bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of dosimetric and radiation safety results of seventeen patients treated with radioimmuno therapy using Iodine 131—Tositumomab for non-Hodgkin’s lymphoma
Authors: Nair M. , Mark R. , Anderson P. J. , Neumann T. 
Published: March 2020

12513 Background: Radioimmunotherapy using radioactive Iodine -131 labeled radioimmuno conjugate called Tositumomab has been used in the treatment of non-Hodgkin’s lymphoma. Radiation dosimetry and safety aspects of this treatment modality are very critical for successful implementation of this treatment. Methods: Since year 2001, we have treated 17 patients using I-131-tositumomab. There were 11 female and 6 male patients at age range of 40 to 82 years. Patient specific dosimetry was performed on all the patents using a tracer dose of I-131. The whole body counts were performed after infusion of 5.0 mCi of I-131-tositumomab and whole body counts were taken at 0, 48 and 178 hours. The total body residence time (TBRT) for 37% of the activity to stay in the body was determined by graphical method. The activity in mCi, for delivering 65 cGy or 75 cGy whole body dose, was calculated based on the TBRT and patient’s weight. Based on the measured exposure rate, we have calculated the total effective dose equivalent (TEDE) to the public. The patients were released to home with radiation safety instructions if TEDE delivered to the public was less than 5.0 mGy. We have studied the platelet count recovery time for all the patients, following treatment. Results: The calculated TBRT ranged from 85 to 175 hours and the the mCi/Kgm varied from 1.4 to 0.6, related inverse proportion with TBRT. For both group of patients, treated with total body dose of 65 cGy and 75 cGy, the mCi/Kgm was the same, for TBRT values exceeding 100 hours. The TEDE to public varied from 1.02 to 3.22 mGy, while the exposure rate measured on the patient at 1 meter was less than the permissible value reported in the literature for safe release. Conclusion: The above results show that the patients can be treated as outpatient using I-131 -tositumomab with radiation safety restrictions lasted for one week. The radiation exposure to the public was less than the maximum permissible dose equivalent. No significant financial relationships to disclose.
Predictive and prognostic impact of plasma vascular endothelial growth factor levels in non-small-cell lung cancer patients treated with gefitinib
Authors: Sone T. , Kasahara K. , Tanbo Y. , Tamori S. , Araya T. , Kimura H. , Yoshimoto A. , Fujimura M. , Nakao S. , Shibata K. 
Published: March 2020

13030 Background: In non-small cell lung cancer (NSCLC), sensitivity to gefitinib is associated with activating mutations of the epidermal growth factor receptor (EGFR). Tumor samples obtained for diagnosis of NSCLC are limited and often unsuitable for analysis of mutations. Other biomarkers are thus needed. We previously reported that serum vascular endothelial growth factor (VEGF) levels were significantly lower in responders to gefitinib than non-responders. To assess levels of circulating VEGF as a predictive and prognostic marker of gefitinib treatment in NSCLC patients, we examined the associations between plasma VEGF levels before gefitinib treatment and clinical outcome. Methods: Eighty four NSCLC patients treated with gefitinib were enrolled into this investigation. Plasma VEGF levels were measured in blood samples before gefitinib administration. Patients were grouped according to VEGF level around a cut-off of 80.7 pg/ml, based on results from normal controls. Response to gefitinib was judged using RECIST guidelines. Time to progression (TTP) and overall survival (OS) following gefitinib treatment were calculated using Kaplan-Meier methods. Groups were compared using log-rank test. We evaluated the immunohistochemical expression of VEGF and EGFR mutations in tumor samples from 37 patients. Results: Response rate was significantly higher with low VEGF level than with high VEGF level (p = 0.0010). Multivariate analysis for response to gefitinib including sex, histology, smoking status, performance status and plasma VEGF level identified only low VEGF level as predictive of response to gefitinib. Low VEGF level was also correlated with prolonged median TTP (4.1 months vs. 1.1 months, p = 0.0081) and OS (11.1 months vs. 5.4 months, p = 0.0290). Multivariate analysis for survival revealed low VEGF level as associated with prolonged TTP (p = 0.0081) and OS (p = 0.0708). Plasma VEGF level was not associated with either VEGF expression or EGFR mutations of tumor tissue. Conclusions: Our results suggest that plasma VEGF levels before gefitinib treatment are predictive of response to gefitinib and prognostic of patients who receive gefitinib. [Table: see text]
Phase I study of lenalidomide, a novel thalidomide analog, in patients with refractory metastatic cancer
Authors: Tohnya T. M. , Gulley J. , Arlen P. M. , Sparreboom A. , Venitz J. , Parker C. , Fedenko K. , Parnes H. , Figg W. D. , Dahut W. L. 
Published: March 2020

