bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early placenta insuline-like peptide (pro-EPIL): A novel biomarker in advanced and metastatic non-small cell lung cancer (NSCLC) patients treated by chemotherapy
Authors: Ayllon J. , Oudard S. , Banu E. , Janneau J. L. , Helley D. , Richon S. , Banu A. , Levy E. , Medioni J. , Bellet D. 
Published: March 2020

20069 Background: Some studies suggest a causal relationship between the early placenta insuline-like peptide encoded by the insulin-like 4 gene and cancer invasiveness. Methods: Serum concentrations of pro-EPIL were measured by ELISA using a novel two-site “sandwitch” assay, based on two monoclonal antibodies (mAb) raised against synthetic peptides analogous to two distinct regions of the pro-Epil polypeptide: mAb EPIL15, and biotinylated mAb EPIL02, used as the labelled indicator. The first mAb EPIL15 was purified and bound to a solid phase. Pro-EPIL was allowed to bind, and unbound proteins were removed by washing. The sensitivity limit of the assay was 3 ng/mL of synthetic peptide, and detection was linear over a range of at 3 pg to 200 ng of the synthetic peptide. As primary endpoint, we studied the Pro-EPIL distribution according to some clinico-biological prognostic factors. Results: Between July 2001 and April 2005, nineteen chemonaive NSCLC pts were treated by chemotherapy in our center and serum determinations of pro-EPIL were performed. Ten pts (63%) overexpressed pro-EPIL before start of chemotherapy with a median value of 1.06 ng/mL (range 0.01–6.75). Median age was 60 years (range 38–80), more than 90% of pts were men with an advanced or metastatic disease. Forty-two percent of pts had a large cell carcinoma subtype, with 25% of adenocarcinoma and 25% of epidermoid type. Immunologic evaluations were performed with a median value of the CD3+ lymphocites of 1290/mm3 (range 610–2138). Significant correlations were observed between age, serum alcaline phosphatase and CD3+ number. A border-line positive correlation was observed between pro-EPIL and CD3+ levels (P = 0.09, R2 = 0.5). Median OS for entire cohort was 7.5 months (95% CI, 5.5–9.4), with 67% deaths. Because our sample size was very low, no survival analysis were performed according to the baseline pro-EPIL value and other prognostic factors. A bootstrapping procedure is planned on our data. Conclusions: This results showed that pro-EPIL was overexpressed in the majority of advanced NSCLC pts. Interactions between this biomarker and immune system are possible. Furthemore, pro-EPIL as a therapeutic target might be tested in prospective studies. No significant financial relationships to disclose.
Clinical and biologic relevance of interferon (IFN) regulated proteins in esophageal squamous cell carcinoma
Authors: Guimaraes D. P. , Oliveira I. M. , Paiva G. R. , Souza D. M. , Marques C. B. , Olmedo D. B. , Pinto C. E. , Hainaut P. , Small I. , Ferreira C. G. 
Published: March 2020

