bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNS atypical teratoid/rhabdoid tumor registry: An update
Authors: Tekautz T. M. , Weng C. , Peterson R. S. , Worley S. , Hilden J. M. 
Published: March 2020

12507 Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system (CNS) in childhood, comprising up to 20% of malignant CNS tumors in patients < 3 years old. Although aggressive approaches including surgery, chemotherapy, intrathecal chemotherapy, high dose chemotherapy with hematopoietic stem cell transplant (HD-HSCT) and/or radiation have resulted in prolonged survival, overall survival remains poor. Methods: We reviewed pediatric patients with AT/RT on an IRB- approved registry formed in 1995 with new insight based on updated outcomes and additional patient enrollment. Upon patient entry, the managing physician submitted pertinent medical records for data abstraction. Physicians were contacted in accordance with privacy regulations for updated records. The Kaplan-Meier method was used to estimate survival time (from diagnosis to death or most recent status update) and groups were compared using the log-rank test at a significance level of p<0.05 with SAS® software version 9.1. Results: Analysis was conducted on 73 patients with a 4:3 male to female ratio. Age at diagnosis ranged from 5 days to 234 months, median = 19 months. Twenty-five patients have no evidence of disease, median 59 months from diagnosis (range 10–140). Forty-three patients (59%) developed recurrent or progressive disease; 6 of these patients are alive at a median of 28 months from recurrence (range 4–38). Forty-four patients (60%) are dead of disease; median time to death was 7 months from diagnosis (range 0–62). Factors correlating with survival are: primary tumor site not in spinal cord (p=0.029), lack of metastatic disease (p=0.024), gross total resection (p<0.001), and upfront radiation particularly in children < 3 years old (p<0.001). HD-HSCT appears to result in improved survival in children < 3 years of age who do not receive radiation, though the small sample size does not yield a statistically significant survival advantage. Conclusions: In treatment of AT/RT, extent of surgical resection and upfront radiation are beneficial for overall survival, particularly in young children. Early information regarding upfront HD-HSCT in lieu of radiation for children < 3 years of age with AT/RT suggests it may be effective. Prospective studies are warranted to further investigate this treatment. No significant financial relationships to disclose.
Reirradiation and chemotherapy with ifosfamide, carboplatin and etoposide (ICE) for recurrent multiforme glioblastoma
Authors: Rodica Maricela A. , Minea L. N. , Oprea L. , Georgescu T. , Isacu I. , Tarlea A. , Bacinschi X. 
Published: March 2020

12508 Background: Despite different treatment options no standard treatment regimen is yet available for patient with recurrent glioblastoma, and the prognosis remain poor. In our study our aim was to assess the efficacy of a schedule consisted in Ifosfamide plus Carboplatine plus Etoposide in recurrent multiform glioblastoma patients. Methods: Between January 2002 - December 2006 32 patients have been treated for recurrent glioblastoma multiforme. They were 18 male and 14 female, with median age 44.6 years old (range 22–65 years old). The ECOG was 0–1-2 , 12/14/6 patients respectively. 15 of them received chronic corticotherapy. All patients were previously irradiated and they have inoperable recurrences. After the confirmation of recurrence 30 of them could be reirradiated with 30 Gy using conformal beam radiotherapy on the tumor bed. Three weeks after completion of radiotherapy they receive six cycles of chemotherapy consisted in Ifosfamide 1000 mg/sqm day 1–3 + Carboplatin 75 mg/sqm day 1–3 + Etoposide 75 mg/sqm day 1–3 every 4 weeks, according to hematological tolerance. Results: Reirradiation associated with ICE chemotherapy resulted in one complete remission, three partial remission, and 8 stable disease. All responders were 37.5%. 26 patients survived at least six month and 22 of them received all six cycles. One year survival rate was 21.8%. Progression-free survival at six month was 31.25%. The regimen was well tolerated with mild toxicities. Haematological toxicity gr.I-II 8 pts, gr.III-IV 3 pt; nonhaematological toxicity: fatigability gr.I-II 12 pts., gr.III-IV 2 pt, gr.III-IV 1 pt, nausea gr.I-II 9 pts, gr.III-IV 4 pt, renal toxicity grade I-II 3 patients, Neurological toxicity grade I-II 5 patients. Conclusions: The treatment scheme has been well tolerated. Results are similar with PCV regimen, even slightly better. This regimen should be reconsider for concomitant radiochemotherapy. No significant financial relationships to disclose.
The role of stereotactic conformal radiation boost in the temozolomide-based chemoradiation for glioblastoma multiforme: Preliminary analysis
Authors: Balducci M. , Manfrida S. , D’Agostino G. R. , Anile C. , Azario L. , Mangiola A. , Dinapoli N. , Apicella G. , Vitucci P. , Valentini V. , Cellini N. 
Published: March 2020

