bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycodelin: A possible new biological marker in colorectal cancer
Authors: Govindarajan R. , Parthasarathy S. 
Published: March 2020

20081 Background: Glycodelin is a 28 kDa glycoprotein expressed in normal human reproductive tract. It is over expressed in various gynecological malignancies and vascular endothelium. Since angiogenesis has been associated with and antiangiogenic therapy is effective in colorectal cancer, it is possible that glycodelin could be a mediator in the pathogenesis and be a potential target in the treatment of this disorder. To assess whether the serum glycodelin was expressed in metastatic colorectal cancer, analysis of serum samples obtained from patients participating in a clinical trial were analyzed. Methods: Serum glycodelin levels from 19 controls (5 males, 9 premenopausal females and 5 postmenopausal females) and 24 patients with metastatic colorectal cancer (15 males and 9 females) enrolled into a phase II treatment protocol were measured. All patients had progressed on prior chemotherapy. Samples were obtained prior to the initiation of any further therapy. Glycodelin levels were measured by an Elisa based immuno assay using polyclonal antibodies raised against a peptide derived from the sequence of human glycodelin. Results: The median age of the patient populatin was 62.5 yrs. (range 29–78); of the males was 65 yrs. (range 57–78); of females was 58 yrs. (range 29–66). The median serum glycodelin level of whole control group was 41 nG/50μL (range 26–61); of 5 males 27 nG/50 μL (range 13–41); of 9 premenopausal females was 64 nG/50 μL (range 46–86); and of 5 postmenopausal women was 38 nG/ 50 μL (range 27–49). The median serum glycodelin level of patients with metastatic colorectal cancer was 128 nG/ 50 μL (range 51–523); of men was 128 nG/50 μL (range 51–523) and of women was 120 nG/50 μL(range 51–377). Serial glycodelin levels dropped by more than 50% in patients who had a clinical response or those who had stable disease. Conclusions: Serum glycodelin level was elevated in patients with metastatic colorectal cancer compared to controls. Whether glycodelin plays a role in the pathogenesis of colorectal cancer; can be a useful index to measure response and be useful as a potential target in the management of patients with colorectal cancers needs further evaluation. No significant financial relationships to disclose.
Inhibition of tumor growth in a murine xenograft model by thalidomide
Authors: Horn L. , Hermes M. , Schwock J. , Brulport M. , Hengstler J. G. 
Published: March 2020

20083 Background: Limitations in the treatment of recurrent disease in cervical carcinoma are for radiation therapy large tumor size and pelvic side wall involvement and for exenteration procedurde previous radiation therapy, bulky disease, and others. Alternative approaches including chemotherapy, chemo-radiation, radiation plus hyperthermia and others are accompanied by a failure rate of 50 to 80%. Recent research has shown that the antineoplastic effect of thalidomide (TD) is due to the inhibition of neo-angiogenesis, a decrease of TNF-a, blocking of nuclear factor κβ-kinase activity, stimulation of the IL-2 and downregulation of cell adhesion molecules. Here, we have studied the effect of TD on a cervical cancer cell line in a murine xenograft model. Methods: We injected 7 × 106 HELA cells s.c. into the dorsal skin of 6–8 week-old male nude mice (cd nu−/nu−; Charles River, Sulzfeld, Germany). The tumor diameter was measured with a caliber rule. The maximum and minimum diameters of the tumor were determined. Tumor volume (V) was calculated by the formula: V = a × b × b/2, where a represents the minimum and b the maximum tumor diameter. As soon as tumors reached a volume of 0.25 cm3 the mice were randomized into a treatment (n = 9) and a control group (n = 9). The mice in the treatment group received 14 daily injections of 300 mg/kg (i.p.) thalidomide for 14 days. Animals were housed under specific pathogen-free conditions. The experiments have been approved by the local animal welfare committee. Results: Thalidomide caused a clear delay in tumor growth. Already 7 days after onset of thalidomide therapy the mean tumor volume was smaller in the treated (0.24 ± 0.03 cm3) compared to the control mice (0.73 ± 0.15 cm3; mean ± standard error; p < 0.01). After 14 days of thalidomide treatment the mean tumor volumes were 0.37 ± 0.05 and 1.05 ± 0.19 cm3 in the treated and in the control mice, respectively (p < 0.01). However, after the end of the 14 days treatment period a new onset of tumor growth was observed. In conclusion, thalidomide delayed tumor growth but did not cause tumor remission. Conclusions: TD is effective in inhibition of tumor growth of a cervical cancer cell line in a mouse xenograft model and might be an alternative drug in patients with recurrent cervical carcinoma without any options for established standard therapy. No significant financial relationships to disclose.
Cross-activity of various established antineoplastic regimens in primary breast cancer cells evaluated by the ex vivo ATP tumor chemosensitivity assay
Authors: Nagel W. J. , Luecke J. , Cree I. A. , Reinhold U. , Kurbacher J. A. , Reichelt R. , Bruch H. R. , Kurbacher C. M. 
Published: March 2020

