bluuebunny/crossref_metadata_2025_split huggingface dataset:
What is the yield of regional lymph node dissection following sentinel lymph node involvement in patients with breast cancer?
Authors: Ortega M. , Ruiz-Echarri M. , Prats E. , Lastra R. , Aguirre E. , Lambea J. , Milastre E. , Mayordomo J. , Razola P. , Tres A. , Banzo J. 
Published: March 2020

10782 Background: Sentinel lymph node is a minimally invasive and accurate staging procedure for patients with invasive breast cancer. Histological SLN involvement with cancer cells requires regional lymph node dissection. Aim: To verify if subgroups of patients with sentinel lymph node involvement in which the risk of histological involvement of additional regional lymph nodes is minimal can be identified. Methods: Ninety six consecutive patients with invasive breast cancer and tumour size less than two centimeters by mammography, had lymphoscintigraphy with colloidal 99Tc and radioisotope-guided sentinel lymph node biopsy in the University Hospital of Zaragoza from 1999 to 2005.Pathological assessment included serial sections of the sentinel lymph node with inmunohistochemistry for cytokeratins in selected cases.39 patients had histological involvement and are presented in this analysis. Results: All 39 patients were females. Median tumour size was 20 mm (range 5–52) Median number of resected sentinel lymph node was 2 (range 1–5) Median number of involved sentinel lymph node was 1 (range 1–4) Regional lymph node dissection was performed in all patients (Axillary dissection in 31; internal mammary dissection in 1, both in 7). Median number of nodes was 13 (range 2–34) At least 1 additional involved lymph node was found in 19 patients (48%) We have correlated patient age, menopausal status, pathological tumour size, histological grade, estrogen receptors, progesterone receptors and Her2 with the risk of histological lymph node involvement in regional lymph node dissection. Conclusions: Tumour size was significantly associated to such risk: No significant financial relationships to disclose.
Retrospective analysis of temozolomide (TMZ) plus BCNU wafers and TMZ alone in the primary treatment of glioblastoma multiforme
Authors: Bota D. A. , Taylor S. A. 
Published: March 2020

11519 Background: GBM is the most common and aggressive primary brain tumor with a median survival around 1 year. Two agents have shown promise and received recent approval by the Food and Drug Administration. A combination of these agents is frequently used with little data about the efficacy or toxicity. Methods: A retrospective review of patients (pts) treated between 1/2000 and 6/2004 was done to look at pts treated in such a manner. This review was approved by the IRB of the University of Kansas. Twenty-three pts were identified who had received TMZ or TMZ after surgery plus BCNU wafers (TMZ/B) at initial histologic diagnosis of their GBM. Median age was 53 years (26–71). Median KPS was 80 (50–100). 65% had subtotal resection and 35% gross total resection. The decision to place the wafers was at the discretion of the surgeon at the time of surgery. 10 pts received the wafers. All pts received standard radiation therapy. All pts received concurrent TMZ at 75mg/m2 during radiation therapy (XRT) and 150–200mg/m2 days 1–5 every 28 days depending upon myelosuppression seen during XRT. Results: Ten patients received TMZ/B and 13 received the TMZ alone. There were no differences between the groups in age or performance status (p>0.3). At this time, 2/10 in the TMZ/B group and 1/13 in the TMZ are alive. Overall survival was the same in both groups. Median overall survival was 534 days for TMZ/B (95% confidence interval 369–700) and 596 days TMZ (95% CI 373–819). Toxicity was the same. Conclusions: This is a retrospective non randomized exploratory study which suggests there is no difference in survival or toxicity between the two treatments. Randomized studies will be needed to confirm this in larger pt numbers. At the present time, pts are frequently ineligible for experimental trials due to the frequent use of the BCNU wafers in the neurosurgical community. The results of TMZ may preclude the need for the wafers. [Table: see text]
Concomitant accelerated hyper-fractionated radiotherapy and temozolomide in the treatment of high grade astrocytoma: Updated results
Authors: Hashem T. , Metwaly H. , Abouelfetouh M. 
Published: March 2020

