bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postoperative radiotherapy (RT) with or without chemotherapy (CT) in anaplastic astrocitoma (AA) patients.
Authors: Brugnara Sonia , Russo Lucianna , DiPasquale MariaChiara , Nagliati Michele , Basso Gianpaolo , Trevisan Diego , Chioffi Franco , Pulcrano Giuseppe , Colarusso Enzo , Barbareschi Mattia , Rozzanigo Umberto , Pellegrin Andrea , Amelio Dante , Donner Davide , Buganza Manuela , Magri Elena , Dallabona Monica , Decarli Nicola L , Galligioni Enzo 
Published: March 2020

e13046 Background: Although the evidence for the benefit of adding temozolamide (TMZ) to RT is limited to glioblastoma patients (pts), there is currently an increased tendency toward a combined RT + TMZ approach also in AA patients. Methods: We report in this study the survival outcome of 2 groups of pts, treated at in 2 different periods at our institution with RT after surgery ± CT. GROUP A (years 1984-2001): pts treated with surgery followed by RT; GROUP B (YEARS 2004-2009): pts treated with surgery followed by radical RT and CT according to the STUPP’s protocol; Results: Data were retrospectively collected on a consecutive series: GROUP A: 17 pts: 10 Males (M), 7 Females (F); median age 50 years (range: 31-65). Ten out of 17 pts received radical surgery and 7 subtotal surgery. All were treated with postoperative RT, median dose 5082 cGy (range: 2160-6300). The mean time between surgery and beginning of RT was 44.7 days (range 20-87). GROUP B: 17 pts: 10 M, 7 F; median age 44 years (25-72). Eleven out 17 pts received radical surgery and 6 subtotal surgery. All were treated with postoperative RT, median dose 5800 cGy (range: 4000-600). The mean time between surgery and beginning of RT was 56.3 days (range 26-111). All patients received TMZ 75 mg/mq for a median of 6 weeks (range 3-7), followed by adjuvant treatment with TMZ (200 mg/mq) for a median of 5 cycles (range 0-13). At a median follow-up of 45 mos , the median OS was 29.1 mos for the group A and 49,1 mos for the group B. Among pts treated with RT + CT after surgery, median OS was significantly longer (p= 0.03), compared to those treated with only RT after surgery. Conclusions: The limited sample sizes of 2 groups and differences such as the median RT dose and the median time between surgery and RT, does not allow any conclusion. However, our data suggest that the combined RT-CT treatment is feasible in AA pts after surgery and may possibly contribute to a prolonged control of disease. These suggestions should be explored in a prospective randomized trial.
Treatment of advanced glioma with an energy restricted ketogenic diet: Case report and literature summary.
Authors: Schwartz Kenneth A. , Noel Mary , Nikolai Michele , Chang Howard T. , Olson Lawrence Karl , Kurniali Peter C. , Pernicone Joseph , Hord Norman , Sweeley Charles 
Published: March 2020

e13047 Background: We initiated a pilot study to evaluate an energy restricted ketogenic diet (ERKD) as treatment for patients with glioblastoma multiforme (GBM) whose brain tumor had progressed with standard therapy. Methods: This reports documents our experience using an ERKD with an IRB approved, clinical trials #NCTO1535911 registered treatment protocol and briefly summarizes the 5 published case reports that document favorable responses with ERKD. Results: Our patient, a 55-year-old white male, presented with a left sided visual field cut, decreased analytical mental skills, a slow methodical wide based gait and a right posterior brain mass with a histological diagnosis of GBM. After documented progression following surgery, radiation therapy and TMZ the patient was treated with ERKD. He was hospitalized to induce a decrease in glucose and an increase in ketones using Ketocal 20-25 Cal/Kg. Adherence and efficacy to the diet was monitored using AM and PM measurements of blood glucose and ketones. Initial treatment with Ketocal decreased his blood glucose so that his PM glucose was <80mg/dl and increased his PM ketones to >3mm(our protocol’s target concentrations). However, his AM glucose was still >80mg/dl and his AM ketones decreased to >2mM. Because of the low palatability of the Ketocal, the patient was switched to a ketogenic regular food diet with a 3:1 ratio of fat to proteins and carbohydrates. Out of the hospital and on this diet his PM ketones remained > 3mM and his AM > 2mM, but his AM and PM blood glucose increased to > 80mg/dl. After 4 weeks of treatment with the ERKD, the patient’s disease advanced; his vision, mobility and cognition decreased and MRI demonstrated tumor growth and he withdrew from the study. Five patients with advanced brain tumors and favorable responses to ERKD have been reported. The best response was a C.R. 5 years after diagnosis. In 4 of the 5 patients ERKD was combined with one of the standard modalities of treatment. At last report 3 of the 5 patients were C.R. and 2 had documented disease progression after stopping the ERKD. Conclusions: Investigation of ERKD in patients with malignant brain tumors using an approved, registered protocol under the guidance of a dietician is feasible.
3'-deoxy-3'-[18F]fluorothymidine position emission tomography for target delineation in resected malignant gliomas before radiotherapy.
Authors: Zhao Fen , Li Minghuan , Fu Zheng , Yu Jinming 
Published: March 2020

