bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low protracted dose of temozolomide (TMZ) and concurrent radiotherapy for brain metastasis of solid tumors
Authors: Addeo R. , Faiola V. , Cennamo G. , Guarrasi R. , Montella L. , Del prete S. 
Published: March 2020

12525 Background. Whole brain radiotherapy (WBRT) remains the mainstay of therapy for brain metastasis of solid tumours not amenable to surgical resection. Chemotherapy with temozolomide (TMZ) has emerged as an alterative approach for recurrent brain metastases. It has been already used alone or in combination with radiotherapy in the treatment of primary brain tumours. Protracted administration of TMZ, even at relatively low daily doses, leads to significant and prolonged depletion of enzyme O6-alkylguaninae-DNA alkyltransferase (AGAT) activity, with may enhance the antitumor activity of the agent. Methods. Patients with histologically or cytologically confirmed breast cancer and NSCLC and inoperable brain metastasis were eligible for the study .We have treated 29 consecutive patients (16 F and 13 M, mean age: 55, range 46–76) affected by brain metastases ( 16 non-small-cell lung cancer and 13 breast cancer) with WBRT at 3 Gy/day administered over a two-week period (on wks 1–2), total dose 30 Gy, and an induction with TMZ 50 mg/m2/day during this period, following TMZ 50mg/m2 fractionated in 21 days every 28 days, for up to 12 cycles. Pts who received at least one cycle of TMZ were assessable for response. Results. Twenty-four patients were subjected to the induction therapy and 124 cycles were performed. TMZ was generally well tolerated, and the main toxicities seen were hematologic. The toxicities were generally between grade 1 or 2 in severity although two patients had grade 3 events. Two CR, in patients with breast cancer and NSCLC. Nine partial responses were recorded in 5/11 patients with breast cancer, 4/13 patients with NSCLC, while a stable disease was achieved in other 5 patients. Eight patients showed progressive BM growth during the treatment. The overall response rate was 45.5% (C.I. 38.7–56.9%), while the disease control rate was 77% (C.I. 61.7–82.4%). At the present, the overall survival at 12 months was 64%. Conclusions. We developed a new regimen based on a different strategy: the utilization of a more intensive TMZ dosing schedule that would permit the concomitant use of a second cytotoxic agent on the primary cancer. Final data analysis will be presented. The schedule was safe and well tolerated and has suggested an encouraging activity in brain metastases. No significant financial relationships to disclose.
Salvage chemotherapy with CPT-11 for recurrent temolozomide-refractory anaplastic oligodendroglioma
Authors: Chamberlain M. C. 
Published: March 2020

12526 Background: There is no standard therapy for alkylator-resistant AO and hence a need exists for new therapies. Methods: Twenty patients (10 men; 10 women) ages 27–47 (median 38), with radiographically recurrent AO were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and adjuvant chemotherapy (TMZ in 14; BCNU in 6). 13 patients were treated at first recurrence with an alternative chemotherapy (TMZ in 6 all previously treated with BCNU; 5 with PCV and 1 each with carboplatin, sorafenib, or cyclophosphamide). 11 patients underwent repeat surgery. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks (350mg/m2 in patients on non-enzyme inducing anticonvulsants or no anticonvulsant; 600mg/m2 in patients on enzyme inducing anticonvulsants), operationally defined as a single cycle. Neurological and neuroradiographic evaluations were performed every 8–9 weeks. Results: All patients were evaluable for toxicity and response. A total of 129 cycles of CPT-11 (median 4.5 cycles; range 3–18) was administered. CPT-11 related toxicity included diarrhea (4 patients; 2 [10%] grade 3), neutropenia (3; 3 [15%] grade 3), fatigue (3; 3 [15%] grade 3), and delayed nausea/vomiting (1; 1 [5%] grade 3). 5 patients (25%) demonstrated a partial radiographic response, 7 (35%) demonstrated stable disease and 8 (40%) had progressive disease following three cycles of CPT-11. Time to tumor progression ranged from 2 - 13.5 months (median: 4.5 months). Survival ranged from 3 - 21 months (median: 6 months). 6-month and 12-month PFS were 30% and 25% respectively. Conclusions: CPT-11 demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent AO all of whom had failed prior TMZ chemotherapy. No significant financial relationships to disclose.
Hypofractionated therapy versus conventional fractionated radiotherapy in elderly patients with glioblastoma multiforme
Authors: Elshenshawy H. , Abd El-Razek A. , Bader H. 
Published: March 2020