20086 Recently, various chemotherapy (Ctx) regimens are established in operable breast cancer (BC). Whereas anthracylines are now standard in high-risk patients (pts), the future role of taxanes or classical CMF is still controversial. Moreover, little is known which Ctx will be individually beneficial. This particular information is unlikely to be obtained from randomized trials because simultaneous treatment of one single pt with different competing protocols is inappropriate. Thus, we used ex vivo sensitivity profiles from native primary BC assessed with the ATP tumor chemosensitivity assay (ATP-TCA) to analyze the cross-activity of different standard regimens in individual pts. Each Ctx was tested at six different levels over 1.5 log range including both therapeutical and supra-therapeutical concentrations. Resistance, complete, and incomplete sensitivity were determined using a semiquantitative score. The following head-to-head comparisons of ex vivo activity were made: CMF, 4-OOH-cyclophosphamide (4-HC)+methotrexate (MTX)+5-Fluorouracil (5-FU) vs. EC, epirubicin (EPI)+4-HC, n = 56; CMF vs. paclitaxel (PCT), n = 34; CMF vs. docetaxel (DCT), n = 49; EC vs. PCT, n = 51; EC vs. DCT, n = 35; EC vs. EPI+PCT (ET), n = 45; PCT vs. DCT, n = 34. The ex vivo response rates were in good agreement with the expected clinical activity: CMF 52%, EC 63%, ET 85%, PCT 52%, DCT 49%. CMF and EC were equally active (=) in 68% BCs, CMF was superior (>) to EC in 16% and inferior (<) in 16%. The corresponding proportions (=/>/<) for the other comparisons were: CMF vs. PCT, 45%/31%/24%; CMF vs. DCT, 40%/40%/20%; EC vs. PCT, 49%/31%/20%; EC vs. DCT, 40%/40%/20%; EC vs. ET, 53%/ 9%/38%; PCT vs. DCT 55%/21%/24%. Generally, ET was the most active regimen, being equal or superior to EC in the majority of cases. However, CMF is clearly not inferior to EC or single agent taxanes. PCT and DCT are apparently not always the same. Facing the broad heterogeneity of chemosensitivity demonstrated in this study, we were able to show that the results of randomized trials cannot always be translated to an individual pt. Cross-activity analyses using the ATP-TCA may thus prove useful to allow for a more rational design of clinical trials in primary BC. [Table: see text]
Microtubule-associated protein tau and in vitro paclitaxel sensitivity in primary breast cancer
Authors: Schmidt M. , Bremer E. , Victor A. , Gehrmann M. , Hengstler J. G. , Koelbl H. 
Published: March 2020