e13052 Background: To analyze the FLT PET image feature of malignant gliomas and evaluate the usefulness in the visualization of residual tumor volume compared with MRI. Methods: Patients with postoperative residual malignant gliomas were enrolled on this prospective trial. MRI and PET were performed in the same week, 1 to 4 weeks after surgical resection.,we compared the SUVmax of tumor and the T/N ratio between the grade III and IV gliomas and the residual tumor volume and the geometric position defined by FLT uptake and the abnormalities signals on MRI were compared using FLT PET/MRI fusion images. Results: 19 patients were analyzed. The SUVmax were 0.86±28 for grade 3 gliomas , and 2.68±2.22 or 2.05±0.44(with or without one gliosarcoma whose SUVmax was as high as 9.6) for grade IV gliomas (P <0.001). The mean (±SD) value of T/N ratio in grade IV gliomas were 15.43±10.47 or 12.48±2.20(including or not of the gliosarcoma ) and 4.84±1.77 in gade III gliomas(P <0.001). The mean Vol-T1, Vol-T2 and Vol-PET was 13.08cm3,33.46cm3 , and 15.04cm3 , respectively. The Vol-PET were not significant larger than the Vol-T1( P>0.05). The areas between the increased FLT PET activity and abnormality in MRI were imperfectly correlated .In 13 (68.4%) and 11 patients(57.90%) , the FLT uptake regions exceeded the area of contrast enhancement and the area of hyperintensity areas on the MRI. In 5 (26.3%) and 4(21.05%) of 19 patients, FLT uptake extended 25 mm from the margin of Gd enhancement and hyperintensity areas. And the FLT uptake was measured up to 43mm and 39mm outside of the Gd enhancement and hyperintensity areas on MRI. Conclusions: FLT PET was found to be useful in assessment of grade in malignant gliomas. FLT PET can provide complement information to the MRI for defining the remaining tumor volume accurately in patients with malignant gliomas postoperative residual .
Relationship between intravenous (IV) busulfan pharmacokinetics (PK) and patient characteristics in allogeneic stem cell transplant patients.
Authors: Simmons Ashley Erickson , Keisler Meredith Deal , Ivanova Anastasia , Rao Kamakshi V. , Shea Thomas C. , Walko Christine Marie 
Published: March 2020

e13507 Background: Busulfan is an alkylating agent commonly used for myeloablation in hematopoietic stem cell transplantation (SCT). Narrow therapeutic index and 2-3 fold interpatient PK variability underscores the need to further explore predictors of busulfan clearance. This analysis aimed to determine patient (pt) characteristics that may impact the clearance of busulfan. Methods: This retrospective analysis assessed allogeneic SCT pts who received a test dose of 0.8 mg/kg IV busulfan, dosed by adjusted body weight, over 2 hours on days -15 to -10 prior to conditioning therapy containing therapeutically dosed busulfan. All pts were treated between June 2004 and July 2012 at the University of North Carolina at Chapel Hill. Noncompartmental PK parameters were calculated from this test dose using Phoenix WinNonlin Pharsight software. A linear model with log of busulfan test dose clearance as an outcome and pt characteristics that included disease state, bone marrow donor type, gender, race, ethnicity, body surface area (BSA), body mass index, type of anticonvulsant prophylaxis used (levetiracetam or phenytoin), total bilirubin and serum creatinine was fit. Results: The study reviewed a total of 88 pts with a mean age of 41.1 (range 18-63). The analysis included 54 males, 76 Caucasians, and 5 African Americans (AA). Seizure prophylaxis with levetiracetam was given to 27 pts, and 51 received phenytoin. After adjusting for pt characteristics, a unit increase in BSA was associated with 0.69 (p = < 0.001) increase in log(clearance). Regression coefficients for phenytoin use with no seizure prophylaxis as reference and for African American race with Caucasian race as reference were significant (0.22, p = 0.033, and -0.31, p=0.13, respectively). No correlation was seen for age (p = 0.357), gender (p = 0.337), levetiracetam use (p = 0.3525), or for any other variable. Conclusions: Our data suggests that higher BSA and phenytoin use are associated with a higher busulfan clearance, while AAs have a lower clearance. These findings may help inform future dosing strategies in order to decrease interpatient PK variability and accurately predict plasma concentrations of busulfan.
Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.
Authors: Staddon Arthur P. , Parekh Trilok V. , Knoblauch Roland Elmar , Keung Chi , Bernard Apexa , Aymes Ana L. , Phelps Charles , Sharma Sunil 
Published: March 2020