12529 Background: To evaluate efficacy of short- course radiotherapy(RT) in elderly (>60years) patients with glioblastoma multiforme(GBM), and compare this biological similar short -course radiotherapy with a standard radiotherapy Methods: Forty-four elderly patients with GBM were randomly assigned after surgery to receive either a short-course of radiotherapy (45 Gy in 15 fractions over 3 weeks ) or standard radiotherapy (60 Gy in 30 fractions over 6weeks) to a target volume described as tumor visible on CT scan and a 2- cm margin . The primary end point was overall survival. Results: The overall response rate and median duration of response were 60%and 8.5 months in short- course RT versus 65% and 8 months in standard RT . Improvement in pretreatment performance status and increase in post- treatment corticosteroid dosage were observed in 50% and 25% in short- course RT versus 40% and 50% in standard RT (P=0.09, P=0.031) respectively. Median survival time was 5.9 months in short-course RT versus 5.6 months in standard RT . Six months, 1-year survival and progression-free survival rates were 40%, 15% and 30% ,10% in short- course RT versus 45%, 10% and 35% , 5% in standard RT , respectively. In both treatment groups, females did significantly better than males, patients with KPS 60–70 did significantly better than those with KPS 50 , patients having tumors 4–5 cm did significantly better than those with tumors 6–8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis , only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild in the two treatment groups. While RT -induced brain necrosis appeared only in one patient received short- course RT, but this patient died from tumor recurrence. Conclusions: Hypofractionated RT is feasible and safe treatment for elderly patients with GBM. No significant financial relationships to disclose.
Intracerebral presentation of Hodgkin’s disease mimicking meningioma
Authors: Apollonsky N. , Karayalcin G. 
Published: March 2020

12533 A 23-year-old woman presented with headaches, diplopia, nausea and vomiting. CT scan revealed frontal extradural mass consistent with meningioma. After excision of the mass light microscopic evaluation revealed a polymorphous variably cellular neoplasm with a background of normal small lymphocytes, eosinophils, histiocytes with large, atypical, often multinucleated cells. Immunohistochemical studies demonstrated large cell strongly positive for CD 30 and focally positive for CD 15 and negative for EMA and ALK1. The morphology, architectural features, and immunohistochemical findings were consistent with Hodgkin disease, the nodular sclerosing type. Systemic work up revealed stage IV disease. Patient was successfully treated with chemotherapy for Advance Stage HD and involved field RT, involving brain. The patient remains disease free 4 years after completion of treatment. Intracranial involvement (IC) of the Hodgkin disease (HD) is a rare entity. In the majority of cases intracranial involvement has been seen during relapsed and progressive disease. Until now nine cases of initial presentation of the HD as a brain tumor with appropriate morphological and histochemical confirmation were reported. Among those patients six patients had isolated primary IC HD and three patients after further investigation were found to have extracranial involvement. Seven of the nine patients had nodular sclerosing histology, one had mixed cellularity and in one case histology was not reported. All patients following resection of the IC mass received cranial RT. Two patients also received intrathecal chemotherapy. Patients with the extracranial involvement received systemic chemotherapy. All patients responded to the treatment and were disease free on the subsequent follow up 6–48 months after the completion of the therapy. No significant financial relationships to disclose.
The influence of radiotherapy and chemotherapy on survival and quality of life of patients with cerebral metastases
Authors: Markulin-Grgi L. , Santek F. 
Published: March 2020