20088 Background: Paclitaxel has an important role in the adjuvant therapy of primary breast cancer. Recently, microtubule-associated protein tau was described as a marker of paclitaxel sensitivity. We attempted to validate these findings in vitro utilizing the ATP tumorchemosensitivity assay (ATP-TCA). Methods: The in vitro drug sensitivity to paclitaxel was evaluated in 48 fresh primary breast cancer specimens using the ATP-TCA. ATP-TCA results were analysed using the area under the curve (AUC) of growth inhibition. These results were correlated with the expression of tau mRNA measured by quantitative RT-PCR (Spearman’s correlation coefficient). Tau was also compared between progesterone receptor (PgR) positive and negative and estrogen receptor (ER) positive and negative tumors, respectively (Wilcoxon test). Results: The correlation of tau with the AUC for paclitaxel was weak (r = −0.20) and disappeared when considering PgR positive and negative tumors separately (r = −0.004 and r = −0.048, respectively). Tau was found to be differentially expressed between PgR positive and negative as well as between ER positive and negative tumors (p < 0.0005 in both tests). Conclusions: The expression of tau does not show independent predictive value for the in vitro paclitaxel sensitivity in primary breast cancer. No significant financial relationships to disclose.
Presentation of splice variants of 1-alpha-hydroxylase in MCF-7 breast cancer cells
Authors: Cordes T. , Diesing D. , Becker S. , Fischer D. , Diedrich K. , Friedrich M. 
Published: March 2020

20097 Background: Calcitriol (1,25-dihydroxyvitamin D3) is the most active metabolite of vitamin D. It is known for its antiproliferative and differentiating effects on many cell populations including MCF-7 and other breast cancer cells. 1α-hydroxylase (CYP27B1) one of the key enzymes has been found in breast cancer cells suggesting an autocrine regulation of producing calcitriol. An alternative splicing of the encoding genes for the1α-hydroxylase might play a role in regulating enzyme levels and can explain tissue specific variations of the enzyme activity. Splice variants containing intron 1 may encode for truncated proteins with deletion of protein domains which are essential for its enzymatic activity. Methods: In order to obtain more information on the abundance of 1α-hydroxylase splice variants, we performed a highly specific nested touchdown PCR in MCF-7 cells. The protein products of the full length enzyme and its slice variants were confirmed by Western Blot. Results: The full length sequence of 1α-hydroxylase and two different splice variants including intron 1 were isolated. Conclusion: We hypothesize that the expression of the splice variants can lead to a quantitatively lower expression the mRNA of the full length enzyme. The abundance of less active 1α-hydroxylase protein products can alter the local synthesis of calcitriol in the cells and may explain variations of enzymatic activity in different cells and tissues. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) expression in colorectal cancer in Slovakia
Authors: Salek T. , Mardiak J. , Ondrias F. , Bodnar J. , Klimcakova L. 
Published: March 2020

20103 Background: EGFR is involved in the epidermal growth factor pathway that regulates cellular processes and is associated with the development of malignancy.EGFR targeted therapy could be an alternative option to improve clinical outcome in tumors with EGFR expression. Methods: From 09/2004 till 12/2005 we evaluated histologic specimens of 130 patients (89 male, 41 female) with colorectal cancer. EGFR expression was examined by immunohistochemistry using theEGFR Detection Kit (Dako Corporation) in paraffin-embedded colon/rectum tumors and graded as percentage of cells stained. Results: EGFR positivity (1% and more) was observed in 106 pts (81.5%) and EGFR negativity in 24 pts (18.5%). Median of positivity in percentage is 40 (1–95). Conclusions: The EGF receptor is overexpressed in many human tumors and is a promising therapeutic target. No significant financial relationships to disclose.
Results of a clinical pharmacokinetic (PK) bioequivalence (BE) study of liposomal paclitaxel (LEP-ETU) versus paclitaxel (T) in patients with advanced cancer
Authors: Tan A. R. , Hanauske A. R. , Gelderblom H. , Scheulen M. E. , Van Warmerdam L. J. , Rosing H. , Fetterly G. J. , Shu V. S. , Sherman J. W. , Rubin E. H. 
Published: March 2020

