bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune response after high-intensity focused ultrasound ablation for H22 tumor
Authors: Zhou P. , Fu M. , Bai J. , Wang Z. , Wu F. 
Published: March 2020

21169 Background: Previous results have shown that high intensity focused ultrasound (HIFU) ablation can potentially activate a host anti-tumor immunity. This study was to investigate whether acoustic cavitaion may enhance host immune responses after HIFU treatment for solid malignancy, and to explore the potential mechanisms regarding the enhanced anti-tumor immunity. Methods: (1) Tumor cell vaccine preparation: H22 cells were irradiated with HIFU (0.8MHz, 1050W/cm2, 90s); H22 cells were heated for one hour in 65°C water bath. (2) Animal study: 150 KM mice were randomly divided into three groups: control group, thermal group, and HIFU group. Each group had 50 mice for immune experiments. By using hypodermic injection, the mice in thermal group and HIFU group received either 0.2ml heat-treated H22 vaccine or 0.2ml HIFU-treated H22 vaccine in the left flank of each mouse. Those in control group received only injection with same amount of saline solution. The vaccination times were 4 sessions, once a week for 4 consecutive weeks. One week after last vaccination, each mouse was challenged with H22 tumor cells. All mice were followed up to observe the long-term survival in each group, and peripheral blood was collected to detect changes in T lymphocytes and their subsets by flow cytometry technique. Results: The tumor incidences and 6-week survival rates were observed 100% and 88% of mice in control group, 72.5% and 40% in thermal group, and 42.5% and 14% in HIFU group respectively. Compared to the values in either control group or thermal group, there was a significant decrease of tumor incidences and 6-week survival rates in HIFU group. The volume of tumor was obviously lower in HIFU group, and a significant difference was observed between HIFU group and thermal group or control group. Compared to the values in control group, there were a significant increase of CD4+ levels and CD4+/CD8+ ratio, and a significant decrease of CD8+ level in both HIFU group and thermal group. Conclusions: Antitumor immune response could be enhanced after HIFU ablation for H22 implanted tumor in mice, and acoustic cavitation could play an important role to stimulate host antitumor immune system. No significant financial relationships to disclose.
Pharmacogenetic analysis of toxicity after 5-fluorouracil (5FU) or 5FU/oxaliplatin therapy for metastatic colorectal cancer: Preliminary results in FFCD 2000–05 trial
Authors: Castaing M. , Loriot M. A. , Barrois M. , Miran I. , Mulot C. , Laurent-Puig P. , Pignon J. P. , Ducreux M. , Boige V. 
Published: March 2020

2508 Background: The FFCD 2000–05 randomized trial compared simplified LV5FU2 followed by FOLFOX6 (arm 1) to FOLFOX6 followed by FOLFIRI (arm 2) in the treatment of metastatic colorectal cancer. The aim was predicting the toxicity profile of oxaliplatin after the first line treatment using pharmacogenetic data. Methods: Patients (pts) with available blood samples were compared to the other pts for clinical prognostic factors (chi2 test). A logistic model was computed to test the association between polymorphisms and toxicity in each arm. An interaction test was used to assess a differential effect according to treatment (predictive effect), in order to identify a predictive effect of oxaliplatin. Grade 3–4 hematological and non-hematological toxicities (H-tox and NH-tox) at 4 months and grade 2–4 neurological at 6 months were the endpoints of the study. Thirteen genetic variants in 10 candidate genes were selected for pharmacogenetic analysis: ERCC1_04 (rs3212961), ERCC1_05 (rs11615), ERCC1_06 (rs3212948), ERCC1_24 (rs3212955), ERCC2_02 (rs1799793), ERCC2_03 (rs13181), ERCC2_06 ( rs238406 ), ERCC2_09 (rs1799787), GSTM1 (null/present), GSTT1 (null/present), TS (TSER, Ins/del6bp) and UGT1A1 (rs8175347). Genotyping was performed using Taqman probes, QMPSF and fragment analysis. Results: 327 pts (156/171) out of 410 were included (61 had no blood samples, 16 had less than 2 cycles, 3 had incomplete data on toxicity, 3 had insufficient DNA). No difference was found between included and excluded pts in the analysis for gender, age, OMS, number of metastatic organs and adjuvant chemotherapy. Pts received similar 5FU doses in both arms. Number of patients with at least one toxicity in arms 1/2 were as followed: 5/54 grade 3–4 H-tox, 28/47 grade 3–4 NH-tox, and 0/103 grade 2–4 neurological. The genotype CC of ERCC2_02 correlated with higher NH-tox at 4 months in arm 2 (p=0.0008, OR=0.31, 95%CI=[0.15–0.62] versus p=0.87, OR=0.93, CI=[0.39–2.21] in arm 1) compared to genotypes CT and TT, with borderline interaction (p=0.05). Conclusions: These preliminary results on early toxicity in first-line are in favour of an effect of ERCC2_02 on NH-tox of FOLFOX6 and a predictive effect on NH-tox of oxaliplatin. [Table: see text]
Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving 5-fluorouracil (FU)/oxaliplatin (OX) as first-line chemotherapy
Authors: Marcuello E. , Pare L. , Altes A. , Rio E. Del , Sedano L. , Barnadas A. , Baiget M. 
Published: March 2020