12513 Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Aim of this analysis was to evaluate tolerance and outcome of the dose intensification by stereotactic conformal radiotherapy (SCRT) and concomitant chemotherapy with temozolomide Methods: From October 2003 to April 2006, 58 patients (34 males, 58.6%, 24 females, 41.4%) with histological diagnosis of glioblastoma multiforme received postoperative radiochemotherapy with SCRT boost. Median age was 58 yrs. ( range 25–80 yrs.). Twenty-nine out of 58 patients (50%) received a total dose of 70 Gy by conformal radiotherapy and SCRT boost delivered as concomitant and sequential, or sequential alone. The remainig 29 patients (50%) received a standard of 5940 cGy (180 cGy/day; CTV3: tumor bed + residual tumor if present + oedema; CTV2: tumor bed + residual tumor if present + 1.5 cm margins. CTV1: tumor bed + residual tumor if present + 0.5 cm margins only for the SCRT group). All patients received concomitant Temozolomide, 75 mg/m2 for a median duration of 28 days (range 14–45, depending on the chemoradiation schedule), and adjuvant chemotherapy with temozolomide for 6 cycles or until disease progression. Toxicity was recorded according to RTOG criteria; Survival analysis was calculated by the Kaplan-Mayer method and log-rank testing was used for groups comparison. Results: A 100% compliance was observed in both the groups of patients. A grade 3–4 acute neurological toxicity was registered in two patients treated with SCRT compared to one patient in the group which did not receive SCRT. One case of radionecrosis was observed in the SCRT group; in no case of either group neurological worsening nor corticosteroidal dependence were registered. At a median follow-up of 19 months (range 4–39), a trend towards a better outcome was observed in patients treated with SCRT, since the 1-year OS was 85.9% for SCRT patients (median not achieved) compared to 68.7% for the remaining patients (p=0.07). Conclusion: Our preliminary analysis suggests that a higher dose of RT delivered by conformal stereotactic boost did not increase acute or late toxicity and could achieve a better outcome in patients affected by GBM No significant financial relationships to disclose.
Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009
Authors: Hau P. , Bogdahn U. , Olyushin V. E. , Mahapatra A. , Parfenov V. E. , Venkataramana K. , Ludwig S. , Jachimczak P. , Heinrichs H. , Schlingensiepen K. 
Published: March 2020

12521 Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment options in recurrence. In three Phase I/II dose escalation trials with AP 12009 in high-grade glioma (HGG) patients complete and long lasting tumor responses had been observed. Methods: The study G004 is an international open-label, randomized, active controlled, dose-finding Phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy. A total of 145 patients with histopathologically confirmed recurrent or refractory HGG (WHO Grades III and IV) were randomized into three treatment arms. Patients received treatment with low dose AP 12009 (10 μM), high dose AP 12009 (80 μMM), or standard chemotherapy TMZ or PCV. AP 12009 was applied by convection-enhanced delivery during using 7-day-on, 7-day-off cycles. Maximum number of cycles was 11. Results: Here we report on patients with recurrent or refractory glioblastoma (GBM, WHO Grade IV; AA patients see separate abstract). Out of 95 GBM patients treated, 28 pts received 10 μM AP 12009, 34 pts AP 12009 80 μM, and 33 pts standard chemotherapy (28 TMZ, 5 PCV). Median age differed between treatment groups (see table ). Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Comparable hazard ratios for survival were seen in the three treatment groups (see table ). Long lasting responses were observed in both AP 12009 groups. Conclusions: The safety profile of AP 12009 in GBM patients was good. The durable responses in both AP 12009 groups and the survival data confirm the proof of concept obtained in Phase I/II trials for treatment of recurrent GBM patients with AP 12009. [Table: see text] No significant financial relationships to disclose.
Modeling and simulation of neutropenia to support dosing regimens for liposome-encapsulated paclitaxel easy-to-use (LEP- ETU)
Authors: Grasela T. H. , Fetterly G. J. , Dul J. L. , LeComte D. , Grahn A. Y. , Fiedler-Kelly J. B. , Sherman J. W. , Damjanov N. , Fishman M. N. , Tan A. R. 
Published: March 2020