12535 Background: The problem of cerebral metastases is a great one and seams to become more and more important thanks to the earlier diagnosis of malignant tumors and to the possibility of effective treatment of carcinomas which leads to prolongation of life of patients with malignant disease. Although many patients with malignant tumors develop symptoms of cerebral metastases in course of their disease, even more cerebral metastatses are found at the post mortem. Because autopsies are undertaken very rarely, the true incidence of cerebral metstases can only be estimated. Surgery is indicated in patients with solitary or 2 adjacent metastases. Radiotherapy is the most common method of treatment, sometimes after surgery, but mostly as the only method and in combination with chemotherapy. Methods: 165 patients with cerebral metastases treated at the Clinic of Radiotherapy and Oncology, School of Medicine, University Hospital Center Zagreb from 1995 to 2000 are discussed. The commonest primary tumor was bronchial carcinoma in 87/165 of patients (52,8%) followed by breast carcinoma in 36/165 (21,8%). In 10/165 (6,1%) of the patients the primary tumor was unknown. The patient were treated by radiotherapy, chemotherapy and surgery in various combinations. Results: The survival was significantly better in younger patients taking into account the median of age as 56 years (p<0,05). In the group of 78/165 patients who were treated only by radiotherapy (47,2%) the median survival was 6 months (1–38 months). In the group of 87/165 (52,8%) treated by radiotherapy and chemotherapy the median survival was 8 months (1–48 months) (p<0,001) There was no influence of duration of the symptoms on survival of our patients (p>0,05) Conclusions: According to treatment modalities, the best survival results were observed in patients treated by a combination of surgery, radiotherapy and chemotherapy (p<0,001). No significant financial relationships to disclose.
Addressing BCR/Abl resistance: Evolving dasatinib to a novel inhibitor of the T315I BCR/Abl mutation
Authors: Zhu H. 
Published: March 2020

13004 We have previously shown that inhibition of the BCR/Abl.T315I mutation can be achieved by using a benzotriazine small molecule in both enzymatic and cell proliferation assays. We have further evolved the benzotriazenes into a class of structurally simplified BCR/Abl inhibitors with enhanced pharmaceutical properties. A representative of this new class, TG101114, inhibits Abl and Abl.T315I enzyme as well as proliferation of cells expressing either BCR/Abl or BCR/Abl.T315I. It displays desirable pharmaceutical properties (e.g. oral bioavailability>20% and T1/2>5 h). Consistent with its potency and PK, orally administered TG101114 inhibits the growth of BCR/Abl-driven tumors in a SCID mouse xenograft model and BCR/Abl.T315I-induced STAT5 phosphorylation in the spleens of mice implanted with BCR/Abl.T315I cells. In an ex vivo assay, TG101114 normalized colony formation of stem cells isolated from a BCR/Abl.T315I+ CML patients. To further expand upon the themes of these structurally simplified scaffolds, we have transformed dasatanib into a potent and selective T315I inhibitor, thus inhibiting both abl and T315I.abl with equal nM potency in enzymatic and cellular assays. TG101477, an exemplary compound from this class, has shown potency in both enzyme and cell proliferation assays as well as appealing PK properties in mice (e.g. oral bioavailability>20% and T1/2>5 h). Furthermore, TG101477 has exceptional selectivity as was demonstrated in a commercial kinase assay in which TG101477 potently inhibited only 6 of 76 kinases in a panel of phylogenetically diverse kinases. We conclude that these classes of BCR-abl inhibitors present new themes for circumventing gatekeeper mutations and represent new prototypes for the treatment of drug resistant forms of CML. No significant financial relationships to disclose.
Population pharmacokinetic and pharmacodynamic (PK-PD) parameters of Erwinia Chrysanthemi (ERW) asparaginase (ASNase) using the fused first-order elimination and Michaelis-Menten (MM) limited physiological model
Authors: Avramis V. I. , Fu C. 
Published: March 2020