20077 Background: The prognosis for SCCE is poor, with less than 10 percent of patients surviving beyond five years. The ability to identify specific markers associated with biological behavior may provide information about the likelihood of both localized and locally advanced disease. The Interferon regulatory factor 1 (IRF-1) act as a tumor suppressor protein by affecting cell cycle progression and/or apoptosis. The Guanylate binding protein-2 (GBP-2) is an interferon regulated protein whose induction requires the IRF-1 activation. Methods: We analyzed the IRF-1 and GBP-2 expression by IHC in 42 patients (pts) with surgically ressected SCCE. A detailed pathologic examination was conducted by selecting single histologic section, which contained a clear transition zone from normal epithelium to invasive cancer. Staining was semiquantitatively scored by two observers based on both intensity and percentage of stained cells. Clinical data information was obtained from medical records. Results: The median age was 58 (39–75); Male/female 61.9/38.1%; Of 39 pts, 53,8% had localized disease (I/IIA) and 46,2% had locally advanced disease (IIB/III). Nineteen pts received standardized radiochemotherapy before surgery. The IRF-1 and GBP-2 were expressed in 100% and 75% of tumors, respectively. Normal epithelium was stained for both IRF-1 and GBP-2 with distinct expression patterns. There was a significant correlation between scores for GBP-2 and IRF-1 tumor staining (p = 0.23). Interestingly, the score for GBP-2 tumor staining was inversely correlated to clinical stage (p = 0.001), tumor invasion of the esophageal wall (T) (p = 0.26), involvement of lymph nodes (N) (p = 0.035) and tumor extension (p = 0.007). There was no correlation between the score of IRF-1 staining and the clinical-morphological parameters. Conclusions: We reported for the first time the expression of GBP-2 protein in esophageal cancer. Our results suggest that GBP-2 expression is related to less aggressive behavior of SCCE. Further studies are required to clarify biological GBP-2 protein function, and possible prognostic implications. No significant financial relationships to disclose.
MBD4 and SEI1 as new prognostic markers in colorectal cancer patients receiving adjuvant 5-fluorouracil
Authors: Ju J. , Formentini A. , Nakajima G. , Kornmann M. , Xi Y. 
Published: March 2020

20085 Background: Previous studies from our laboratory have identified a number of marker genes associated with chemosensitivity to 5-fluorouracil (5-FU). In this study, the in vivo significance of several marker genes in terms of prognostic potential were evaluated using colorectal cancer patient samples treated with 5-FU based therapy. Eight marker genes were selected based on their functional roles and significant fold changes in expression. They are SERTA domain containing 1(SEI1), Ribonucleotide reductase M2 polypeptide (RRM2), Origin recognition complex, subunit 6 homolog-like (ORC6L), Eukaryotic translation initiation factor 4E (EIF4E), Thymidylate Synthase (TS), SET and MYND domain containing 3 (SMYD3), Dickkopf homolog 4 (DKK4) and Methyl-CpG binding domain protein 4 (MBD4). Methods: Forty eight snap frozen clinical colorectal samples (24 normal and 24 paired colorectal cancer patient samples) were selected with detailed clinical follow-up information. cDNAs were synthesized and the expression levels of marker genes were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using two tailed paired T-test. Kaplan-Meier survival curve was generated and analyzed by Logrank test. Results: Based on the quantitative expression analysis, RRM2 (p = 0.0001, 95% CI, 2.0 to 4.5), ORC6L (p = 0.0001, 95% CI, 1.8 to 4.6), EIF4E (p = 0.0002, 95% CI, 0.3 to 0.9), TS (p = 0.0005, 95% CI, 0.7 to 2.2) and SMYD3 (p = 0.0001, 95% CI, 0.8 to 1.5) was over-expressed in tumor tissues. However, the expression of SEI1 was decreased in tumors (p = 0.02, 95% CI, 0.1 to 1.3), consistent with the function of SEI1 as a potential tumor suppressor. Kaplan-Meier survival analysis indicated that MBD4 is a significant prognostic factor for patient’s survival (p = 0.03). MBD4 was a key protein involved in DNA methylation. The expression of TS was associated with tumor stage as it had significant higher expression level in UICC stage I and II compared to stage IV patients (p = 0.03). Conclusion: MBD4 may be potential novel prognostic markers for predicting patient survival for colorectal cancer. No significant financial relationships to disclose.
registHER: Baseline characteristics of a cohort of HER2-positive metastatic breast cancer (MBC) patients
Authors: Kaufman P. , Mayer M. , Paik S. , Ulcickas Yood M. , Yardley D. , Tan-Chiu E. , Brufsky A. M. , Rugo H. , Tripathy D. , Wang L. 
Published: March 2020