13038 Background: Lenalidomide (L), CC5013, is a thalidomide (T) analog that has shown activity in multiple myeloma and myelodysplastic syndromes (MDS); including activity in pts refractory to T. Preclinical studies suggest L has more potent immunomodulatory and antiangiogenic activity than T. We have conducted a phase I clinical trial of L to determine the maximum-tolerated dose (MTD), characterize the side-effects, characterize pharmacokinetics (PK) in pts with solid tumors. Methods: Pts with refractory metastatic cancer were treated on a modified Fibonacci dose-escalation scheme with an oral daily dose of L. Therapy was continued until MTD or disease progression. Results: Forty-five pts have been enrolled (M/F: 37/8). Median age 68 yrs (range, 25–89 yrs). Tumor types include prostate cancer (36 pts), adrenal carcinoma (3 pt), renal cell carcinoma (1 pt), choleangiocarcinoma (1 pt), small intestine cancer (1 pt), colon cancer (2 pt), and melanoma (1 pt). Dose levels were: 5 mg (n = 3), 10 mg (n = 6), 15 mg (n = 3), 20 mg (n = 3 + 7), 25 mg (n = 6), 30 mg (n = 8), 35 mg (n = 6) and 40 mg (n = 3). Due to side effects the dosing schedule was modified from daily dosing to daily dosing for 21 out of 28 days. Therapy has been well tolerated with most frequent gr 1 and gr 2 toxicities include nausea (43%), myalgia (38%), pruritis/rash (54%), and fatigue (38%), neutropenia (30%) with gr 3 diarrhea (n = 1), hypotension (n = 1), pulmonary effusions (n = 1), thromboses (n = 2) and gr 4 neutropenia (n = 2), arrhythmias (n = 1), hemolysis (n = 1). Dose escalation continues. There were no differences observed between dose levels for either oral clearance values (p = 0.47) or the apparent volume of distribution (Vz) values (p = 0.23). Dose-normalized AUC(0-∞), dose-normalized peak concentrations (Cmax), or half-life (t1/2) did not vary between dose levels (p > 0.12). Conclusion: L has been well tolerated up to 35 mg/d (21 days on; 7 days off), doses higher than the recently FDA-approved doses of 5 and 10 mg/d. In this dose range L exhibits linear PK. Tolerability to myelosuppression the dose-limiting toxicity in pts with MDS may therefore be improved in pts without hematological malignancies. No significant financial relationships to disclose.
A phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) TheraCIM-h-R3 (nimotuzumab) in patients with advanced solid tumors
Authors: Brade A. M. , Siu L. , Oza A. M. , Southwood B. , De Borja M. , Pond G. R. , Sherman I. A. , Chen E. 
Published: March 2020