2017 Background: LEP-ETU is an easy-to-use liposomal formulation of paclitaxel developed to reduce toxicities associated with the excipient polyoxyethylated castor oil that is used in paclitaxel (Taxol [T]), while maintaining or enhancing efficacy. A phase I study of LEP-ETU demonstrated an MTD of 325 mg/m2 and a similar PK profile at a dose of 175 mg/m2 compared to published T data (Damjanov et al, J Clin Oncol 2005;23 Suppl:147s). Methods: This randomized, two-period crossover, clinical BE study was designed to directly compare the PK of paclitaxel following intravenous administration of LEP-ETU and T delivered over 180 minutes at a dose of 175 mg/m2 in patients with a variety of advanced solid tumors. Patients were randomized to receive either one treatment cycle of LEP-ETU followed by one cycle of T, or one cycle of T followed by one cycle of LEP-ETU. Eligible patients were permitted to continue LEP-ETU treatment in an extension study. Results: Fifty-eight patients were treated, and 32 evaluable patients were analyzed for BE. The latter group of patients met pre-specified evaluability criteria of having received 100% of each dose during the specified administration interval and having had the necessary blood samples drawn to determine Cmax and AUC. Mean total paclitaxel Cmax values for LEP-ETU and T were 4955.0 ng/mL and 5108.8 ng/mL, respectively. Mean total paclitaxel AUC0–8 values for LEP-ETU and T were 15853.8 ng·h/mL and 18550.8 ng·h/mL, respectively. Ratios of the geometric means of LEP-ETU divided by T for Cmax were 97% (90% CI, 91%-103%) and for AUC0–8 were 84% (90% CI, 80%-90%). These results meet the established 80–125% BE criteria. The most frequently reported adverse events were fatigue, alopecia, and myalgia. Of the 37 patients deemed suitable to continue LEP-ETU treatment in the extension study, 57% have received = 4 cycles of LEP-ETU with at least stable disease. Conclusion: LEP-ETU has met BE criteria compared to T. A comparative efficacy and safety study of LEP-ETU and T at a dose of 175 mg/m2 has been planned to confirm the potential of LEP-ETU to have comparable or improved treatment effect with a better safety profile than T. [Table: see text]
Determination of uracil/UH2 ratio as a potential surrogate for DPD status in cancer patients presenting with severe toxicities during fluoropyrimidine treatment
Authors: Mercier C. , Yang C. , Ciccolini J. , Balti M. , Evrard A. , Blesius A. , Dahan L. , Richard K. , Seitz J. , Lacarelle B. , Favre R. 
Published: March 2020

2020 Background: DPD deficiency is a rare pharmacogenetic syndrome leading to overexposure to fluoropyrimidine drugs, with subsequent exacerbation of toxicity and, possibly, fatal outcome in the most severe cases. Methods: We developed a simple and rapid surrogate method for evaluating the DPD status of cancer patients. This method was retrospectively validated by following 860 patients treated with fluoropyrimidines over a 3-year period at our institute. We applied the Uracil to UH2 ratio measurement as an indirect insight into DPD functionality in a subset of 120 patients (14%), who had presented with severe toxicity (grade 3–5, WHO) after fluoropyrimidine administration. We also searched for the canonical IVS14+1G>A single nucelotide permutation (SNP), which is associated with severe DPD deficiency. Results: More than 70% of the patients with severe toxicity and 80% of those with fatal outcome displayed U/UH2 ratios out of the range previously defined with a separate reference, non-toxic population thus strongly suggesting a correlation. In contrast, IVS14+1G>A SNP was not found to be a reliable marker for predicting toxicities. Conclusions: Taken together, our data indicate U/UH2 ratio appears to be frequently implicated in the occurrence of iatrogenic events with fluoropyrimidine therapy. In addition, our simple and rapid HPLC method may meet the requirements of routine screening, allowing identification of patients who might be at risk of severe toxicity during fluoropyrimidine administration, at relatively low cost. The predictive value of our test is being investigated in a prospective study with pharmacokinetic support. No significant financial relationships to disclose.
Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors
Authors: Jones S. F. , Plummer E. R. , Burris H. A. , Razak A. R. , Meluch A. A. , Bowen C. J. , Williams D. H. , Hodge J. P. , Dar M. M. , Calvert A. H. 
Published: March 2020

2027 Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity. [Table: see text]
Population pharmacokinetics of trabectedin (ET-743) in subjects with cancer
Authors: Perez Ruixo J. J. , Zannikos P. , Hirankarn S. , Stuyckens K. , Liolios K. , Soto-Matos A. , Lopez-Lazaro L. , Pico C. , Yver A. , Owen J. 
Published: March 2020