13010 Background: Using the linear PK first order (FO) compartmental approach, the methodical and computational uniformity in modeling various linear systems (ERW) is the dominant characteristic of the population PK analyses. However, saturation of the enzymatic reaction results in nonlinear kinetics based on the MM equation, i.e., the deamination of ASN by ERW, which complicates the PK-PD model. The PK with FO & the MM PK-PD model is theoretically better when single dose of ERW is given. To simulate the PK-PD data and to project patient (pt) data using this model, we used simultaneous integration of the FO+MM equations. Methods: In the 1990’s, ERW was used in pediatric ALL pt (n=23, 1st cohort evaluated for PK-PD). The current study was started to assess if the parallel MM+FO (MM+FO) PK-PD model fit the limited ERW (25K) data better than the MM model, and to validate the MM+FO model and its population parameter estimates. Results: The population PK-PD model best-fitted serum ERW & ASN-time pairs obtained in 23 and from 5 pediatric pt with ALL, using nonlinear mixed-effects modeling (NONMEM). The validity of the MM+FO population PK-PD model and the estimated parameters were tested using the naive prediction method. Patients were administered ERW 6K or 25 K IU/m2 when allergy to E. coli formulations appeared. High correlation between ERW peak serum levels calculated from limited individual pt’ KM (900 μM) & Vmax values in 5 pediatric pt (2nd cohort) and the observed ERW trough levels & its substrate (ASN) were found. The T1/2 averaged 16 hr (25K ERW), and the trough level of 0.1–0.2 IU/ml was correlated with ASN <3 μM. These PK-PD parameters validated those obtained from the 1st cohort. When simulations on population parameters were conducted, the MM+FO predicted the multiple dose steady-state serum ERW & ASN levels nicely. Therefore, the MM+FO model was clearly superior to either the FO or the MM PD models. Moreover, simulations compared favorably ERW 25K Q2 days x3 doses & x2 weeks vs. Pegaspargase 2,5K Q2 weeks. Conclusions: The NONMEM PK-PD model for ERW fitted the simultaneous analyses of data from different doses and regimens better than either standard Two-stage or MM could. No significant financial relationships to disclose.
Breast cancer: Draining lymph node of vaccination site targeted by adjuvant GM-CSF in an autologous vaccine
Authors: Garcia-Giralt E. , Lasalvia-Prisco E. , Cucchi S. , Aghazarian M. , Larrañaga J. , Brent M. , Walton D. 
Published: March 2020

13506 Background: We have reported the sensitization against Tumor Associated Antigens (TAA) and the tumor antiprogressive effect of Autologous Thermostable Hemoderivative-Cancer Vaccine (ATH-CV) in breast cancer patients (E. Garcia-Giralt et al ASCO, 2006). Systemic immune response elicited by TAA is started by a locoregional immune response at the microenvironment constituted by the antigens source and the draining lymph node. The antigens source can be a tumor or a vaccination site and respectively, the draining lymph node is the sentinel lymph node (SLN) or the Sentinel Immunized Node (SIN). Tolerogenic or protective locoregional immune response is decisional because it starts a corresponding systemic immune response, tolerogenic or protective. GM-CSF is a conditioner of SLN and SIN, switching the locoregional immune responses from tolerogenic to protective (ML Disis et al Blood, 1996; AJ Cochran et al Nat Rev Immunology, 2006). Therefore, to optimize the ATH-CV antitumoral effect, we have explored GM-CSF as a locoregional adjuvant. Methods: Thirty six M1 breast cancer patients, ER+,HER 2-, hormone and chemotherapy resistant, performance status = 2, and CA 15–3 rising level, were included in this prospective, IRB-approved phase I/II trial. Patients were 3-group (G) randomized (12 each), submitted to different treatments: G1, no additional oncology treatment; G2, ATH-CV; G3, ATH-CV plus GM-CSF at vaccination site 150 μg/day, 5 days. Statistic assessment (Student’s t-test) was performed at the 30-day end point: ATH sensitization by Delayed Type Hypersensibility test (DTH) and Lymphocyte Proliferative Assay (LPA); PSA serum level and immunophenotyping of lymph node cells in biopsies of SIN scintigraphy-localized. Results: Significant differences (p<0.05): DTH test > 5 mm: G1, 0/12; G2, 3/12 and G3, 6/12. LPA > 2.0: G1, 0/12; G2, 4/12 and G3, 7/12. Immunophenotyping: MHC-II+CD83+ (Mature Dendritic Cells):G3>G2>G1. 30 days CA 15–3 increase: G1>G2>G3. No relevant toxicities were evidenced. Conclusions: In advanced breast cancer, ATH-CV sensitization and tumor antiprogressive effect were potentiated by GM-CSF as local adjuvant. Increase of SIN mature dendritic cells is suggested as mechanism of action. No significant financial relationships to disclose.
Induction of tumor cell death by anti-GD2 monoclonal antibodies (MoAb): Requirement of antibody Fc and a long residence time (slow koff)
Authors: XU H. , Hu J. , Cheung N. V. 
Published: March 2020

