bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing changes in oncology trial records over time using automated semantic web-mining.
Authors: Cocker David J , Lievens Johanna Caroline , Geentjens Kristof , Van Remortel Piet , De Cre Mireille , Naudts Bart 
Published: March 2020

e13073 Background: Incorrect assumptions and poor feasibility are often cited as the major cause of study delay and outcome resolution. Trial placement and recruitment can be optimized by monitoring and regular assessment of trial registries. However, just a snapshot analysis does not take into account retrospective editing of records. This paper evaluates the effectiveness of a robotic, semantic analysis of registered oncology trials to assess individual changes in trial records over time. Methods: Evaluating individual trial records from 2008 to 2012 with state-of-the art natural language processing and semantic linking of data fields within clinical trial registries and literature databases to add increased resolution to erroneous or inadequate registry fields. Results: Substantial modifications are made to registration records over the life cycle of a clinical trial. Quantifiable fields as recruitment, site numbers and end dates all deviate significantly from the study roll-out. Analysis of oncology trials recruiting over 200 patients between 2008 and 2012 shows two thirds of trials deviate from the initial record. Most frequently study end date is delayed (about 50% of all trials) or enrollment targets are amended (at least 25%). Over all oncology indications, enrollment increases are twice more frequent as decreases. However, there are notable exceptions such as lung cancer, where enrollment is frequently decreased. A differential analysis of countries and sites in commercial oncology phase III trials over the period revealed a marked shift of research to sites in France, Spain, the UK and China. However, when sites were added to ongoing trials this general trend was not entirely followed as Poland, Japan, Belgium, Argentina and Switzerland were frequently chosen as additional countries above the normal distribution, suggesting these are preferred countries for trial “rescue”. Conclusions: This paper demonstrates the effectiveness of automated semantic web-mining to identify incorrect clinical trial assumptions and subsequent remediation.
Pharmacokinetics of samarium-153-EDTMP (153Sm) prior to and following zoledronic acid (ZA) in prostate cancer (PC) patients with bone metastases (BM).
Authors: Bauer Kenneth S , Tavakkoli Fatemeh , Bazzi Mouhamad , Molchanova-Cook Olga , Chen Wengen , Hussain Arif 
Published: March 2020

e13075 Background: 153Sm and ZA are often employed to manage complications related to BM. Although 153Sm and ZA bind to overlapping sites within the bone, there is a paucity of information on potential pharmacokinetic (PK) and pharmacodynamic interactions between the two. In this study we report the pharmacokinetics of 153Sm when administered in combination with ZA. Methods: The study was carried out as two independent phase I trials assessing the effects of escalating dose 153Sm (0.5, 0.75, 1.0, and 1.25 µCi/kg) administered prior to or immediately after intravenous ZA 4 mg. Study 1 recruited 12 ZA-naive PC pts, while Study 2 enrolled 10 PC pts who had received at least 3 months of ZA prior to trial entry. On study, pts received 2 doses of 153Sm given 3 months apart and 6 doses of ZA given monthly. In Cycle 1 of both trials, 153Sm was administered on day1 and ZA on day 2. In Cycle 2, ZA was administered 1 hour prior to 153Sm on the same day. Blood samples for radioactive analysis were obtained at 5 min, and 0.5, 1, 2, 4, and 24 h post 153Sm dosing. PK analysis was performed by both model independent and PK modeling methods using WinNonlin. Results: The PK parameters of 153 Sm were highly variable between patients. The coefficient of variation of the Cmax/Dose was greater than 50% in all subgroups. A dose related increase in exposure to 153Sm was observed with high variability as well. The estimated terminal half-life (t1/2) was similar across all dose levels within each study. The t1/2 for Cycle 1 was 4.73 ± 1.27 for Study 1 and 6.73 ± 3.92 h for Study 2. The dose normalized Cmax (Cmax/Dose) was 0.068 ± 0.036 and 0.061 ± 0.043 µCi/mL for Study 1 and Study 2, respectively. Pharmacokinetic parameters for Cycle 2 were similar to those calculated for Cycle 1 within each study. Conclusions: The Cmax and t1/2 reported here are similar to previous studies of 153Sm with doses ranging from 1.0 to 3.0 µCi/kg in ZA-untreated pts. Although not statistically significant, the subtle differences in the pharmacokinetics of 153Sm merit further investigation.
Retrospective safety assessment of bendamustine in patients with renal impairment.
Authors: Nordstrom Beth L , Knopf Kevin B. , Teltsch Dana , Engle Robert , Beygi Hooman , Sterchele James A. 
Published: March 2020