20095 Background: HER2 is amplified in 25% of breast cancers and is associated with poor survival. registHER captures the natural history, treatment patterns and outcomes in 1000 newly-diagnosed HER2-positive MBC patients (pts) throughout the U.S. This observational study recruits pts in both academic and community centers. Methods: This ongoing prospective cohort study collects clinical, pathologic and treatment data at enrollment, quarterly until death, loss to follow-up or 3 years after the last enrollment. We describe baseline pt and clinical characteristics in registHER compared with HER2-positive MBC pts in the phase III pivotal trial (Slamon DJ, et al. N Engl J Med. 2001;344:783–792). Results: Between December 2003 and September 2005, 813 eligible pts were enrolled at 280 study sites. Most pts were seen at community-based (76%) vs academic (18%) clinics; a few pts did not fall into either category (6%). A comparison of baseline characteristics is shown below. Conclusions: registHER pts tended to have a shorter disease-free interval and more estrogen receptor positive disease than pts in the pivotal trial. Reasons for these differences could reflect trial referral and/or diagnostic testing differences. Fewer registHER patients were white, but other characteristics were similar between the two groups. These findings support the hypothesis that observational studies describe a broad patient population which may not exactly duplicate clinical trials. Within registHER, there was some variation between academic vs community clinics (eg. nodal status and adjuvant therapy). Treatment pattern analyses are ongoing. [Table: see text] [Table: see text]
EGFR expresion in liver metastases in patients with colorectal cancer EGFR negative primary tumour and response to systemic chemotherapy
Authors: Petrovic Z. , Tarabar D. , Doder R. 
Published: March 2020

20104 Background: To evaluate expresion of EGFR in liver metastases in patients with colorectal carcinoma EGFR immunohistochemistry (IHC) negative primary tumor and to evaluate response to systemic chemotherapy in this group of patients. Methods: A group of 19 patients with IHC negative EGFR in primary tumor with synchronous liver metastasis were analysed. All patients received irinotecan and/or oxaliplatin based chemotherapy regimen in combination with oral fluoropyrimidines - capecitabine. Results: 10 pts. had EGFR IHC positive expresion in liver metastases. EGFR IHC negative liver metastases were present in 9 pts. In patients with EGFR IHC negative liver metastases 2 pts. had PR, 1 pts. had SD and 6 pts. had PD after chemotherapy. In patients with EGFR IHC positive liver metastases 3 pts. had PR, 2 pts. had SD and 5 pts. had PD after chemotherapy. All pts. with PR were underwent to surgery and/or RFA. Pts. with SD and PD received cetuximab with previous systemic chemotherapy. PFS in this group of pts. is 4,1 month. Conclusions: This study is ongoing. At this moment the results do not support routine determination of EGFR status on distant metastatic sites in patients with colorectal carcinoma and for response to chemotherapy. No significant financial relationships to disclose.
Radiosensitive effect of gemcitabine on nasopharyngeal carcinoma CNE-1 cell line
Authors: Chen Y. , Yu X. 
Published: March 2020

20105 Background: To observe the effect and mechanism of gemcitabine-induced radiosensitization on CNE-1 nasopharyngeal carcinoma cell line. Methods: The cell survival curves were obtained with clonogenic assay. The cell cycle phases were measured with flow cytometric analysis. Results: No cytotoxic effect was observed in 0.1 μM and 2 μM gemcitabine alone group. The radiosensitivities were observed in the groups treated with radiation and gemcitabine exposed in different consistencies and times. The SER were 1.35,1.82; 1.55 and 2.16 respectively. The G1 cell cycle phase block was observed in the two consistency groups after exposing to gemcitabine for 24 hours. Dq were rather lower in 2 μM groups especially that exposed for 24 hours. Conclusions: The radiosensitivity was obviously observed in the groups treated with two consistencies of gemcitabine. The effect was more obviously as the consistency and the exposing time increased. The block of cell cycle from G1 to S and the decrease of sublethal damage repair might be contributed to the mechanism. No significant financial relationships to disclose.
BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families
Authors: Piras G. , Fancello P. , Monne M. , Santona M. , Landriscina G. , Gabbas A. 
Published: March 2020