13054 Background: Nimotuzumab is a humanized mAb against the extracellular ligand binding domain of EGFR. Although well tolerated when combined with radiotherapy in previous studies, the pharmacodynamics (PD) of nimotuzumab has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of nimotuzumab. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and performance status of ECOG 0–2. Nimotuzumab was administered intravenously weekly × 6 and then every other week (6 weeks = 1 treatment cycle). Tumor and skin biopsies were obtained at baseline and after 2 weeks of treatment. Results: To date, 9 patients (7 m/2 f, median age 60, 7 colorectal cancer, ECOG 0:1:2 = 5:3:1, prior therapy 1:2:3+ = 1:3:5) have been treated on the first 2 dose levels (100 mg and 200 mg) for a total of 13 treatment cycles. The most common toxicities, mainly grade 1- 2, were lymphopenia (n = 8 patients), fatigue (n = 8), abnormal liver function tests (n = 7) and anemia (n = 6). Observed grade 3 toxicities include: pain (n = 3), hyponatremia (n = 2), elevated ALP (n = 2), fatigue (n = 1), hyperglycemia (n = 1) and hyperkalemia (n = 1). One patient at the first dose level experienced grade 3 fatigue, at least possibly attributable to nimotuzumab, and thus considered as a dose-limiting toxicity (DLT). No DLT were observed in the expanded cohort and dose level 2. No skin toxicities were observed. Stable disease was seen in 3 patients with colorectal cancer. PD from tumor and skin biopsies will be presented, and may clarify the reason for the lack of skin toxicity. Conclusions: Overall nimotuzumab was well tolerated, with disease stabilization observed in heavily pretreated patients. Accrual continues at dose level 3 (400 mg) with one further planned dose level (800 mg). [Table: see text]
A novel, selective, orally active, potent small molecule inhibitor of Hsp90
Authors: Steed P. M. , Fadden P. , Hall S. 
Published: March 2020

13067 Background: The preclinical and clinical data evaluating derivatives of the natural product geldanamycin, including 17-AAG and 17-DMAG, reveal that inhibition of the molecular chaperone HSP90 results in multiple anti-tumor effects. SNX-5422 and SNX-5542 are potent, novel, highly specific, water soluble and orally active small molecule inhibitors of Hsp90. Here we describe the preclinical efficacy and toxicity evaluation of these compounds. Methods: The PK profile of SNX-5422 and SNX-5542 was determined following oral and iv dosing in mice and rats. HT29 xenografts were performed oral doses of SNX-5542 on a schedule of Q2DX3,2 for 2 weeks or 17-DMAG on the previously reported regimen of bid×5,2 for 2 weeks, with tumor progression and body weight monitored. Plasma, tumor and other tissues were harvested for evaluation of HSP70 induction and levels of HSP90 client proteins. Rats were treated with varying oral doses on a schedule of Q2DX3,2 for two weeks. Clinical observations were noted and standard hematology and clinical chemistry parameters were monitored. Results: SNX-5542 exhibited 37% oral BA in rats and >75% in mice, with t½ >7h in each species. SNX-5542 was well tolerated in normal and tumor-bearing mice at 300 mg/m2 Q2DX3,2 for 2 weeks, 0.9% weight gain. 17-DMAG at 30 mg/m2 bid×5,2 for 2 weeks caused 3.3% body weight loss. At these doses, SNX-5542 exhibited 78% median tumor growth inhibition of HT29 tumors while 17-DMAG exhibited 23% inhibition. Mechanistic indicators of HSP90 inhibition correlated with efficacy across multiple dosing levels. At 120 mg/m2 Q2DX3,2 for 2 weeks SNX-5422 was well tolerated in rats, with no significant effect on any clinical, hematology or clinical chemistry parameter with the exception of a slight increase in blood urea nitrogen levels. Histopathological evaluation of liver, thymus, spleen and kidneys revealed no significant treatment-related effects. At 120 mg/m2 Q2DX3,2 for 13 days SNX-5422 does not exhibit any of the toxicities reported for 17-DMAG (bidX5,2 for 8 days at 24 mg/m2). Conclusions: SNX small-molecule HSP90 inhibitors have favorable pharmacokinetic profiles, oral bioavailability, tolerability and superior anti-tumor activity compared to the natural product derivative 17-DMAG. [Table: see text]
Dose-finding study of fixed dose rate (FDR) infusion of gemcitabine in combination with bevacizumab and escalating doses of irinotecan in patients with advanced gastrointestinal (GI) tumors
Authors: Chopitea A. , Rodríguez J. , Viúdez A. , Viteri S. , De La Cámara J. , Reyna C. , Olier C. , Aramendía J. M. , García-Foncillas J. 
Published: March 2020