2509 Background: Chemotherapy using oxaliplatin, 5-fluorouracil is known to be effective in the treatment of CRC patients. Optimization of this therapy is complicated due to wide variability in drug response that may be due to functional genomic polymorphisms in genes related to the drug target, to the metabolizing or to the DNA repair. We report the evaluation of polymorphisms in the TS, MTHFR (drug target) ERCC1, XPD and GSTP1 (repair enzymes) genes. Methods: We treated 109 CRC patients with a first line oxaliplatin/5-FU chemotherapeutic regimen. Genetic polymorphisms were determined by PCR based RFLP or by Real-Time PCR on an ABI PRISM 7000, using DNA from peripheral blood. The investigated polymorphisms were: TS (VNTR in the 5’ UTR, the 3R G>C SNP and the 1494del6), ERCC1 (Asn118Asn, 8092C>A, 19716 G>C), GSTP1 (Ile105Val) and XPD (Lys751Gln). Clinical response (CR), progression free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: The patients were classified according to the clinical risk assessment (CRA) defined by EORTC in three groups with different DFS (12, 9, 7 months; P= 0.008) and different OS (41,19,11 months; P= 0.0002). In the univariate analysis for CR, ERCC1 and XPD polymorphisms were significant (P=0.03, P= 0.047, respectively). After adjustment for the mentioned clinical risk assessment, only ERCC1 retained significance (P=0.037; HR: 4.2, C/C vs T/T). In the univariate analysis for PFS, only ERCC1 polymorphism was significant (P=0.034). After adjustment for the clinical risk, this genotype did not retained its significance (P=0.37). Finally, TS, ERCC1 and XPD polymorphisms were significant in the univariate analysis for overall survival, (P=0.032, P=0.003, P=0.016 respectively). Following the adjustement for the clinical risk, all three genotype variables retained significance (P=0.019, P=0.002, P= 0.024, respectively). Conclusions: i) The EORTC risk assessment classification was a very useful predictor of DFS and OS in our group of patients; ii) Germline genetic polymorphism of ERCC1 predicted response to FU/OX in CRC patients and iii) Polymorphisms in the TS, ERCC1 and XPD genes were good predictors of overall survival. No significant financial relationships to disclose.
Analysis of renal function in patients entered onto CTEP-sponsored phase I studies since 1979
Authors: McHayleh W. M. , Sehgal R. , Potter D. M. , Royds R. B. , Nekrassova T. G. , Ivy S. P. , Ramalingam S. , Belani C. P. , Naret C. L. , Egorin M. J. 
Published: March 2020

2519 Background: The NCI and FDA utilize different criteria for classifying renal dysfunction. We analyzed renal function in all patients entered onto CTEP-sponsored phase I clinical trials since 1979 to evaluate the percentage of patients with acceptable renal function according to criteria utilized by the National Cancer Institute, as compared with those advocated by the Food and Drug Administration. Methods: Data from 12575 patients entered onto CTEP-sponsored phase I studies since 1979 were evaluated. Renal function was characterized by calculating creatinine clearance (CrCl) by three different formulae (Cockroft-Gault, Jelliffe, and Levey), as well as GFR according to MDRD. Results: Of the 12,575 patients, data were available to calculate renal function with all the 4 formulae in 5,177. Distributions of CrCl and GFR were defined, and patients were classified as having normal renal function or severe, moderate, or mild renal dysfunction according to FDA or NCI criteria. The resulting distributions are indicated in the table below. Conclusions: Approximately 40% of patients entered into CTEP-sponsored phase I trials have mild renal dysfunction according to FDA criteria and approximately 95% have CrCls > 50 ml/min. These data imply that moderate and severe are the only renal dysfunction categories that need to be evaluated in renal dysfunction studies of novel antineoplastic agents and that FDA guidelines should be applicable. Whether patients in the NCI database with CrCls of 50–80 ml/min experience more toxicities than those with creatinine clearances > 80 ml/min is undergoing evaluation. [Table: see text] [Table: see text]
Pharmacokinetics of lenalidomide in subjects with various degrees of renal function
Authors: Chen N. , Lau H. , Kong L. , Zeldis J. , Knight R. , Laskin O. 
Published: March 2020