e13081 Background: Patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are at risk for renal impairment as the median age at diagnosis is >65 years. Bendamustine is a bifunctional alkylating agent with efficacy via several pathways and a manageable toxicity profile in NHL and CLL. There has been no published research on its safety in renally impaired NHL and CLL patients. Methods: In this retrospective study of 2 electronic medical record databases from US outpatient oncology practices, patients with NHL and CLL who had received ≥1 dose of bendamustine alone or with rituximab were identified and divided into investigator-defined subgroups: nonrenally impaired (creatinine clearance [CrCL] ≥40 or ≥60 mL/min) and renally impaired (CrCL <40 mL/min). Patients who received drugs with >5% risk of causing renal damage (eg, cisplatin, cyclosporine) were excluded. The study’s primary aim was to evaluate laboratory toxicities in the NHL and CLL groups. Results: Of 379 CLL patients, 42 had CrCL <40, 144 had CrCL ≥40-60, and 193 CrCL ≥60 mL/min; of 561 NHL patients, 62 had CrCL <40, 153 had CrCL ≥40-60, and 346 had CrCL ≥60 mL/min. Baseline characteristics were similar, except for more advanced age, shorter mean disease duration, and a slightly lower initial bendamustine dose in renally impaired patients. Mean total bendamustine exposure was 12 weeks for renally impaired vs 15 weeks for nonrenally impaired CLL patients, and ~16 weeks for both NHL groups. No statistically significant differences in laboratory toxicities were seen among the CLL groups, but renally impaired NHL patients had an increased risk for grade 3/4 thrombocytopenia (Cox hazard ratio [HR]: 2.57; 95% CI: 1.13, 5.85) vs those with CrCL ≥60 mL/min. In combined CLL and NHL groups, only grade 3/4 BUN increase was significantly higher for renally impaired patients vs those with CrCL ≥40 mL/min (HR: 2.36; 95% CI: 1.15, 4.86) or ≥60 mL/min (HR: 4.46; 95% CI: 1.79, 11.14). Conclusions: Though sample size and time of exposure limit the power of this study, the results support the safety of bendamustine in renally impaired NHL and CLL patients. Monitoring blood counts and renal function is probably prudent. Support: Teva Pharmaceutical Industries Ltd., Frazer, PA.
Adjudication rate as an indicator of read quality in clinical trials using progression-related endpoints assessed by imaging.
Authors: Raunig David , Goldmacher Gregory V. , Conklin James J 
Published: March 2020

e13082 Background: Progression-free survival determined by serial tumor burden assessments is a common oncology trial endpoint. Images are often assessed by two reviewers, with disagreement on progression date resolved by an adjudicator. Adjudication rate (AR) is a widely used metric of read quality, with AR > 40% thought to indicate poor data. We examined factors that determine AR and the potential impact of overreliance upon it as a measure of data quality, using a statistical model of independent blinded review. Methods: Reads were simulated as a binary series of progression assessments with an underlying Gaussian decision process. Tumor burden increased in a linear fashion, with true progression at 21 weeks. Tumor measurement variability was constant, while visit frequency varied from 2 to 16 weeks. 1,000 runs of 100 patients were performed. For each run, AR and the variance and bias of time to progression were computed. Results: See table. Decreasing the visit interval relative to the progression rate increased AR but increased the accuracy and precision of the time to progression estimate. AR was less sensitive than other statistical tests of asymmetry for detection of reader bias. Conclusions: AR is affected by biological, image, and reader variability, progression rate, and visit interval. Frequent visits relative to progression increase AR, but lower bias and variance in time to progression estimates. High AR may occur even with strong readers, while very low AR may indicate loss of reader independence and data integrity. High ARs should be investigated to determine the effect on the progression endpoint. AR is not itself an endpoint, and is not a reliable indicator of read quality. Blindly attempting to minimize AR without understanding the cause may waste resources, divert attention from critical factors such as bias, and decrease a trial’s ability to detect differences between treatment arms. Other reader metrics, such as measures of asymmetrical disagreement, are recommended as alternative measures of read quality for oncology trials. [Table: see text]
Phase I clinical trial of temsirolimus (T) and vinorelbine (V) in advanced solid tumors.
Authors: Lee Grace Lauren , Ji Lingyun , Gitlitz Barbara Jennifer , Dorff Tanya B. , Iqbal Syma , El-Khoueiry Anthony B. , Roman Lynda , Edwards Susan , Menendez Xiomara , Cheng Phillip , Quinn David I. , Cole Sarah , Garcia Agustin 
Published: March 2020