13068 Background: Gemcitabine (GMB), Bevacizumab and Irinotecan (CPT-11) are active agents in GI tumors with preclinical evidence of synergism. The purpose of this study was to assess the maximum tolerated dose (MTD) of FDR GMB, Bevacizumab and CPT-11 in patients (pts) with advanced GI malignancies. Preliminary evidence of antitumor activity was also evaluated. Methods: A biweekly schedule of FDR GMB at a dose of 1000 mg/m2, Bevacizumab 5 mg/kg and CPT-11 (100–160 mg/m2 with a 10 mg/m2 increase in each cohort level) was analysed. The dose of CPT-11 was escalated in cohorts of three pts until the MTD was defined. Results: Thirty eligible pts with GI tumors were included (oesophagus: 2; gastroesophagic junction: 1; gastric: 2; pancreas: 2; colon: 17; rectum: 6) The median age was 60 years. ECOG status was 0–1 in 70% of pts. Male/female ratio was 21/9. Twenty-nine pts had received prior chemotherapy. The median number of cycles administered was six. Two of three pts at a CPT-11 dose of 160mg/m2 had grade 3 asthenia that required hospitalization. Recommended dose was thus established at CPT-11 dose of 150 mg/m2. Nine additional pts were included in this cohort and no further toxicity was observed. Antitumor activity was seen in 13 pts, with 3 complete responses and 10 partial responses. Conclusions: The recommended dose for phase II studies is CPT-11 150 mg/m2, GMB 1000 mg/m2 in FDR infusion and Bevacizumab 5 mg/kg on a biweekly schedule. Overall, this is a feasible regimen with a promising activity. No significant financial relationships to disclose.
1249G>A polymorphism of ABCC2 (MRP2) is associated with altered gene expression in human liver
Authors: Kroetz D. L. , Liu W. , Nguyen T. D. , Zwecker B. M. , Ramirez J. , Innocenti F. , Ratain M. J. 
Published: March 2020

13072 Background: MRP2, encoded by ABCC2, is an ATP-binding cassette transporter that plays a critical role in the biliary elimination of various drugs and xenobiotics. Although SNPs in this gene have been identified and reported, their functions are not fully understood. T he purpose of this study was to evaluate the effect of polymorphisms/haplotypes of the ABCC2 gene on its mRNA expression in human liver. Methods: Two hundred human liver samples were genotyped for the following polymorphisms: −1549G>A, −1019A>G, −24C>T, 1249G>A (V417I), −34T>C (intron 27) and 3972C>T. Haplotypes and diplotypes were predicted and assigned to each individual. Haplotype-specific expression was then tested using 3972C>T and 1249G>A as markers. Heterozygous Caucasian samples for 3972C>T and 1249G>A were selected and the two SNPs were genotyped in the PCR and/or RT-PCR products from both DNA and the corresponding mRNA. The minisequencing-based SNaPshot method was used to genotype and quantify the expression level of each allele. The relative expression of both alleles in the mRNA was normalized to that in the DNA. Results: There is no haplotype-specific expression discriminated by the 3972C>T polymorphism. However, when using 1249G>A as a marker, the haplotypes containing the 1249A allele had significantly higher mRNA levels when compared with haplotypes containing the 1249G allele (one sample t test, p < 0.001, n = 37). Conclusions: The 1249G>A substitution in the ABCC2 gene may be associated with gene expression in human liver. Significant variability of the relative expression of ABCC2 in the population suggests that other functional polymorphisms and environmental factors may also be involved in the regulation of ABCC2 expression. No significant financial relationships to disclose.
A dose finding study with erlotinib in combination to irinotecan and capecitabine in metastatic colorectal cancer (mCRC) patients
Authors: Di Bartolomeo M. , Bajetta E. , Buzzoni R. , Ferrario E. , Mariani L. , Gevorgyan A. , Dotti K. , Longarini R. , Platania M. , Canova S. 
Published: March 2020