2520 Background: Lenalidomide is a novel oral immunomodulatory drug approved for treating myelodysplastic syndrome (MDS) and multiple myeloma (MM). As unchanged lenalidomide is eliminated predominantly by urinary excretion, the present study investigated the effect of renal impairment (RI) on pharmacokinetics (PK) of lenalidomide. Results were used to refine initial dosing recommendations based on a subject’s estimated creatinine clearance. Methods: The study was conducted at 3 clinical centers. Thirty male and female subjects aged 39–76 years were stratified into 5 groups based on their creatinine clearance (CLCr) values: normal renal function (NRF) (CLCr > 80 mL/min; N = 7), mild RI (50 = CLCr = 80 mL/min; N = 5), moderate RI (30 = CLCr < 50 mL/min; N = 6), severe RI (CLCr < 30 mL/min, but not on dialysis; N = 6), and end stage renal disease (ESRD, requiring dialysis; N = 6). Subjects with NRF, mild, moderate or severe RI received a single 25-mg oral dose of lenalidomide. Subjects with ESRD received 2 single 25 mg doses which were separated by 7–10 days: one dose on a non-dialysis day and the other dose 3 hours before a 4-hour haemodialysis. Assessments included PK and safety parameters. Results: All subjects completed the study. Total and renal clearance of lenalidomide were strongly correlated with CLCr (R > 0.9, p < 0.01). As a result, AUC8 increased with decreasing CLCr. The mean difference in AUC8 between NRF and mild RI was < 20%. Compared with the pooled data from NRF and mild RI groups, mean AUC8 increased approximately 140% in moderate RI, 240% in severe RI, and 360% in ESRD (off dialysis). There was no correlation between Cmax or Tmax and CLCr. Approximately 10% of the dose was recovered in the dialysate of subjects with ESRD. Protein binding of lenalidomide was not markedly affected by RI (∼35 - 44%). The drug was well tolerated. On the basis of these data, recommendations for initial starting doses were made ( Table below). Conclusions: Lenalidomide dosage adjustment should be considered for patients with CLCr < 50 mL/min. [Table: see text] No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients with liver dysfunction (LD): Pharmacokinetic results
Authors: Paule B. , Saliba F. , Gil-Delgado M. , Puozzo C. , Favrel S. , Ravaud A. , Delord J. , Fumoleau P. 
Published: March 2020

2523 Background: VFL is a novel microtubule inhibitor of the vinca alkaloid class that has shown high antitumour activity in several in vivo tumour models and in clinical trials. VFL is mainly eliminated through metabolism and bile excretion. Therefore this trial was designed to determine if LD could increase exposure and toxicity of VFL and require a dose-adjustment. Methods: This trial had a sequential design with the objective of determining the maximal tolerated dose (MTD) and the recommended dose (RD) in three groups of LD based on clinical and biological criteria: mild (PT > 70% and UNL < serum bilirubin = 1.5xUNL), moderate (Child-Pugh A) and severe (Child-Pugh B). VFL and 4-O-deacetylvinflunine (DVFL), its only active metabolite, were quantified in whole blood during cycle 1. PK parameters (AUCinf, Cltot) were estimated using a non-compartmental analysis and were compared using a one-way ANOVA with group factor either between groups or between groups and a control group of 49 patients without LD enrolled in phase I trials). Results: Three VFL doses were investigated: The inter-individual variability (CV) in AUCinf was approximately 30% for all groups. Even if AUCinf increased between mild and moderate groups, no difference was demonstrated between moderate and severe LD groups. All individual values were within the range of control values. Cltot were also similar between groups and the control group. Statistical analysis did not evidence any significant difference between groups. No difference was observed in blood concentrations of DVFL compared to the control group. No relationship between dose limiting toxicity and blood exposure was evidenced. Conclusions: The results showed that vinflunine and DVFL pharmacokinetic parameters do not appear to be affected by the degree of LD. However, the dose of VFL has to be adjusted to the level of LD for safety reasons. [Table: see text] No significant financial relationships to disclose.
Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC-PAMM-NDDG
Authors: Joerger M. 
Published: March 2020