11523 Background: The safety and efficacy of accelerated hyper-fractionated radiotherapy (RT) combined with temozolomide (TMZ) in patients with high grade astrocytoma have already been reported.Updated results on survival will be presented. Methods: Twenty-four patients with newly diagnosed and histologically proven high grade astrocytoma were enrolled onto this study. Treatment protocol included RT delivered in fractions of 150 cGy 3 times daily with at least 4-hour intervals between fractions to a total dose 4050 cGy. The target volume was the tumor plus the edema with a 2-cm margin. A boost of 1800 cGy was given to the tumor plus a 2-cm margin to a total dose of 5850 cGy delivered in 39 sessions over 2.5 weeks. TMZ dose was (150 g/m2/day 7 d/wk) given 2 hours prior to RT, throughout the course of RT. Results: Of the 24 patients included 5 (21%) developed G2 & G3 neutropenia, and 4 patients (17%) developed G2 & G3 thrombocytopenia. Non-hematologic toxicities were: G2 & G3 vomiting in 8 (33%) patients, G2 & G3 fatigue in 13 (54%) patients, G2 skin rash in 4 (17%), and G2 acute radiation reaction in 2 (8%) patients. The12 months and 18 months survival rates were 67% and 51.5% respectively. Patients aged <45 years and those who underwent debulking surgery had better survival rates (69% & 70%) in comparison to those aged ≥45 years and those who underwent biopsy only (27% & 36%). Conclusions: The results achieved particularly with respect to survival are promising and should be confirmed. No significant financial relationships to disclose.
Pharmacokinetic and pharmacodynamic correlations of flavopiridol in the treatment of chronic lymphocytic leukemia
Authors: Phelps M. A. , Wu D. , Byrd J. C. , Lin T. S. , Blum K. A. , Schaaf L. , Johnson A. J. , Colevas A. D. , Grever M. R. , Dalton J. T. 
Published: March 2020

12000 Background: Previous clinical trials with 72-hr and 24-hr infusions of flavopiridol were unsuccessful in producing responses in significant numbers of patients (pts). We utilized pharmacokinetic (PK) modeling to develop a 4.5 hr IV infusion strategy with a 30 mg/m2 loading dose delivered in the first 0.5 hr. and an equal or increased dose delivered over the following 4 hrs to achieve target concentrations of 1.5 to 2.0 μM. This strategy was employed in a phase I study for single agent treatment of CLL. Methods: Plasma samples obtained from pts up to 48 hrs after the start of infusion were extracted and analyzed via LC/MS/MS for parent drug concentration. Non-compartmental analysis was employed in WinNonlin® to analyze flavopiridol plasma concentration vs. time data in 42 patients receiving one or two dosing levels. Patient biographical and response or pharmacodynamic (PD) data, including age, gender, previous treatment, hepatic and renal function, phosphate, albumin and lactate dehydrogenase (LDH) levels, lymph node status, and splenomegaly were collected. In addition, genomic analysis for single nucleotide polymorphisms (SNPs) in flavopiridol metabolizing and transporting enzymes along with correlation of PK, PD and genomic data is underway. Results: Complete PK data has been generated on 41 of the 42 patients treated in cohorts 1 through 3 and is summarized below. 14 of the 42 patients received an escalated dose in cycle 2. As anticipated, the escalated dose achieved concentrations within the targeted window 1.5 to 2.0 μM. This dosing strategy has resulted in response in 45% (19 of 42) of pts treated. Conclusions: PK modeling enabled accurate dose determination for achieving targeted clinical flavopiridol plasma concentrations. Ongoing analysis for correlation of modeled PK parameters with PD and pharmacogenomic data will further enhance our understanding of flavopiridol action in CLL and other malignancies. [Table: see text] No significant financial relationships to disclose.
A pharmacokinetic study of gemcitabine at fixed dose rate infusion in patients with impaired hepatic function
Authors: Felici A. , Di Segni S. , Colantonio S. , Milella M. , Ciccarese M. , Cecere F. , Nuvoli B. , Ferretti G. , Citro G. , Cognetti F. 
Published: March 2020

