib (23), vandetinib (9), or olaparib + carboplatin (16). Median tumor size was 2.7cm (1-14.5cm). Bx sites were abd/pelvic masses 42, liver 40, lymph nodes 42, abd/chest wall 12, lung 4 (3 pleural, 1 parenchymal), and psoas muscle 1. Minor complications were observed in four pts (3%; uncomplicated liver subcapsular hematoma [1]; vasovagal syncope responding to fluids [2]; uncomplicated pneumothorax without intervention [1]) and there were no major complications. The median number of tumor cores was 3 (1-6) at the baseline, 2nd (during or at the end of the first cycle) and 3rd time point (during cycle 2). Conclusions: Core needle bx of deep internal lesions such as intra-abdominal masses and retroperitoneal lymph nodes can be obtained percutaneously under imaging guidance. Sequential tumor bx are feasible and safe for pts on anti-angiogenic and chemotherapeutic agents.
Phase I immunotherapy trial using glioblastoma apoptotic body-pulsed dendritic cells.
Authors: Moertel Christopher L. , Olin Michael , Dahlheimer Tambra , Gustafson Michael , Sumstand Darin , McKenna David , Low Walter , Nascene David , Dietz Allen , Ohlfest John 
Published: March 2020

2546 Background: We recently reported that tumor cell vaccines cultured in 5% oxygen (O2) had enhanced the immunogenicity relative to those grown in standard atmospheric O2. In order to develop an “off-the-shelf” source of whole cell antigen we screened a panel of primary glioblastoma (GBM) cell lines, leading to identification of (GBM6) as an ideal candidate. GBM6 was extensively characterized and shown to express glioma-associated antigens (IL13Ra2, Sox2, Epha2, etc.). A Phase I clinical trial was initiated to evaluate the safety and feasibility of a vaccine consisting of dendritic cells (DC) pulsed with apoptotic bodies from GBM6 grown in 5% O2. Methods: Patients ranging from 3 to 71 years with recurrent GBM (n=6) or ependymoma (n=1) were enrolled. Monocytes were collected via apheresis, matured into DC and pulsed with apoptotic bodies derived from GBM6. The first three patients received escalating doses of DC (5x106, 10x106, and 15x106), the remainder received 15 x 106 DC. Pulsed dendritic cellswere injectedsubcutaneously into the supra-scapular region. Imiquimod cream was applied at the injection site just prior to vaccination and 24 hours later. The vaccine schedule dictated administration every 2 weeks for 8 weeks (total of 5 doses) then monthly to progression or a total of 52 weeks. Prior to each vaccination, patients met eligibility parameters and had no progression on MRI. Patients were imaged monthly and blood was drawn to evaluate toxicity and immune response. Results: No vaccine-related toxicity has been reported. Time to progression ranges from 6.5 weeks for the patient treated at the first dose level to 35 weeks for one patient receiving 15 x 106 DC. The latter patient experienced a partial response at 20 weeks. Two patients have stable disease at 18.5 and 28 weeks, respectively. One patient was not evaluable. Flow cytometric analysis demonstrated expansion of central memory T cells amidst declining effector memory cells following vaccination in three patients at a dose of 15x106 DC. Conclusions: Apoptotic body-pulsed DC vaccination was well tolerated and preliminarily demonstrated clinical activity but a minimum of 15x106 DC was required for a modulation of central memory T cells.
Effect of dexrazoxane on doxorubicin-induced testicular toxicity.
Authors: Ben-Aharon Irit , Tzabari Moran , Savion Naftaly , Shalgi Ruth , Stemmer Salomon M. 
Published: March 2020

2556 Background: Seminal advances in anti-cancer therapy result in growing numbers of young male cancer survivors for whom treatment-induced infertility represents a major late-term concern. Doxorubicin (DXR) has been previously shown to exert toxic effect on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we aimed to study its potential effect to reduce DXR-induced testicular toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg DXR or 100mg/kg DEX or the combination of both and scarified at one month post treatment. Saline-injected mice served as controls. Testes were excised, weighed and further processed. For oxidative stress determination glutathione assay was performed on testes' lysates and P38 protein levels were determined by western blot analysis. Bax levels were used to assess apoptosis. Immunohistochemistry and confocal microscopy were used to study the effect of DXR, DEX and their combination, on the testis histology as well as on the spermatogonial reserve. Results: One month after DEX and DXR treatment, a striking decline in testicular weight was observed (decrease by 60% compared with control values; decrease of 54% in DXR-only treated mice; p<0.05). DEX prevented DXR-induced oxidative stress. However, DEX enhanced DXR-induced apoptosis within the testes and furthermore, the combination depleted the spermatogonial reserve one month after treatment. Conclusions: DEX activity in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate DXR-induced testicular toxicity.