2529 Background: Paclitaxel (P) and carboplatin (C) are considered standard first-line treatment in advanced ovarian cancer following cytoreductive surgery. Threshold-models have been used to predict P PKPD, whereas the time above P plasma concentration of 0.05- 0.2 μmol/L (P tC>0.05–0.2) predicts neutropenia. The objectives of this study was to build a population PKPD-model of PC in ovarian cancer patients. Methods: 139 ovarian cancer patients received P 175 mg/m2 over three hours followed by C AUC 5 over 30 min. Plasma concentration-time data of PC were measured, and data processed using nonlinear mixed-effect modelling. Semiphysiological models with linear or sigmoidal maximum response, and threshold models were adapted to the data. Results: 105 patients had complete PK and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Mean P tC>0.05 was 61.4 hrs. P tC>0.05 was significantly higher in patients with a complete (91.8 hrs) or partial response (76.3 hrs) compared to patients with progressive disease (31.5 hrs) (p=0.02 and 0.05, respectively). Patients with P tC>0.05 > 61.4 hrs had a longer time to disease- progression compared to patients with P tC>0.05 < 61.4 hours (89.0 vs 61.9 weeks, p=0.05). P tC>0.05 was a good predictor for severe neutropenia (p=0.01), while carboplatin exposure (Cmax and AUC) was the best predictor for thrombocytopenia (p<10-4). Conclusions: In this group of patients, P tC>0.05 is a good predictive marker for severe neutropenia and clinical outcome, while C exposure is a good predictive marker for thrombocytopenia. (Biomed grant PL96–2333, JHM Schellens coordinator) No significant financial relationships to disclose.
Prospective analysis of mRNA expression signatures as predictive tests in primary breast cancer
Authors: Hannemann J. , Halfwerk H. , Velds A. , Loo C. , Rutgers E. J. , Rodenhuis S. , van de Vijver M. J. 
Published: March 2020

2531 Background: Preoperative chemotherapy is increasingly employed to treat primary breast cancer, allowing an ‘in vivo chemosensitivity test’. Markers which predict a pathological complete response are urgently needed to refine this strategy. This study was conducted to evaluate the use of gene expression profiling to predict response to neoadjuvant anthracycline- or taxane-based chemotherapy. Methods: Patients with operable or locally advanced HER2-negative breast cancer received preoperative chemotherapy: either dose- dense doxorubicin and cyclophosphamide (ddAC) or capecitabine and docetaxel (CD). Core needle biopsies were taken before treatment and gene expression profiling was performed using 35k oligo microarrays. Results: Gene expression profiles were obtained from pretreatment biopsies of 63 tumors. 27% of the patients achieved a (near) pathologic complete remission (pCR), 40% of the patients had a partial remission and 33% of the patients did not respond to chemotherapy. Based on the gene expression profiles, tumors were assigned to the previously identified “molecular subtypes” luminal, basal-like or ERBB2-like (Sorlie et al., PNAS 98: 10869, 2001). 13 out of 25 patients with a basal-like tumor (52%) achieved a complete remission, whereas for the luminal tumors a pCR was only obtained in 2 out of 29 patients. Using four published gene expression classifiers of response to chemotherapy, a reasonable separation between responders and non-responders could be observed for two of these. We also performed exploratory supervised classification analyses on our dataset to identify a novel classifier. This resulted in a classifier for response to therapy irrespective of the chemotherapy regimen used and a second classifier specifically associated with response to ddAC chemotherapy. We will perform validation of these classifiers in samples from patients that are currently being enrolled in the study. Conclusions: Basal-like tumors have a better response to neoadjuvant chemotherapy as compared to other tumor types. The identification of robust gene expression signatures for better response prediction may require larger patient groups and should probably be established separately for each of the molecular subtypes of breast cancer. No significant financial relationships to disclose.
Pharmacogenomic (PG) analysis for prediction of individual response to paclitaxel in 5-FU-refractory metastatic gastric cancer: Prediction formula of tumor response using novel marker genes and genotypes associated with the toxicity
Authors: Ikeda R. , Yoshida K. , Takagane A. , Tsuburaya A. , Kobayashi O. , Sunouchi H. , Matsukawa M. , Tanimoto K. , Hiyama K. , Nishiyama M. 
Published: March 2020