20118 Background: Germline alterations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1/2 mutations, identification of mutation carriers is clinically rilevant in view of the options for surveillance and prevention. The general aim of the present research is to contribute to the molecular epidemiology of BRCA1/2 genes in the italian region of Sardinia as a prerequisite for a prevention program based on DNA analysis. Methods: Fifty-two of 172 patients diagnosed with primary invasive breast carcinomas (n = 150) or ovarian cancer (n = 18) and 4 male with breast cancer referring to our departments between 2003 and 2005, had a positive family history for breast and/or ovarian cancer and were selected for BRCA1/2 mutation screening by denaturing high-performance liquid chromatography and DNA sequencing. Onehundred DNAs from healthy women originating from the same geographical area were used as population controls. Results: We identified 7 BRCA sequence alterations: 3 were already described polymorphisms while 4 novel BRCA variants were found in 11 out of 52 (21%) probands. The BRCA23951del3insAT is a novel deleterious mutation which leads to protein truncation at codon 1258 and co-occurred with the missense BRCA2S2546P in 6 probands originating from the same village and in none of the controls. Segregation analysis suggested the cis-position of the two mutations. All mutation carriers shared a common disease-associated BRCA2 haplotype indicating the presence of a founder effect. The BRCA2N272I was first observed in our population and was found in 3 unrelated probands and in none of 200 control chromosomes. The missense BRCA1E1352K mutation was present in 3 patients from two unrelated families with breast and ovarian cancer cases in three generations. Conclusions: In the present study, BRCA2 are more recurrent than BRCA1 mutations as reported for the northern part of the island. Our findings provide new epidemiological data that may be useful in defining the prevalence, mutational spectrum and penetrance of BRCA1/2 in the genetically homogeneous population of Sardinia. A comprehensive map of the BRCA mutations may facilitate screening/testing for inherited risk of breast cancer. No significant financial relationships to disclose.
Different prediction of distant recurrence risk in primary breast cancer patients stratified by ER and ERBB2 status
Authors: Urban P. , Vuaroqueaux V. , Labuhn M. , Delorenzi M. , Wirapati P. , Dieterich H. , Ehret S. , Fürstenberger G. , Morant R. , Eppenberger U. , Eppenberger-Castori S. 
Published: March 2020

20120 Background: Molecular profiling recently defined biological characteristics of several long-recognized breast cancer subtypes including ER-positive (luminal subtype), ER-negative/ERBB2-positive (ERBB2 subtype) and ER-negative/ErBB2-negative (basal-like subtype). Each of these particular subtypes has different impact on patient outcome and should be therefore taken in consideration for individual scoring calculations. Methods: The quantitative RNA expression levels of 70 relevant genes were simultaneously determined in fresh frozen samples of 317 primary breast cancer (BC) patients comprehending ER-positive (70%), ER-negative/ERBB2-positive (15%) and ERBB2-negative/ER-negative (15%) and with known follow-up data. Five years distant recurrence scoring systems were calculated by means of Cox-hazard regression models. Results: Two main prognostic scoring systems were developed: one based on genes relative to proliferation representing tumor growth and its velocity, the other based on proteases. A low proliferation score identified 30% of patients at very good prognosis (probability of distant recurrence 12%, CI: 1.5–22%) all belonging to the ER-positive subcategory as compared to cases with higher proliferation (probability of distant recurrence 31%, 32–38%). The probability to develop distant recurrence within 5 years for 30% of ERBB2-positive patients was of only 12% (CI 0–25%) when accompanied by low levels of proteases as compared to the remaining ERBB2-positive patients with a probability of recurrence of 40% (CI 22–54%). Conclusions: ER, ERBB2 and the expression levels of the few identified genes involved in tumor proliferation and invasion can be easily and precisely detected by means of QRT-PCR. This robust method allows fine tuned prognosis and gives predictive information for the treatment of individual breast cancer. [Table: see text]
Pharmacokinetics of PT523, a novel aminopterin analogue, in patients with solid tumors
Authors: Supko J. G. , He X. , Sao N. , D’Amato F. , Blaszkowsky L. , Clark J. R. , Shapiro G. I. , Bhargava P. , Appleman L. J. , Eder J. P. 
Published: March 2020