e13084 Background: T, an mTOR inhibitor that regulates a signaling cascade which controls growth factor-induced cell proliferation was combined with V, an anti-mitotic drug in a phase I study. Synergistic effects have been reported with this combination. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to evaluate safety and tolerability. Methods: Eligible pts had advanced solid tumors, performance status 0-2, adequate organ function, and signed consent. Pts were treated with escalating doses of T and V. A 3+3 design was used. 4 dose levels were planned: Level I (T 20mg + V 20 mg/m2), Level II (T 25 + V 20), Level III (T 25 + V 25) and Level IV (T 25 + V 30). T was administered IV on days 1, 8, 15, and 22 while V was administered IV on days 1 and 15. Cycles were repeated every 28 days. MTD was defined as the highest dose tested in which fewer than 33% of pts experienced dose-limiting toxicity (DLT). DLTs included grade 3-4 non-hematologic toxicity (excluding inadequately treated nausea, vomiting, diarrhea, alopecia, myalgia, fatigue), hyperglycemia, hypertriglyceridemia, and grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Results: Nineteen pts were enrolled (10 female, 9 male, median age 62 (35-79)), tumor types: lung (5), bladder (2), endometrial (7), prostate (2), neuroendocrine (1), vagina (2) and received a total of 50 cycles. All pts had received prior chemotherapy. Six pts were inevaluable and replaced (1 disease progression, 4 missed doses, 1 withdrew consent). Four pts were enrolled at dose level I, 9 to dose level II and 6 to dose level III. There was 1 DLT at level II (1 pt with grade 3 anorexia and dehydration) and 2 at level III (1 pt grade 3 hypokalemia; 1 pt grade 4 neutropenia). Two pts died on dose level III (1 not study related, disease progression; 1 study related, grade 4 neutropenia). Grade 3/4 toxicities were anemia (2), edema (1), hyperglycemia (1), anorexia (1), dehydration (1), hypertriglyceridemia (1), hypokalemia (2), and neutropenia (1). Dose level II was the MTD. One pt had a partial response (prostate), 6 stable disease. Conclusions: The recommended phase II dose of T + V is T 25mg and V 20mg/m2. At this dose, treatment was well tolerated.
Treatment of liver cancer by nanomedicine.
Authors: Wagner Wolfgang , Krukemeyer Manfred Georg 
Published: March 2020

e13091 Background: Oncological surgery as a therapy branch of general surgery is registering a rapid development in the form of neoadjuvant treatment. Therapies of liver tumors display diverse treatment alternatives. Methods: The administration of cytostatics coupled with and without iron oxides (Fe3O4) has been presented in an experimental series with 36 animals with prior implantation of an R1H rhabdomyosarcoma in the liver, since iron undergoes selective phagocytosis in the liver. In Group I, mitoxantrone is injected into the lateral tail vein of the animals (n = 12) in a dosage of 1 mg/kg of body weight. Group III (n = 12 animals) received mitoxantrone coupled with iron oxide (Fe3O4), and Group II (n = 12 animals) received NaCl, in the same dosage for all groups. In the sonography and in the measurement of the volume, a significantly smaller tumor growth is found in Group II compared with Group I and III. The volume was measured manually postmortally in mm3(length x breadth x height). Results: The tumor volume showed the lowest growth in Group II, which was treated with mitoxantrone-coupled iron oxides. 3 animals from Group II died. The autopsy revealed no indication of the cause of death. There were neither thromboses nor allergic reactions in any of the animals. It can be clearly seen that Group I has a smaller mean volume and less scatter than Group II. The mean of Group I is also below that of Group II. Conclusions: It has been possible to demonstrate in animal studies that mitoxantrone-coupled iron oxide (Fe3O4) reduces the tumor volume in the liver to a greater extent that administration solely of mitoxantrone. The studies should be verified in a clinical study on humans.
Pattern of chemotherapy dosing in obese patients in a community hospital.
Authors: Thwin Malar , Soe Aye Min , Tun Nay Min , Villani Gina M. 
Published: March 2020