12009 Background: The aim of this study was to evaluate if hepatic dysfunction leads to increased toxicity of gemcitabine (gem) at fixed dose rate, and to characterize the pharmacokinetic (PK) of gem and its major metabolite (2`,2`-difluorodeoxyuridine- 2dFdU) in patients (pts) with normal and altered liver function. Methods: Eight pts with metastatic pancreatic or biliary tract cancer were treated with the followed schedule: gem 1000 mg/m2 at 10/mg/m2/min fixed rate days 1,8, and 15 every 28 days for a maximum of six cycles. Three pts had normal serum bilirubin level and AST level less than two times the upper limit of normal (ULN) (Cohort I); four pts had bilirubin level from 1.6 to 7.0 mg/dL and normal AST level, one pt had serum bilirubin level less than 1.6 mg/dL and AST level greater than two times the ULN (Cohort II). The PK parameters measured were: plasmatic peak concentration (Cmax), area under the plasma concentration-time curve (AUCexp), total plasma clearance (Cl p) and half life (t1/2). Results: Patient characteristics were: median age 62 yrs (range 28–75), male/female 4/4, median cycles cohort I: 6 cycles (3–6), median cycles cohort II: 3 cycles (1–5), median follow-up: 30 weeks (range 3–79) and median weeks of treatment: 14 (1–25). The rate of dose reduction was the same in the two cohorts, as the rate of omitted administrations. Patients with liver dysfunction tolerated gemcitabine without increased toxicity and neither AST nor bilirubin elevation was observed after drug administration. PK parameters were calculated at the first cycle and the results are presented below (see table ). Conclusions: The pharmacokinetics of gemcitabine at fixed dose rate in patients with impaired liver function seems similar to control; no difference between the two cohorts was observed in terms of toxicity and dose reduction. [Table: see text] No significant financial relationships to disclose.
A phase I study of triapine in combination with irinotecan in refractory tumors
Authors: Schelman W. R. , Holen K. , Mulkerin D. , Kolesar J. , Thomas J. , Kruse M. , Oliver K. , Marnocha R. , Eickhoff J. , Wilding G. 
Published: March 2020

12011 Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m2) and Triapine (85 mg/m2/day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m2 and 60 mg/m2/day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m2) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1. [Table: see text]
Pharmacokinetic (PK) and tolerance profiles of oral tegafur/uracil (UFT) given as three versus two daily intakes
Authors: Etienne-Grimaldi M. C. , François E. , Renée N. , Cardot J. M. , Douillard J. Y. , Gamelin E. , Chateau Y. , Clouet J. , Dupuis S. , Milano G. 
Published: March 2020