13011 Background: LEP-ETU is a liposomal formulation of paclitaxel designed to reduce toxicities while maintaining or enhancing the efficacy of the drug. A PKPD model was used to characterize the time course of neutrophils in relation to blood exposure of LEP-ETU in patients with solid tumors. Simulations were performed to provide justification for dosing schedule in Phase 3 trials. Methods: Data from 63 patients in two phase I studies with advanced malignancies were utilized. LEP-ETU was infused intravenously over 90 min. at 135, 175, 225, 275, 325, and 375 mg/m2 every 21 days (Q3W). A separate cohort received 175 mg/m2 of LEP-ETU infused over 3 hours following a Q3W regimen. Population PKPD modeling and simulations were performed to assess the influence of dose and schedule (275 - 325 mg/m2 Q3W vs. 90 - 110 mg/m2 QW) on neutropenia. Results: The temporal relationship between circulating neutrophils and paclitaxel concentrations was adequately characterized using a model representative of progenitor cells undergoing differentiation and maturation into neutrophils. Mean predicted (%SEM) baseline ANC was 4.3 (6) x 109/L, representative of a normal neutrophil count. Mean transit time (%SEM) was 80 (8) hr, representing a post-mitotic time delay to neutrophil maturation. The neutrophil T1/2 was 14 hr, comparable to published values. The drug effect (Slope·Cp) on the proliferation rate constant is decreased by 9- and 91-fold when 10 or 100 units of drug is present, indicative of paclitaxel’s inhibition of progenitor cell production in bone marrow. Simulations suggest a higher risk of neutropenia with the Q3W regimen and dose-dependent severity for both the Q3W and QW regimens. The predicted incidence of grade 4 toxicity increased from 33% - 42% across the dose range of 275 - 325 mg/m2 Q3W. For a dose of 110 mg/m2 given QW, the incidence of grade 4 neutropenia was 16% compared to 42% for the same total dose of 325 mg/m2 given Q3W. Conclusions: Modeling and simulation predict that a Q3W regimen of 325 mg/m2 LEP- ETU (MTD) provides acceptable neutropenia outcomes comparable to 175 mg/m2 paclitaxel Q3W, while minimizing the Cremophor- associated adverse events. Future consideration of QW regimens may be explored. No significant financial relationships to disclose.
Phase I dose escalation trial of biweekly pemetrexed in combination with docetaxel in advanced solid tumors
Authors: Garland L. L. , Cranmer L. , Gerstner G. , Walker R. , Obregon Y. , Ebbinghaus S. 
Published: March 2020

13019 Background: Pemetrexed (PEM) and docetaxel (DOC) are cytotoxic agents with a broad range of activity in solid tumors and relatively non-overlapping toxicities. We are conducting a single site dose escalation trial of biweekly dosing of PEM + DOC in advanced solid tumor patients (pts) to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and preliminary antitumor activity for the combination. Eligible pts have had 0–1 prior therapies, a performance status of 0–1, and creatinine clearance of =45 ml/min. Methods: Escalating doses of PEM (10 min infusion, d1 and 15) and DOC (1 hr infusion, d1 and 15) are administered q 28 days. Pretreatment vitamin supplementation consists of 1 mg IM vitamin B12 repeated q 9 weeks and daily oral folate 350–1,000 mcg. DLT is defined as grade 4 neutropenia =5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3–4 non-hematological toxicity in cycle 1. Results: To date, 12 pts ages 40–70 have been enrolled at 3 dose levels. Tumor types (N pts) include leiomyosarcoma (3); schwannoma (1); synovial sarcoma (1); transitional cell carcinoma of the bladder (1) and non-small cell lung carcinoma (NSCLC) (6). One patient was withdrawn for early progressive disease. Grade 3/4 treatment-emergent toxicities for 11 pts include neutropenia (3), anemia (1), mucositis (1), hyperglycemia (1), anorexia (1), weight loss (1), hyponatremia (1), pain (1), dehydration (1), fatigue (1), and thromboembolism (1). In addition, one pt had grade 5 pneumonitis during cycle 3. Dose level 3 has been expanded due to DLT in 1 pt. Antitumor activity for 11 evaluable pts includes 2 confirmed partial responses (by RECIST) in uterine leiomyosarcoma after adjuvant AIM therapy and pretreated NSCLC; stable disease in 5 pts; and progressive disease in 4 pts. Conclusion: Biweekly dosing of PEM + DOC is feasible and shows activity in a number of advanced solid tumors. The MTD has not been reached. *Pt with early progression replaced [Table: see text] No significant financial relationships to disclose.
Prostate cancer: Vaccine Sentinel Immunized Node (SIN) target for adjuvant locoregional chemotherapy in autologous vaccine
Authors: Lasalvia-Prisco E. M. , Garcia-Giralt E. , Cucchi S. , Vazquez J. , Brent M. , Walton D. 
Published: March 2020