e13099 Background: Obesity has increased to epidemic proportions, with 32.2% of US adults aged 20 years or older classified as obese (body mass index ≥ 30 mg/m2). In view of altered pharmacokinetics and possible excessive toxicity in obese patients, chemotherapy dose reductions are often employed in treating obese cancer patients. To our knowledge, there are no reports in the literature identifying patients who should have empiric dose adjustment because of obesity or the best method of dosing chemotherapy to standardize drug exposure in patients with varying degrees of obesity. As practice varies among institutions, we carried out a retrospective study to evaluate the chemotherapy dosing pattern in our obese patient population. Methods: Charts of patients who received chemotherapy at our institution during the year 2010 were reviewed. Data on age, height, weight, type and stage of cancer, date of chemotherapy, and type and dose of chemotherapy were retrieved from chart review. Only details of the first chemotherapy cycle at our institution were collected. Body surface area (BSA) was calculated by using the Mosteller formula. Independent samples t-test and Pearson chi-square statistics were used to investigate the difference between the means and proportions respectively. Results: Data from 191 patients were analyzed. Distributions (mean and range) of age, height, weight, body mass index (BMI) and BSA were 60 years (26 - 88), 65 inches (53 - 79), 166 pounds (90 - 340), 27.44 kg/m2 (14.52 - 56.57) and 1.85 m2 (1.36 - 2.66), respectively. Patients who had a full dose (n = 164) had a mean BMI of 27 kg/m2 (standard deviation (SD) 6.5) and a mean BSA of 1.82 m2 (SD 0.24) whereas those with a reduced dose had BMI (n = 27, mean 30.2, SD 7.1) and BSA (mean 1.97, SD 0.25). There is a significant difference between the means of the two groups (full dose and reduced dose) in terms of both BSA and BMI (p = 0.033 and p = 0.01, respectively). Significantly higher proportion of patients with BSA ≥ 2 received reduced dose compared to those with BSA < 2 (14 out of 48 (20.3%) versus 13 out of 143 (9%), p = 0.001). Conclusions: Patients with BSA ≥ 2 were more likely to get empiric chemotherapy dose adjustment at our institution. Further studies on chemotherapy dosing in obese patients are warranted.
Effect of VAL-083, a novel N7 alkylating agent, on growth of temolozomide-resistant primary adult glioblastoma multiforme (GBM) cells providing a new potential treatment option for GBM.
Authors: Dunn Sandra E. , Hu Kaiji , Fotovati Abbas , Chen James , Triscott Joanna , Bacha Jeffrey A. , Brown Dennis , Toyota Brian 
Published: March 2020

e13123 Background: Glioblastoma (GBM) remains one of the most difficult tumors to treat first because many new agents fail to cross the blood brain barrier (BBB), and second due to intrinsic drug resistance. Temozolomide (TMZ) is a front-line therapy for the treatment of GBM; however, it is often ineffective due to drug inactivation by O6-methylguanine-DNA methyltransferase (MGMT). Cancer stem cells (CSC) are a subpopulation of the tumor that resist therapy and give rise to relapse. Here we describe VAL-083, a novel alkylating agent that creates N7 methylation on DNA, and readily crosses the BBB. VAL-083 is currently undergoing human clinical trials in the USA in refractory GBM patients. We previously described how VAL-083 can overcome resistance associated with MGMT in cell lines, and targets brain tumor CSCs. This demonstrates that VAL-083 has the potential to surpass the standard-of-care. Methods: To provide further preclinical support for VAL-083 we examined the effect of VAL-083 on primary adult GBM cells in culture, isolated fresh following surgical resection, in cases where clinical activity of TMZ was known to be limited and high expression of MGMT had been observed. Results: VAL-083 (5uM) inhibited cell growth in these primary adult GBMs that did not show significant sensitivity to TMZ in vitro. VAL-083 also inhibited the growth of CSCs by 100% in neurosphere growth assays. Conclusions: In summary, VAL-083 demonstrates in vitro efficacy against primary adult GBM cells where TMZ has limited activity thereby further supporting the potential of VAL-083 to surpas the standard-of-care.
An evaluation of phase I clinical trial designs of chemotherapeutic agents tested on solid tumors and approved in last 10 years.
Authors: Deshmukh Chetan Dilip , Divekar Ganesh , Bondarde Shailesh Arjun , Jain Minish Mahendra , Prabhash Kumar 
Published: March 2020