e13512 Background: Trabectedin (Yondelis; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m2, IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (Cmax) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by Cmax and AUClast. The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]
Prediction of individual tamoxifen activation in breast cancer patients.
Authors: Gusella Milena , Bertolaso Laura , Fraccon Anna Paola , Barile Carmen , Rizzi Anna , Carturan Sabrina , Modonesi Caterina , Ghiotto Cristina , Crepaldi Giorgio , Mion Marta , Segati Romana , Padrini Robeto , Toso Silvia , Zaninelli Marta , Ramello Monica , Tomassi Ottaviano , Magazu' Marcello , Minicuci Nadia , Bassan Franco , Pasini Felice ,   Italian TAM Group
Published: March 2020

e13514 Background: Endoxifen (EN), the main active metabolite of tamoxifen (T), reaches steady state (SS) plasma levels after about 4 months of administration. It derives principally by cytochrome CYP2D6 activity, which is highly variable among patients. In order to predict individual SS EN exposure, three different approaches were investigated. Methods: Before starting T administration, 73 breast cancer patients (median age: 59 yrs, range: 30-89) were characterized by means of: 1) a phenotyping test of CYP2D6 activity, based on the urinary metabolic ratio of dextromethorphan/dextrorphan (log transformed, LMR). 2) CYP2D6 genotyping (alleles *1, *3, *4, *5, *6, *9, *10, *41), to classify patients in 3 functional groups: Extensive (EM), Intermediate (IM) and Poor (PM) Metabolizers. After starting T treatment (20mg/day), EN plasma levels were measured after 1 month (1M EN, pre- steady state) and 4 months of therapy (SS EN). ANOVA, paired and unpaired T test and linear regressions were performed to analyze associations between LMR, CYP2D6 genotype, 1M EN and SS EN. Multivariate linear regression was used to create a predictive equation; its mean prediction and absolute errors (MPE% and MAE%) and the positive and negative predictive values (PPV% and NPV%, according to median SS EN) were calculated. Results: SS EN plasma levels varied between 2.4 and 39.2 (median: 8.7) ng/ml. LMR (median: -1.6; range: -3.1- +1.2) showed a significant linear correlation with SS EN (r=-0.59; p<0.0001). CYP2D6 genotypes (EM=35.6%; IM=50.7%; PM=13.7%) were significantly associated with SS EN (ANOVA, p<0.0001). First month EN plasma levels (median: 5.9 ng/mL; range:1.2-27 ng/ml) were significantly lower than (p<0.0001), and correlated (r=0.87; p<0.0001) with, SS EN. Multiple regression analysis including age, LMR, CYP2D6 genotypes and 1M EN gave the following predictive equation: SS EN= 0.055-1.53 x LMR + 1.11 x 1M EN; (r=0.88; p<0.0001). MPE was 4.1% and MAE was 30%; PPV was 88.5% and NPV was 84.6%. Conclusions: Individual EN exposition at steady state can be reliably predicted by measuring baseline CYP2D6 activity, through the log (dextromethorphan/dextrorphan) metabolic ratio, and EN plasma concentration after 1 month of tamoxifen treatment. Funded by Regione Veneto. Clinical trial information: 532.
SMAD5 expression and inhibition of the mitotic kinase aurora-A on sensitivity of breast cancer cells to chemotherapy.
Authors: Opyrchal Mateusz , Iankov Ianko , Ingle James N. , Salisbury Jeffrey L. , Galanis Evanthia , D'Assoro Antonino 
Published: March 2020

e13516 Background: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A will lead to increased sensitivity to chemotherapy. Methods: The hypothesis was tested in vitro. Cellular proliferation was tested using MTT assay and protein levels were determined on Western blots. Results: In ER+ cell line, MCF7, constitutive activation of Raf-1/MAPK signaling pathway leads to aberrant activation of Aurora-A kinase activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to parental MCF7 cells. This effect is even more pronounced with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by novel inhibitor, Alisertib. This was further explored in triple negative cells (MDA-MB-231) and cells expressing Her-2/neu (BT474) which express higher levels of Aurora-A. Combination of Alisertib and paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are investigating a role of Aurora-A in developing chemoresistance through activating SMAD5. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing. Conclusions: Inhibition of Aurora-A by Alisertib resulted in decreased SMAD5 nuclear phosphorylation and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be extremely useful in developing more effective treatments for breast cancer patients both in neo-adjuvant, adjuvant and metastatic settings.
A French prospective pilot study for identifying dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients (pts) receiving capecitabine (cap).
Authors: Etienne-Grimaldi Marie-Christine , Ferrero Jean-Marc , Thomas Fabienne , Bobin-Dubigeon Christine , Merlin Jean Louis , Pinguet Frederic , Ferrand Christophe , Boyer Jean-Christophe , Romieu Gilles , Bachelot Thomas , Pivot Xavier , Dieras Veronique , Largillier Remy , Mousseau Mireille , Goncalves Anthony , Roche Henri Hubert , Bonneterre Jacques , De Clercq Beatrice , Milano Gerard 
Published: March 2020