13507 Background: Anti-GD2 MoAbs have shown clinical activities against neuroblastoma (NB) and other neuroectodermal tumors. Besides complement mediated (CMC) and antibody-dependent cell mediated cytotoxicities (ADCC), they can directly induce cell death. However, MoAb and their genetic constructs differ substantially in death-inducing efficiency. Although multivalent binding is important for these functions, the roles of association on rate (kon), dissociation off rate (koff), valency and Fc have not been carefully defined. Methods: We tested a panel of purified anti-GD2 MoAbs, MoAb fragment, and single chain variable fragment (scFv) fusion protein. The kinetics of in vitro binding was measured by surface plasmon resonance (SPR) using BIACORE 2000. NB cell lines (LAN1, NMB7, BE(2)C, SKNER, SKNJD and SKNLP) were treated with MoAb in vitro, their survivals were studied by the chromogenic assay and IC50 derived using Sigmaplot. Results: The most efficient cell kill against NB was 3F8 (mIgG3) with an average IC50 of 4.7 ug/ml. In contrast, IC50 was >30 ug/ml for 14.G2a (mIgG2a), ME361 (mIgG2a) and S220–51 (mIgG3). It was >100 ug/ml for 3F8 class-switch variant 3G6 (mIgM), 3F8-F(ab’)2(fragment), and 5F11scFv-streptavidin (tetramer). By SPR, the apparent affinity Kd (equilibrium dissociation constant) of 3F8 [1.1x10-8M] was higher than that of 3F8-F(ab’)2 [3.3x10-8M], 14.G2a [9.0x10- 8M], ME361 [4.6x10-7M], and S220–51 [4.6x10-6 M], but lower than that of decameric IgM 3G6 [6.5x10- 9 M] and tetrameric 5F11scFv-streptavidin [2.6x10-9M]. The affinity advantage of 3F8 over other bivalent MoAbs was primarily due to its slower koff [3.0x10-4 sec-1] when compared to other MoAbs [1.1x10- 3-7.3x10-2 sec-1]. Conclusions: Different structural forms of anti-GD2 MoAb have distinct efficiency in inducing NB cell death as well as binding affinity to GD2. Since these properties can affect CMC and ADCC, they may in turn influence the clinical efficacy of immunotherapy. Our findings suggest the importance of an intact IgG3 molecule (the presence of Fc), as well as a long residence time (slow koff). No significant financial relationships to disclose.
Effect of the immune modulating peptide, SCV-07, in the murine B16 melanoma model
Authors: Tuthill C. W. , Liu Y. , Cai Q. , Wang H. , Kung A. 
Published: March 2020

13514 Background: SCV-07 (gamma-D-glutamyl-L-tryptophan) is a synthetic peptide with proven immune stimulating effects and efficacy against various viral and bacterial infections. As several cancers, including melanoma, are known to be sensitive to immune modulation, it was of interest to evaluate the effects of this compound in the murine B16 melanoma model. Methods: Tumors (1x106 B16 melanoma cells) were implanted subcutaneously (sc) into the right axillary area of C57BL/6 mice (Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, P. R. China). SCV-07 was dissolved in phosphate buffered saline (PBS) and administered once daily via sc administration (at a different site from tumor implantation) at doses of 0.01, 0.10, 1.0, or 5.0 mg/kg for 14 consecutive days. Positive control, dacarbazine (DTIC) was given at a dose of 50 mg/kg once daily for 14 consecutive days via sc injection. Tumor size (by caliper) and body weights were measured once every 3 days throughout the study. The study was terminated on day 17, and the animals euthanized. The tumors were excised, separated, and weighed. Results: SCV-07 treatment led to a significant inhibition of tumor growth compared to vehicle control, with decreases of 16.5% (p=0.030) and 30.2% (p=0.014) seen at the highest doses of 1.0 and 5.0 mg/kg, respectively, on day 15 at the end of treatment. Growth inhibition in the DTIC control was 95.1% (p<0.001). Evaluation of tumor weight also demonstrated a significant inhibition by SCV-07, compared to vehicle, of 23.5% (p=0.008) and 30.8% (p=0.015) at dose levels of 1.0 and 5.0 mg/kg SCV-07. DTIC treated animals had a decrease in tumor weight of 85%. Evaluation of animal body weights demonstrated a significant decrease in those treated with DTIC, suggesting a toxic effect, while no decrease was noted in any SCV-07 treatment groups. Conclusions: Administration of SCV-07 once daily for 14 consecutive days via the sc route is effective against B16 melanoma tumor growth. Tumor growth in animals treated with dose levels of 1 or 5 mg/kg of SCV-07 was significantly reduced compared to the vehicle control group. The overall animal body weights were unchanged after treatment with SCV-07, indicating a lack of toxicity of the test article. No significant financial relationships to disclose.