bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actions of a novel therapeutic formulation: Zn, Se and Mn plus Lachesis Muta venom (O-LM) on radiation deleterious immune effects
Authors: Rivera E. , Cremaschi G. , Genaro A. M. , Croci M. , Sambuco L. , Cricco G. , Martin G. , Bergoc R. , Crescenti E. 
Published: March 2020

14116 Background: We have previously reported that O-LM inhibits malignant cell proliferation and increases survival in rodent tumor models (Int J Cancer S13:183, 2002). Molecular and immunological basis of O-LM action were reported (J Clin Oncol 24:18S, 2006). As O- LM selectively protects normal tissues from high doses of ionizing radiation (Proc Int Cancer Congress,1495–9, 1998), we here investigated O- LM protective action upon radiation effects on immune cells. Methods: Balb/c mice (n=15 each group) were employed: control (C); 2Gy whole body irradiated (IR); treated with O-LM (Zn, Se, Mn 4μg/ml each; L. Muta 4 ng/ml; 0.1 ml/day, sc) for 15 days and 2Gy irradiated (O-LM+IR). Mice were sacrificed at day 3, 7 or 15 post-irradiation (PI). Proliferation was evaluated in lymphocytes by [3H]- Thymidine incorporation after T- or B selective mitogen stimulation. In cell-free supernatants (SN) from mitogen-stimulated cultures cytokines involved in lymphocyte regulation and/or inflammation were determined by ELISA. Results: Irradiation induced a decrease in T lymphocyte proliferation at 3 and 7 days PI (% of decrease in IR: 47.6±9.0, p<0.05; 42.0±7.2, p<0.02 respectively). Pretreatment with O-LM recovered proliferation to basal values (day 3 PI 93.4±10.2%; day 7 PI 130.9±15.3%, O-LM+IR vs. C; p=NS). No modifications were observed in B cells. At day 3 PI, a marked decrease in IFN? levels was obtained in SN of IR mice that was reverted by O-LM treatment (pg/ml: IR 1653±419; C 10884±2783, p<0.02; O-LM+IR 16924±4284, p<0.05 vs C). Also, at day 7 PI, an important increase in TNFa was observed in IR mice, that were reverted by O-LM (pg/ml: IR: 300.7±62.3 vs O-LM+IR: 28.7±2.3, p<0.02). No differences were found in IL-2 levels. Conclusions: The therapeutic action of O-LM is based on its ability of targeting simultaneously multiple pathways involved in cancer development. Present data demonstrate that O-LM protects animals from irradiation by recovering the immune function, improving T lymphocyte activity and modulating the production of key cytokines as IFN? and TNFa. The reported effect may represent a potential benefit for cancer patients undergoing radiotherapy. No significant financial relationships to disclose.
Effect of celecoxib, a specific cyclooxygenase 2 inhibitor, on the apoptotic and mitotic indexes of breast cancer in patients with early stage disease
Authors: Tfayli A. H. , Cherry M. , Yang J. , Kojouri K. , Jafari M. , Thor A. , Ozer H. 
Published: March 2020