e13519 Background: For fluoropyrimidines, and especially cap, Health Authorities point out that DPD deficiency confers a significant risk of major toxicity (tox). Identification of at-risk pts is thus relevant. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping for predicting severe cap-related tox in metastatic breast cancer pts. Methods: 303 pts were included (15 institutions), 88% received cap as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment dihydrouracil (UH2) and uracil (U) plasma concentrations were measured in 286 pts (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was done on 281 pts. Severe tox (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 tox (diarrhea, vomiting, hematoxicity, hand-foot syndrome) was observed in 19.6% of pts (one toxic death). A marked trend for higher U (median 12.7 vs 10.2 ng/ml, p=0.014) and UH2 (median 110 vs 93 ng/ml, p=0.011) concentrations was observed in pts developing severe tox vs those who didn’t. However, ROC curves showed that these differences were too small for use as reliable tox predictors. The distribution of UH2/U ratio was similar between pts with or without tox (median 9.1 vs 9.6, respectively, p=0.80). The patient with toxic death had a UH2/U ratio of 6.5 and U concentration of 17 ng/ml. Among the 7 pts with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe tox (including toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe tox was 4.60 in mut pts vs wt pts (95%CI 2.95-7.16, p=0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: These data point out that breast cancer pts harbouring a DPD variant allele are candidate to develop severe, up to lethal, cap-related tox. In contrast, pre-treatment UH2/U ratio and U measurements are not reliable predictors of cap tox. Clinical trial information: Eudract 2008-004136-20.
Focal adhesion kinase (FAK) inhibitors VS-6063 and VS-4718 target cancer stem cells.
Authors: Xu Qunli , Kolev Vihren N , Wright Quentin G , Shapiro Irina M , Vidal Christian M. , Padval Mahesh , Keegan Mitchell , Paterson Daniel , Horobin Joanna , Pachter Jonathan A 
Published: March 2020

e13523 Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates cellular signaling through integrins and growth factor receptors and functions in multiple steps of tumorigenesis. Both VS-6063 and VS-4718 are potent, selective, and orally active FAK inhibitors. In a phase I clinical trial, VS-6063 was well tolerated and demonstrated preliminary clinical activity. VS-4718 is in late stage preclinical development and has been shown to inhibit tumor growth and metastasis in tumor models. We report here that the FAK inhibitors VS-6063 and VS-4718 effectively abrogate cancer stem cells (CSCs). Methods: VS-6063 and VS-4718 were evaluated in the ALDEFLUOR and Side Population (SP) CSC assays in vitro and in xenograft tumors in vivo. Results: Treating SUM159 breast cancer cells with FAK inhibitors reduced the percentage of ALDEFLUOR+ and SP CSCs. Similar inhibitory effects on CSCs were observed in the ovarian cancer cell lines OVCAR-5 and OVCAR-8 and the mesothelioma cell line H2052. In direct contrast, cytotoxic agents paclitaxel, carboplatin and pemetrexed increased the percentage of CSCs, suggesting that these agents do not effectively target CSCs. Importantly, combination of either VS-6063 or VS-4718 with cytotoxic agents blocked induction of CSCs by these agents. The effect of a FAK inhibitor on CSCs in vivo was evaluated in an MDA-MB-231 human breast cancer orthotopic model. Oral administration of FAK inhibitor substantially reduced the number of ALDH1- positive cells in tumors as assessed by immunofluorescence. Following dissociation of cells from tumors, CSCs were found to be reduced in FAK inhibitor-treated tumors as measured by multiple assays. Furthermore, cells isolated from FAK inhibitor-treated tumors showed reduced tumor-initiating capability upon re-implantation into immunodeficient mice. FAK inhibitor also decreased ALDH1-positive CSCs in an orthotopic MM87 mesothelioma model. Conclusions: Our results provide clear demonstration that FAK inhibitors target cancer stem cells both in vitro and in xenograft tumors in vivo and support the planned clinical development of VS-6063 and VS-4718 to achieve durable clinical responses for cancer patients.