2052 Background: Nα-(4-Amino-4-deoxypteroyl)-N5-hemiphthaloyl)-L-ornithine (PT523) is a nonpolyglutamatable aminopterin analogue selected for clinical evaluation based upon properties that confer potential therapeutic advantages over classic and nonclassic antifolates. This report describes the pharmacokinetic (PK) behavior of PT523 in cancer patients as determined in the first phase I trial of the drug. Methods: Adult patients with refractory solid tumors received PT523 as a 5 min iv infusion every 7 days for 3 weeks. Plasma samples were obtained at -5, 4, 10, 15, 20, 30, 45 min; 1, 2, 3, 4, 6, 8, 24, and 48 h after starting the first weekly infusion. Urine was collected and pooled from 0–8, 8–24, and 24–48 h. An LC/MS assay was used to measure PT523 in plasma and urine. Interday accuracy and precision were both <15% at the lowest concentrations measured in plasma (0.50 ng/mL) and urine (50 ng/mL). PK parameters were estimated by standard noncompartmental methods. Results: The PK of PT523 was characterized in 24 patients with normal renal and hepatic function, and a median age of 52 years (range, 28 - 77 years). Data was obtained from groups of at least three patients receiving doses of 5, 6.7, 9, 12, and 16 mg/m2. The PT523 concentration in plasma decreased in a polyexponential manner and the terminal log-linear phase was achieved 4–6 h after dosing. In the 7 patients receiving doses of 16 mg/m2, the mean peak drug concentration in plasma (Cmax) was 5,650 ± 300 ng/mL and the median plasma concentration 48 h after dosing was 1.7 ng/mL (range, 1.0 - 23.4 ng/mL). The apparent biological half-life (t1/2,z), total body clearance (CL) and apparent volume of distribution at steady-state (Vss) were all independent of the dose. Mean ± SD values of PK parameters for the entire cohort of 24 patients were: CL, 1.16 ± 0.31 L/h/m2; t1/2,z, 5.3 ± 1.2 h; Vss, 7.7 ± 1.5 L/m2. The mean amount of the dose excreted as unchanged drug in urine over 48 h was 40 ± 15%. Conclusions: PT523 exhibits linear PK with moderate interpatient variability when administered as a 5 min iv infusion at doses of 5 - 16 mg/m2. Renal clearance is a major route of elimination. Association between the CL of PT523 and creatinine clearance should be evaluated in a future study to assess whether dose modification is warranted for patients with diminished renal function. No significant financial relationships to disclose.
Continuous intravenous infusion (CIVI) topotecan may be safely combined with tipifarnib
Authors: Hills D. , Liebes L. , Muggia F. , Wright J. , Pavlick A. , Buckley M. , Fry D. , Farrell K. , Hochster H. 
Published: March 2020