13075 Background: Erlotinib is an oral selective and reversible small molecule inhibitor with specificy for the EGFR/HER1. This study evaluated the maximum tolerated dose and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine. Secondary objectives included the safety profile and the response rate of the combination. Methods: Twenty-two pts (median age 57 yrs, range: 39–69; M/F:12/10) with mCRC refractory to first-line therapy (oxaliplatin-combinations) were accrued. Five dose level combinations with irinotecan (from 180 to 240 mg/m2, day 1, q21), capecitabine (1500 to 2400 mg/m2/d, days 2–15 q21) and erlotinib (50 to 150 mg/d., continuously until progression) were planned. Cycles were repeated every 3 weeks, maximum of 6–8 cycles. Tumor assessments (RECIST criteria) performed every 3 cycles. Maximum tolerated dose was defined as the highest dose where the toxicity rate does not exceed the 30% target level. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results: Three pts entered the first dose group (no DLT), six the second (1 DLT; G4 neutropenic fever), six the third dose group (2 DLT; G3 diarrhea, G4 neutropenic fever), and one (protocol deviation in the dose escalation scheme) the fourth dose group (1 DLT; G3 diarrhea and vomiting). Cutaneous rash and mucositis G3 (no DLT), were documented in one pt (dose group 2). To confirm these results, six pts were additionally accrued in dose groups 2 and 3 showing no DLT. Among twenty evaluable pts, two had an objective response, 15 showed disease stabilization and completed the 6-cycle treatment, 3 had disease progression. Conclusions: Erlotinib at a dose of 100 mg/d, combined with irinotecan 240 mg/m2 and capecitabine 1500 mg/m2/d, (as correspond to dose group 3) has an acceptable safety profile and appears suitable for further investigation. Editorial Assistance by the Scientific Service of the I.T.M.O. group. No significant financial relationships to disclose.
A phase II, multi-center study of a new non-cytotoxic A3 adenosine receptor agonist CF101, dose-finding (randomized blinded) in patients (pts) with refractory metastatic colorectal cancer
Authors: Stemmer S. , Shani A. , Klein B. , Silverman M. , Lorber I. , Farbstein M. , Shmueli E. , Figer A. 
Published: March 2020

13082 Background: The A3 adenosine Gi protein-coupled receptor is highly expressed in malignant compared to normal cells. Activating the A3 adenosine receptor (A3AR) with the highly selective non-cytotoxic agonist, CF101 (IB-MECA), inhibit of colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models, via down-regulation of the Wnt and NF-κB signal transduction pathways. Oral CF101 has been shown to inhibit colon, prostate, melanoma, pancreatic and hepatocellular cancer growth in experimental animal models. Methods: A phase II dose-finding, randomized, blinded study of oral CF101 (0.1, 1& 4 mg PO BID), was conducted to define activity and safety in heavily pre-treated metastatic colorectal cancer pts. From 6/1/2003–7/4/2004, 70 pts, median age 62 with measurable colorectal cancer, PS ≤2 were enrolled, 21 pts progressed after irinotecan and 49 pts after both irinotecan and oxaliplatin-based regimens. Results: The median time on treatment was 10.3 weeks. No objective response was observed; however, SD for 8 wks duration was achieved in 24 pts (34%), for 16 weeks in 8 pts (11%) and 2 pts were treated for more than 24 weeks. The median time to treatment progression was 72 days and for overall survival was 254 days without any significant difference among the 3 trial doses [8 survivors till today]. There were no obvious treatment related serious adverse events. Conclusions: The final results of the study show that CF101 is well tolerated and may stabilize disease for at least 2 months in 35% of the pts. The median survival time (8 months) compared with other targeted therapy investigated lately is encouraging. Combining CF101 with chemotherapy may be beneficial in the treatment of metastatic colorectal cancer. No significant financial relationships to disclose.
AG-013736, a novel VEGF receptor and PDGF receptor inhibitor with potent activity against human bladder carcinoma in vitro and in vivo.
Authors: Zhu K. , Pino M. , Siefker-Radtke A. O. , Shalinsky D. , Hu-Lowe D. , McConkey D. J. 
Published: March 2020