e13127 Background: Phase I trials are performed with the aim of finding the maximum tolerated dose and often start with a very low dose that is subsequently escalated based on the toxicity seen. As a result patients treated on these trials often receive doses of chemotherapeutic agents that are frequently either below or above the biologically active level, thus reducing their chances for therapeutic benefit or increasing chances for toxicity. This evaluation was undertaken to determine how phase I trials are currently conducted and to correlate phase I doses tested with MTD and marketed doses. Methods: Published phase I trials of 16 chemotherapeutic agents tested on solid tumors and approved in last 10-years were identified by searching the Medline database and reviewed to determine methodology employed, cohorts taken to complete the trial, definition of dose limiting toxicity (DLT), number of cohorts treated below MTD, relation between MTD and marketed dose and DLT (dose limiting toxicity). Results: Twenty-three published trials involving 891 patients were identified. These trialsused the standard method of enrolling cohorts of patients at increasing dose levels and observing toxic effects to determine next dose.. Of these 15 used traditional dose escalation, 6 used accelerated titration, 2 used continual reassessment method. Six trials that used accelerated titration method of dose escalation, 2 were used to test cytotoxic agent (5 trials) while 1 tested targeted therapy. Sixty five cohorts were treated below MTD. Average number of cohorts required to complete trial were 6.2. Nineteen trials defined MTD as a dose below DLT dose while 4 trials defined MTD being DLT. Five of 23 trials were completed with-out reaching MTD. Marketed dose for these 16 chemotherapeutic agents was 0 to 50% lower than MTD. DLT reported was myelosupression, fatigue, rash, hypertension or diarrhea. Conclusions: These results show the need for methods to reduce cohorts to reduce number of patients recruited at doses significantly lower than MTD and complete the trials rapidly so that effective agents can be marketed sooner.
Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model.
Authors: Yamashita-Kashima Yoriko , Shu Sei , Harada Naoki , Fujimoto-Ouchi Kaori 
Published: March 2020

e13502 Background: The efficacy and safety of T-DM1 combined with pertuzumab in HER2-positive breast cancer is currently being investigated in a phase III clinical trial (MARIANNE). Anti-HER2 therapy with T-DM1 combined with pertuzumab in HER2-positive gastric cancer is of great interest. In a previous study in a HER2-positive gastric cancer xenograft model, T-DM1 in combination with pertuzumab demonstrated enhanced antitumor activity compared with each agent alone, and potentiated ADCC and apoptosis activity (AACR, 2011). In this study, we investigated the mechanisms underlying the enhanced activity observed with these two drugs. Methods: The binding of T-DM1 to cell surface HER2 was measured in a HER2-positive human gastric cancer cell line (NCI-N87) by flow cytometry using Alexa Fluor 647-labeled T-DM1. The phosphorylation status of HER signaling molecules was assessed by Western blot, and cellular localization of T-DM1 was determined by fluorescence microscopy using labeled T-DM1 in the presence/absence of pertuzumab. Results: Binding of T-DM1 to cell surface HER2 was significantly increased in the presence of pertuzumab. Concomitant treatment with T-DM1 and pertuzumab led to a reduction of phosphorylated (p)EGFR or pHER3 in EGF or heregulin-stimulated cells, respectively, resulting in suppression of downstream pERK or pAkt pathways. Fluorescence microscopy revealed that pertuzumab facilitated the internalization of HER2-bound T-DM1 from the cell surface into the cytoplasm. Conclusions: Results suggest that the enhanced antitumor activity observed with the combination of T-DM1 and pertuzumab may be attributed to 1) increased binding of T-DM1 to HER2, which could potentially augment ADCC and diminish downstream HER2-signaling, and 2) increased T-DM1 internalization into the cytoplasm, which may potentiate tumor cell death caused by DM1. These results suggest that T-DM1 in combination with pertuzumab may provide clinical benefit for patients with HER2-positive gastric cancer.