2064 Background: Dose limiting (DL) myelosuppression occurred when topotecan 1.0 mg/m2/d × 5d was combined with tipifarnib (Proc ASCO, 2001, abst 321). We now report on a 3+3 cohort design to determine the safety and pharmacokinetics (PK) of this combination with topotecan given as CIVI in patients (pts) with refractory solid tumors. Methods: Pts were treated with escalating dose levels of topotecan (0.2–0.4 mg/m2/d) given as 21-day infusion in combination with tipifarnib 200 mg PO bid for 21 d every 28 d. Blood was drawn for topotecan PK and intracellular (PBMC) toposisomerase I on d 1 (baseline) and d 5 (tipifarnib omitted d1, cycle 1), and weekly × 8 for ras-farnesylation (membrane bound fraction). Plasma levels of the closed form of topotecan were determined by SPE and HPLC with fluorometric detection. Topoisomerase I in PBMCs was detected by Western blot. Results: 14 patients were accrued at 3 dose levels: topotecan 0.2 mg/m2/d (3 pts), 0.3 mg/m2/d (3), and 0.4 mg/m2/d (8), combined with tipifarnib. Median age was 50 years (33–62). 32 cycles (median 2) were given. Grade 1–3 fatigue, nausea, thrombocytopenia, neutropenia and anemia were common, and at dose level 3, two heavily-pretreated patients had DL myelosuppression. Six others had no significant toxicity over prolonged times. Of nine evaluable for response, a mucinous peritoneal cancer had a minor response for 5 m, an ovarian granulosa cell tumor had a mixed response in lung metastases for 15 m, and a PNET of bone had a minor response for 17 m; six had progression. Mean steady state (± SD) levels of topotecan for dose levels I, II and III were, respectively, 0.48 ± 08 (N = 3), 1.26 ± 0.32 (N = 3) and 1.47 ± 0.1 (N = 5) ng/ml, and were linear with respect to topotecan dose (r = 0.95). By the end of the 21 d infusion, 90% of baseline topoisomerase I signal was depleted in PBMCs. Conclusions: In contrast with bolus topotecan, CIVI topotecan may be combined at known effective doses with tipifarnib. Recommended phase II doses are 0.4 mg/m2/d × 21 days and 200 mg bid daily for those with limited prior therapy. Phase II studies in gynecologic and breast tumors are planned. Supported by UO1- 76642; CA 16087. [Table: see text]
HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: Results of a phase 1 and PK study
Authors: Chow L. Q. , Eckhardt S. G. , Gustafson D. L. , O’Bryant C. , Hariharan S. , Diab S. , Fox N. L. , Corey A. , Padavic K. , Brown M. , Cohen R. B. 
Published: March 2020

2515 Background: HGS-ETR1 (mapatumumab) is a fully-human monoclonal antibody agonistic to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1, DR4). Activation of TRAIL-R1 by HGS-ETR1 initiates a caspase cascade leading to apoptosis. HGS-ETR1 in combination with platinum or taxanes results in at least additive activity in preclinical models. Phase 1 and 2 trials have demonstrated that single agent HGS-ETR1 is well tolerated. Methods: This Phase 1 study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of HGS-ETR1 in combination with standard doses of paclitaxel and carboplatin. Patients received 3, 10 or 20 mg/kg HGS-ETR1 with paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 21 days for up to 6 cycles in the absence of disease progression. Results: Enrollment is complete; 28 patients have received 106 cycles of HGS-ETR1, including 12 patients in each of the 10 mg/kg and 20 mg/kg cohorts. Fourteen of 28 pts received at least 3 cycles (median = 2.5, range 1–12). Dose-limiting toxicity has been neutropenic fever (attributed to chemotherapy) and hypersensitivity (attributed to HGS-ETR1). Other non-dose limiting adverse events at least possibly related to HGS-ETR1 include fatigue, myalgia, transaminitis, anorexia and arthralgia. Preliminary analyses reveal that carboplatin and paclitaxel PK are not affected by HGS-ETR1. Similarly, the PK profile of HGS-ETR1 is not affected by paclitaxel and carboplatin, with plasma HGS-ETR1 concentrations consistent with those observed in the Phase 1 single agent trials. Three patients with NSCLC and 1 with adenocarcinoma of an unknown primary have experienced a confirmed partial response. Conclusions: HGS-ETR1 can be safely administered with carboplatin and paclitaxel. Evaluation of HGS-ETR1 in combination with other chemotherapeutic regimens is warranted. [Table: see text]