13500 Background: In cancer patients, the systemic immune response elicited by Tumor Associated Antigens is started by a locoregional immune response at the microenvironment constituted by the antigen source (the tumor) and the draining sentinel lymph node (SLN). The locoregional immune response is decisional because it starts a systemic immune response configured as the SLN response: tolerogenic or protective (AJ Cochran, Nat Rev Immunol, 2006). Cancer vaccines reproduce this locoregional immune response: the vaccination site as the tumor antigen source and the draining SIN as the SLN (ML Disis, Blood, 1996). In experimental models, several chemotherapy drugs, especially Etoposide, injected in the vaccination site switch the locoregional immune response from tolerogenic to protective (RJ Scheper, Invest New Drugs, 1984). This study explores Etoposide as a locoregional adjuvant of the previously described Autologous Thermostable Hemoderivative-Cancer Vaccine ATH-CV (E Lasalvia-Prisco, ASCO, 2006). Methods: Thirty three M1 prostate cancer patients, hormone and chemotherapy resistant, performance status = 2, and PSA rising level, were included in this prospective, IRB-approved phase I/II trial. Patients were 3-group (G) randomized (11 each), submitted to different treatments: G1, no additional oncology treatment; G2, ATH-CV; G3, ATH-CV plus Etoposide 200 μg at vaccination site days 1–4 after vaccine. 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 cells immunophenotyping in biopsies of SIN scintigraphy-localized. Results: Statistical significant (p<0.05): DTH test > 5 mm: G1, 0/11; G2, 4/11 and G3, 8/11. LPA > 2.0: G1, 0/11; G2, 5/11 and G3, 9/11. Immunophenotyping: CD4+ CD25+ (Treg): G1>G2>G3. 30 days PSA increase: G1>G2>G3. No relevant toxicity was evidenced. Conclusions: In advanced prostate cancer, when all other treatments are exhausted, the sensitization and tumor antiprogressive effect of ATH-CV were potentiated by Etoposide as local adjuvant. SIN depletion of tolerogenic cells is suggested as mechanism of action. No significant financial relationships to disclose.
Specific immune responses against hepatocellular carcinoma induced by dendritic cell- HepG2 fusion cells derived- exosomes
Authors: Zhang H. , Zhang L. W. , Liu W. C. 
Published: March 2020

13511 Background: To assess the properties of exosomes secreted by fusion cells of hepatoma patient-derived dendritic cells(DCs)and hepatoma cell line (HepG2) and to evaluate the function of these exosomes to trigger efficient T cell responses against HepG2 cells in vitro. Methods: Peripheral blood mononuclear cells (PBMC) from hepatoma patients were isolated and in the presence of GM-CSF and IL-4, PBMC were cultured in vitro for one week to induce dendritic cells (DC). Fusion cells of DC with HepG2 cells (DC- HepG2) were achieved by PEG and were isolated by magnetic device with HLA Class II Dynabeads. Exosomes were then prepared from the supernatants of the fusion cells by ultra filtration centrifugation and sucrose gradient ultracentrifugation. T lymphocytes were pulsed with exosomes directly in the presence of IL-2. After co-cultured with target cells, the stimulated lymphocytes were tested by IFN-? release assay and cytotoxicity capacity assay. Results: After fusion, DC-HepG2 expressed expressed high level of DC surface molecules, including CD83 87.4%, CD80 94.9%, CD86 90.13% and HLA-DR 98.62%. Application of the isolation procedure to fusion cells also revealed exosome vesicles by transmission electron microscopy. Protein analysis by FCM was performed and revealed that the costimulatory molecule CD86 and AFP protein was detectable. The fusion cell- derived exosomes could directly activate T lymphocytes which lysed HepG2 target cells much more effectively than T cells alone did (P<0.05). To determine whether the lysis was HepG2 tumor cell-specific, SMMC7721 and K562 cells were used as target cells and nearly no lysis of these cells was observed. Furthermore, IFN-? in the culture supernatants of exosomes- activated T cells was significantly higher than that in normal control T cells (P<0.05). Conclusions: Exosomes could be purified from the supernatants of fusion cells. These exosomes could activate T cells directly and could induce effective HepG2 secific CTL responses. DC- HepG2 fusion cells-derived exosomes may represent as a promising approach of immunotherapy for HCC. No significant financial relationships to disclose.
Clearance of monoclonal antibody (mAb) CP-675,206 by therapeutic plasma exchange (TPE) or plasmapheresis
Authors: Sharma A. , Bumerts P. , Gomez-Navarro J. , Pavlov D. , Ribas A. 
Published: March 2020