2030 Background: Trabectedin (T) is a DNA minor-groove intercalating agent. The objective of this study is to characterize the population pharmacokinetics of T in cancer subjects. Methods: A total of 603 subjects (945 cycles) receiving intravenous T as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as 1, 3 or 24 hrs infusion every 21 days; 3 hrs infusion on day 1, 8, 15 every 28 days; or 1 hr infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and non-linear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe a total of 4251 concentrations from 274 subjects (Index Dataset) using NONMEM V. The effect of selected covariates on T pharmacokinetics was investigated. Model was evaluated using goodness of fit plots and relative error measurements for 2362 concentrations from 329 subjects (Test Dataset). Computer simulations were undertaken to evaluate the covariate effects on T pharmacokinetics. Results: Mean (SD) of T terminal half-life was ≈180 (61.4) h. Plasma accumulation was limited when T was given every three weeks. Systemic clearance, 31.5 L/h (CV = 51%), was 19.2% higher in subjects receiving concomitant dexamethasone. Typical values of volume of distribution at steady-state for males and females were 6070 L and 5240 L, respectively. Age, body size variables, AST, ALT, LDH, creatinine clearance, albumin, total protein and presence of liver metastases were not related to T pharmacokinetics. No difference in model parameters was observed for the infusion durations evaluated. T AUC and Cmax were dose proportional for each schedule evaluated and consistent across cancer types. Conclusions: The integration of phase I/II pharmacokinetic data demonstrated T linear elimination, dose-proportionality up to 1800 μg/m2, and time-independent pharmacokinetics. Given the moderate to large interindividual variability in T pharmacokinetics, the clinical relevance of dexamethasone and gender covariates is probably limited since a substantial overlap in simulated concentration-time profiles was observed. [Table: see text]
Phase I study of the effects of hepatic impairment on the pharmacokinetic (PK) and safety of satraplatin in patients with refractory non-hematologic cancer
Authors: Setlik R. F. , Preston G. , Jones C. B. , Sarantopoulos J. , Dufresne T. , Petrone M. E. , Nathan F. E. , Greene D. , Anthony T. , Takemoto C. 
Published: March 2020

2045 Background: Satraplatin (S) is a third-generation oral platinum analog that has demonstrated activity in the treatment of patients with platinum-sensitive malignancies. A worldwide double-blind, placebo controlled randomized phase III trial evaluating S as 2nd line therapy for HRPC has recently completed enrollment. The current study was designed to determine the effect of hepatic impairment on S pharmacokinetics in patients with refractory cancer, as well as treatment efficacy and toxicity. Methods: S was administered orally at a dose of 80mg/m2/day (d) on d1–5 every 35 days. Study groups (cohorts) were defined at 4 levels of hepatic impairment - Group 1 (G1) = control; G2 = Child-Pugh Class A; G3 = Child-Pugh Class B; and Group 4 = Child-Pugh Class C. Results: 19 pts have been enrolled to date (11 M/ 8 F); median age is 57 (range 44–80). Pts with prostate (2), pancreas (4), colorectal (3), adenocystic (2), and 1 each neuroendocrine, hepatocellular, melanoma, breast, ovarian, SCLC, and anal cancers were enrolled. 8 pts were in G1, 3 pts in G2, 4 pts in G3, and 5 pts in G4. Accrual is ongoing in this study with a total of 8 pts planned for each group. The median number of prior regimens was 5 (range 2–8). A total of 35 cycles of S have been given: median 2/pt (range 1–4). 9 pts have completed 2 cycles of S. Hematologic toxicities during the first 2 cycles included grade (G) 3/4 thrombocytopenia in 15 %. There were no cases of G 3/4 neutropenia or anemia. One case of G3 hypokalemia, was reported. Two patients developed acute renal failure; one of which was due to uncontrolled nausea (N) and vomiting (V) and the other was associated with rapid disease progression in the liver. Both were G4 patients. Otherwise, N, V, and diarrhea were mild to moderate, and controlled with oral therapy. Conclusions: S is, in general, well tolerated in patients with mild or moderate liver impairment. Severe thrombocytopenia is the most common side-effect. Of the patients enrolled to date 15% did not have progression of disease. PK data will also be presented. [Table: see text]