13109 The receptors for vascular endothelial growth factor and platelet-derived growth factor (VEGFR-2 and PDGFR) play essential and complementary roles in angiogenesis, and combined inhibition of these receptors may therefore result in potent antitumor activity in vivo. Here we characterized the effects of a small molecule tyrosine kinase inhibitor AG-013736 (Pfizer) in HUVEC and human bladder cancer cells. Previously, AG-013736 was reported to inhibit VEGFRs with picomolar potency and PDGFRs with nanomolar activity. All of the cell lines examined displayed cell surface VEGFR-2 and PDGFR α and β expression as measured by flow cytometry. Low nanomolar concentrations of AG-013736 blocked the HUVEC cell proliferation with inhibition of VEGF receptor 2 and PDGF receptor phosphorylation. AG-013736 caused regression of established subcutaneous human bladder cancer xenografts, effects that were associated with inhibition of VEGFR-2 and PDGFR β phosphorylation but not EGFR phosphorylation and reduction in tumor microvessel densities (MVDs). Our results demonstrate that AG-013736 has substantial anti-angiogenesis activity in preclinical models of human bladder cancer, which warrants further exploration either alone or with the combination of other pre-clinical drugs in bladder cancer treatment. No significant financial relationships to disclose.
Gene expression profile related to oxaliplatin resistance in a panel of sensitive human colorectal cancer cell lines with acquired resistance to the drug
Authors: Martinez-Cardus A. , Martinez-Balibrea E. , Manzano J. L. , Bandres E. , Malumbres R. , Marti C. , Taron M. , Garcia-Foncillas J. , Abad A. 
Published: March 2020

13143 Background: Platinum drugs resistance acquisition is a complex process based in the alteration of genes that belong to several pathways related to drug metabolism. To clarify the multifactoriality of these mechanisms, we analyzed gene expression profile in the four CCR cell lines HT29, LoVo, DLD1 and LS513, and their sublines HTOXAR, LOVOXAR, DLDOXAR y LSOXAR that we induced oxaliplatin resistance in our laboratory. The aim of this work consisted on comparing gene expression profile between resistant cells group (cluster R) and sensitive cells group (cluster S) to determine genes and pathways that could play a role in oxaliplatin resistance acquisition process. Methods: Resistance level determination by MTT assay. Gene expression profile analysis through microarray technology (Human 19K oligo): labeled with Genisphere 3DNA Array350 (Dye Swap), and data analysis using Imagene 4.1, ArrayNorm1.7.2 y Genesis 1.5.0 (ANOVA). Results: According to ANOVA analysis of cluster R versus cluster S, we obtained 32 genes that showed significant changes in expression. 15 of these genes were up regulated and 17 were down regulated. We emphasize genes that belong to pathways previously related to oxaliplatin metabolism (AKT1, TRIP and NLK), family of genes that does not expressed in the same chromosome (KIAA0232 and KIAA0256, SLC39A9 and SLC30A9), and family of genes that had previously related to carcinogenesis processes (KRT19, KRT18 and KRT8). Conclusions: It is possible to develop oxaliplatin resistant CCR cell lines. In our oxaliplatin acquired resistance model, 32 genes showed gene expression changes between groups. These genes belong to signal transduction pathways and cellular integrity mechanisms and they could be a future oxaliplatin resistance prediction profile in colorectal cancer patients. No significant financial relationships to disclose.