2538 Background: Taxanes offer hope for improving outcomes of metastatic gastric cancer patients including 5-FU failure cases, but the response remarkably varies among patients. We conducted this prospective PG study for paclitaxel monotherapy to develop a prediction formula of efficacy and to identify potent genetic markers of toxicity. Methods: Paclitaxel was intravenously given on Days 1, 8, and 15, every 4 weeks in 5-FU failure metastatic gastric cancer patients with typical eligibility criteria. Tumor and blood samples were collected before the initial paclitaxel administration for PG. PK analysis was done on day 1 of cycle 1. Tumor response and toxicity were evaluated by RECIST and CTCAE, respectively. Results: Forty-nine pts were enrolled, and up to date, 48 and 44 pts have been determined for worst toxicity and best tumor response, respectively. Observed response rate was 27.3% (12/44), and common grade 3/4 toxicities were neutropenia (31.3%) and leucopenia (20.8%). PG analysis demonstrated that CYP2C8*1C (w/v=27, v/v=5) and CYP2C8 -411T>C (w/v=24, v/v=10) were weakly associated with grade 3/4 leucopenia (p=0.087 and 0.092), and CYP2C8 IVS7+49T> A (w/v=9, v/v=6) might correlate with grade 3/4 anemia (p=0.039), although none of them correlated with any PK parameter. We identified 4 novel potent marker genes (SEPT5, MARN2, PER3, and PISA3) for paclitaxel efficacy in vitro through microarray expression analysis, and then successfully developed the best linear models, which converted the quantified expression data into objective clinical response, in terms of best tumor response (r=0.985, AICS=-5.269) and overall survival (r=0.980, AICS=6.953), using 15 and 13 data sets of gene expression and clinical response, respectively. At present, utility-confirmation analyses using other clinical samples appeared to show that the formulae could accurately predict tumor response. Conclusions: Polygenetic strategies using several known polymorphisms for toxicity and a prediction formula using 4 novel genes for efficacy would be of predictive value for individual response to paclitaxel. No significant financial relationships to disclose.
Prospective phenotypic screening for DPD deficiency in patients upon fluoropyrimidines administration: Impact on the reduction of drug-induced toxicities
Authors: Mercier C. , Ciccolini J. , Dupuis C. , Secq V. , Padovani L. , Pignon T. , Dahan L. , Duffaud F. , Seitz J. , Lacarelle B. , Favre R. 
Published: March 2020

2541 Background: DPD deficiency is a pharmacogenetic syndrome associated with severe toxicities upon 5-FU/capecitabine intake. To detect patients at risk upon fluoropyrimidines administration we developed a simple, rapid and inexpensive phenotypic method for DPD status evaluation. Here, clinical relevance of DPD deficiency a priori determination was studied. Methods: This method was used prospectively in 50 head and neck cancers patients (60±7 years, 37M/13F). Screening for DPD deficiency was performed prior to the beginning of the platinum + 5-FU (± radiation therapy) administration. DPD status was evaluated by HPLC monitoring U/UH2 ratio levels in plasma as a surrogate marker. Only 5-FU doses were adjusted according to the level of detected impairment (mild deficiency: -20%, severe: - 50%, total: no 5-FU). Drug-induced toxicities and subsequent impact on treatment schedule were carefully monitored next for comparison with a retrospective subset of 50 patients (mean age: 58±9 years, 40M/10F), treated with standard dosage of the same chemotherapy or radio- chemotherapy schedule. Results: DPD determination permitted the detection of 11 patients with DPD impairment out of 50 (22%). These 11 patients had their 5-FU doses customized and, consequently, neither severe toxicity nor delays in the administration radiation therapy or chemotherapy were reported in this group. Conversely, 7 out of 50 (14%) patients administered with standard dosage of 5-FU displayed severe toxicities (>grade-3, WHO grading), with subsequent postponement of the following courses. One patient (2%) did not recover from his toxicities. Of these 8 patients, retrospective determination of DPD status suggested impaired function in 7 of them (87%), including the toxic- death one. Conclusions: Although non randomized, this study suggests that prospective use of DPD status has an immediate clinical benefit by, reducing the drug-induced toxicities incidence in patients treated with 5-FU, and allowing an optimal administration of several courses in a row. Our preliminary results advocate systematic DPD status screening in patients eligible for treatment with fluoropyrimidine drugs. Survival and response study still on going. No significant financial relationships to disclose.