13515 Background: CP-675,206 is a fully human, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blocking mAb with immune stimulating properties under development for the treatment of metastatic melanoma. The pharmacokinetics of CP-675,206 is similar to endogenous IgG, with a long plasma half-life (22 days). We explored the use of TPE in two patients (pts) receiving CP-675,206, postulating that TPE could be used to remove mAb in cases where toxicities are thought to result from persistence of mAb in circulation. Methods: For both pts, five TPEs were performed over 7 days using a Cobe Spectra blood cell separator (TPE daily x 3, 2 days rest, and TPE daily x 2). One plasma volume was processed per TPE and replaced with a 60%/40% albumin/saline solution. Plasma CP-675,206 concentration was measured at baseline and after the 3rd and 5th TPE. Results: Patient 1 was a 62 year-old with metastatic melanoma who received 8 monthly doses of CP-675,206 (10 mg/kg). Six days after the last dose, the pt was found to have elevated ALT and bilirubin and detectable anti- smooth muscle and anti-microsomal antibodies. Based on a suspicion of therapy-related autoimmune hepatitis, the pt underwent TPE. Plasma CP-675,206 concentration declined by 96% following the 5th TPE, and ALT and bilirubin normalized over the 4 weeks following TPE with no other evidence of clinical hepatitis. Patient 2 was a 78 year-old with in-transit melanoma who received 3 monthly doses of CP-675,206 (10 mg/kg) and was responding to therapy. Two weeks after the last dose the pt developed diffuse bilateral arthralgias. The pt was diagnosed with rheumatoid factor-negative rheumatoid arthritis, presumably related to therapy with CP-675,206, and underwent TPE. Pre- and post-TPE plasma CP-675,206 concentrations are pending. The arthralgias persisted, and the pt subsequently received oral methotrexate with slow improvement in symptoms over the next 6 months. Conclusions: TPE is highly effective for reducing the plasma concentration of CP-675,206 and may be useful to avert the progression of drug-related adverse events. Clinical benefit from TPE may vary depending on the interval from dosing and may be limited by slow reversibility of T-cell immunostimulation. [Table: see text]
Interactions of breast cancer cells and tumorantigen-reactive T-cells derived from bone marrow
Authors: Schuetz F. , Sachsenweger C. , Rom J. , Schneeweiss A. , Schirrmacher V. , Beckhove P. , Sohn C. 
Published: March 2020

13517 Breast cancer is an immunogenic tumor which is usually recognized by the cellular immunosystem via tumor-associated antigens (TAA) presented by antigen-presenting cells like dendritic cells. Although we were able to find tumorantigen-reactive CD8+CD45R0+ T-memory cells (TMC) in the bone marrow of 67% of primary breast cancer patients by using interferon-?-ELISPOT-analysis there seem to be a minority of non-responers. In comparison to classic tumor characteristics non-responders can be find more often in non-differentiated, hormone-receptor negative tumors. In a phase-1 trial of a cellular immunotherapy with reactivated tumorantigen-reactive autologous TMC derived from bone marrow we measured CD4+ T-cell (TC) responses in stimulation cultures ex vivo to examine whether there are other immunological answers in non-responder. TC were activated by dendritic cells pulsed with TAA from MCF-7 lysate under IL-2 co-stimulation. We were able to show that next to a classic TH1-response with high levels of IFN-a there seems to exist TH2-responses mediated by high levels of TGF-β1 and low levels of IFN-a. The relation of both cytokines was directly related to the detection of tumorantigen-reactive TC and to tumor grading. Multiplex-cytokine analysis was able to confirm these findings. Additionally there seems to be an important impact of regulatory TC in responders as well as in non-responders. In patients with tumorantigen-reactive TC a combined active and passive vaccination therapy was done. These results may play an important role in further active and passive vaccination strategies. No significant financial relationships to disclose.