12013 Background: This phase II randomized bioequivalence cross-over study compared the tolerance and PK profiles of oral UFT (tegafur-uracil) given as 3 daily intakes (tid, usual schedule) to that obtained with 2 daily intakes (bid). Methods: Twenty-one metastatic colorectal cancer patients were enrolled (16 men, 5 women ; mean age 64, extremes 42–79 ; ECOG PS ≤ 1). Tegafur-uracil (300 mg/m2/d) and leucovorin (90 mg/d) were given for 2 consecutive four-week cycles separated by one rest week. Patients were randomized for receiving 1st cycle either tid (arm A, 12 patients) or bid (arm B, 9 patients). For each schedule, PK was evaluated at steady state, over 24 h. Plasma concentrations of tegafur, uracil and fluorouracil (FU) were analyzed by HPLC. Results: Analysis of tolerance (digestive toxicity mainly, OMS grade) showed a tendency (p = 0.08) for a greater toxicity with the bid schedule (29% grade 2, 14% grade 3) relative to tid (24% grade 2 only). Although daily doses were similar, FU and uracil AUC0–24h were respectively 1.8 and 2.0-fold higher for bid as compared to tid (95% CI were 1.5–2.1 and 1.6–2.6, respectively, p < 0.0001). For tegafur, the 1.2-fold difference was of borderline significance (p = 0.057). The greater the FU AUC0–24h, the higher the toxicity intensity (p = 0.044). Analysis of systemic exposure with respect to daily time revealed that FU (p < 0.01) and uracil (p < 0.03) AUC corresponding to the morning intake were significantly higher than those corresponding to the afternoon or evening intakes, with AUC ratio as high as 1.6 for FU and 2.9 for uracil. Such a circadian influence was not observed for tegafur. Conclusions: To reach bioequivalence, bid tegafur-uracil administration will require lower doses than those given tid. The circadian variability observed for FU and uracil PK concords with that previously reported for dihydropyrimidine deshydrogenase activity. No significant financial relationships to disclose.
Safety, efficacy and pharmacokinetics of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, as monotherapy in patients with locally advanced or metastatic pancreatic cancer (PC)
Authors: Strumberg D. , Scheulen M. E. , Hilger R. A. , Krauss J. , Marschner N. , Lordick F. , Bach F. , Reuter D. , Edler L. , Mross K. 
Published: March 2020

12504 Background: Nimotuzumab (OSAG101, Theraloc) is a humanized monoclonal antibody (mAb) that binds to the EGFR. In preclinical studies the antibody has shown potent antitumor activity. Based on phase I data, the recommended dose has been established at 200 mg weekly. A previous phase II study in children with high grade brain tumors showed activity of nimotuzumab as a monotherapeutic agent, even in prognostically very unfavorable pontine glioma. No drug related side effects were reported. The present ongoing phase II study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic PC. Methods: Pts who failed standard chemotherapy with gemcitabine or another first line regimen for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given iv as induction therapy at 200 mg once weekly for 6 weeks. Follow up by CT was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), time to disease progression, and safety. Blood samples were collected prior to first dose, at end of infusion, and 3h, 6h, 48h, as well as every time before subsequent nimotuzumab doses were administered. Nimotuzumab concentrations in serum were measured by cellular ELISA. Results: Enrollment is complete, with treatment ongoing. In total, 55 pts were treated (28 women/ 27 men; ECOG status of 1 [n= 41] or 0 [n=14], median age 63.6 yrs [range 46–83 yrs]). Pts evaluable for response: n= 36; CR:0; PR:0; SD:6 pts (median TTP 19.2 weeks; 14.1–26.1). The only reported treatment-related adverse event was rash grade 1 in 1 pt. After 200 mg single dose, the mean value of Cmax was calculated to 141 ± 33 μg/ml. The t1/2 was calculated to 45 h, volume of distribution to 1.46 ± 0.3 l, respectively. The total clearance was determined to 23 ± 6 ml/h. The trough values after 168 h were 6.2 ± 6.3 μg/ml. Conclusions: These data confirm that nimotuzumab is safe and well tolerated. To improve efficacy, a combination trial with gemcitabine is planned. [Table: see text]
Trastuzumab mimotope vaccination of HER-2/neu transgenic mice results in prolonged tumor-free survival and reduced tumor load
Authors: Riemer A. B. , Brämswig K. H. , Pehamberger H. , Scheiner O. , Zielinski C. C. , Jensen-Jarolim E. 
Published: March 2020

12510 Background: Passive immunotherapy with the humanized monoclonal antibody trastuzumab (Herceptin) to date is the most effective treatment for patients with HER-2/neu overexpressing breast cancer. In previous studies we could show that active immunization with peptide mimotopes, i.e. structural mimics of the epitope recognized by trastuzumab, leads to formation of antibodies again recognizing HER-2/neu in mice. Functional in vitro analyses of the induced antibodies demonstrated “trastuzumab-like” properties, such as receptor internalization, inhibition of signaling, and antibody-mediated cytotoxicity against HER-2/neu overexpressing breast cancer cells. The aim of the present study was to test the effects of trastuzumab mimotope vaccination in vivo, namely in a HER-2/neu transgenic mouse model. Methods: We used BALB-neuT mice, which carry the activated neu oncogene on the BALB/c background. These mice constitute the most aggressive animal model for HER-2/neu driven carcinogenesis, as all females uniformly develop mammary carcinomas at the age of 12 weeks. One group of mice was immunized with the previously described trastuzumab mimotope - KLH conjugate, a control group with the carrier protein KLH alone, and a further control group was left naïve. Mice were palpated weekly to monitor tumor development and size, and blood samples were taken at regular intervals to follow up the induced immune responses. Results: Trastuzumab mimotope immunizations lead to delayed tumor development and thus to an increase in tumor-free survival. When tumors occurred, they were smaller and grew more slowly than in the control mice. In contrast, control KLH immunizations did not affect tumor growth kinetics as compared to the naïve mice. Serum analysis demonstrated that all immunized animals had mounted an anti-KLH immune response, so we accredit the observed tumor-inhibitory effects in the mimotope group to the biologic properties of induced anti-HER-2/neu antibodies. Conclusion: These results indicate that epitope-specific vaccination with mimotopes elicits trastuzumab-like antibodies that are effective in vivo against HER-2/neu overexpressing tumor cells also in HER-2/neu expressing organisms. [Table: see text]
Establishment of a predictive classifier of node-positive breast cancer patients treated by FEC100 chemotherapy using gene expression profiling
Authors: Campone M. , Charbonnel C. , Magrangeas F. , Minvielle S. , Genève J. , Martin A. , Deporte R. , Bataille R. , Campion L. , Jézéquel P. 
Published: March 2020

13004 Background: In breast cancer treatment, biomarkers providing information about chemotherapy sensitivity are needed. FEC100 combination, frequently prescribed in Europe, is still applied empirically to patients. Our study’s goal was to establish a classifier of sensitivity to this regimen using gene expression data and classical clinicopathologic parameters. Methods: The study retrospectively included 151 patients belonging to the FEC100 arms of two multicentric phase III clinical trials: PACS01 (n = 128) and PEGASE01 (n = 23) (FNCLCC). Patients had unilateral breast cancer, showed no evidence of distant metastasis, were node-positive, aged less than 65-year-old. Median follow-up was 5 years. The number of relapses were respectively 23 and 10. We used cDNA nylon microarrays containing 7,000 genes to analyze gene expression profiles of tumor. Patients were split into a training set and a test set. A 3-step analysis based on Cox regression was applied: 1) elimination of non discriminant genes, 2) robust (resampling) univariate selection of discriminant genes and 3) development of multivariate models combining the discriminant genes, the Nottingham Prognostic Index (NPI) (developed in 2 binary variables) and the hormonal receptors. As a final step, after dichotomization of the retained genes, a risk score was built and applied first on the test set, and then on the whole cohort. Kaplan-Meier curves and logrank tests were performed to assess the new risk score. Results: The new risk score (one gene [G6224] and NPI) permitted to separate patients from the test set in 3 significantly different groups; it was also an improvement on NPI (test set: NPI, p = 0.0005; risk score p = 0.0001 - whole cohort: NPI, p = 2.10−5; risk score, p = 1.10−10). Conclusions: We identified G6224 whose expression combined with NPI showed a good capacity for classifying breast cancer patients who received FEC100 chemotherapy. Our results strengthen the interest of G6224 since it was previously described in various solid tumors as a prognostic biomarker with a tumor-suppressor activity. No significant financial relationships to disclose.