14132 Background: To assess whether the administration of celecoxib, a specific cyclooxegenease-2 (COX-2) inhibitor, to patients with breast cancer alters the proliferative and apoptotic indexes of their tumors. Methods: Women newly diagnosed with non metastatic breast cancer were enrolled into the study after undergoing a diagnostic core needle biopsy. Patients received celecoxib treatment at 400 mg orally twice a day for 14 days, and then underwent surgical excision of their tumor. Core biopsies obtained at the time of initial diagnostic procedure and surgical excision specimens were stained for Ki-67, as well as COX-2 and cleaved poly (ADP-ribose) polymerase (PARP) expression (as an apoptosis marker). Appropriate negative and positive controls were included. We assessed the difference in Ki- 67, COX-2 and cleaved PARP expression levels, before and after treatment using the Wilcoxon’s matched-pair ranks test and the McNemar’s test. Results: 16 patients were enrolled. The median age was 54.6 years. ER and/or PR expression was present in 81% of tumors; Her-2 neu overexpression was present in 25%. No significant change in COX-2 or cleaved PARP expression was noticed in the post intervention specimen compared to the core biopsies. Surprisingly, there was a significant increase in the Ki-67 expression (p < 0.009). Conclusions: we have conducted a short term prospective study to assess the effects of celecoxib, on the proliferative and apoptotic indexes in patients with early stage breast cancer. We have found an increase in the Ki-67 activity, with no significant down regulation of COX-2 or increase in cleaved PARP expression with 14 days of therapy. This could be partly due to the small sample size. [Table: see text]
A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors
Authors: Holkova B. , Kummar S. , Glauber P. , Chen A. , Strong J. M. , Parker R. J. , Collins J. , Murgo A. J. , Doroshow J. H. , Gutierrez M. E. 
Published: March 2020

14137 Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m2/hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (Css) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that < 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO Css appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text] No significant financial relationships to disclose.
Growth suppression of human pancreatic cells by a novel PKCβ inhibitor, enzastaurin
Authors: Cheng H. , Yan J. G. , Jiang Y. 
Published: March 2020

14141 Background: Human pancreatic cancer is a devastating disease. Standard therapy, gemcitabine, is not able to alter the natural history of the disease. Targeting intracellular signaling molecules has proven to be a powerful approach in cancer therapy. Protein kinase C (PKC) family has been implicated in many human cancers including pancreatic cancer. Methods: In this pre-clinical study, we evaluated the effect of a novel small molecule inhibitor, enzastaurin, for PKCβ on human pancreatic cancer cells. We utilized MTT assay to assess cell proliferation and viability. To evaluate cell transforming activity, soft agar colony forming assay was used. Results: We showed that with addition of 20μM enzastaurin into the culture, the proliferative growth of two pancreatic cancer cell lines, Panc1 and L3.6p1, was significantly attenuated, as measured by the MTT assay. In addition, the combination of enzastaurin and a low dose of gemcitabine (25 nM) resulted in a synergistic cytotoxic effect in L3.6p1 cells. Further, the in vitro tumorogenicity assay demonstrated that the L3.6p1 cells treated with enzastaurin (20μM) formed much smaller colonies than the control parental cells in 0.4% soft-agar. Consistent with the in vitro cell proliferation results, the combination of enzastaurin and the low concentration of gemcitabine (25nM) further reduced the numbers and sizes of colonies in the soft-agar. Conclusions: Collectively, our data indicate that enzastaurin can effectively suppress the proliferation and in vitro transforming activity of the pancreatic cells, and more effectively when applied in combination with the low dose of gemcitabine. No significant financial relationships to disclose.
The Biomarkers Consortium: A public-private partnership of the Foundation for NIH
Authors: Lee D. , Altar T. 
Published: March 2020

14142 Background: In October 2006, the Foundation for the National Institutes of Health (FNIH) announced the launch of a major public-private biomedical research partnership, The Biomarkers Consortium, to search for and validate new biological markers-biomarkers- to accelerate dramatically the delivery of successful new technologies, medicines, and therapies for prevention, early detection, diagnosis, and treatment of disease. The Foundation for NIH is managing The Biomarkers Consortium under direction of the consortium executive committee, with guidance from leading scientists within and outside the member organizations, plus input from a public representative and private industry and non-profit funding partners. FNIH, CMS, FDA, NIH, and the pharmaceutical, biotechnology, diagnostics, and medical device industries recognize the critical need for a coordinated cross-sector partnership effort to more rapidly identify and qualify biomarkers to support basic and translational research, guide clinical practice and, ultimately, support the development of safe and effective medicines and treatments for a wide range of diseases. The Biomarkers Consortium will harmonize approaches to identifying viable biomarkers, verifying their individual value, and formalizing their use in research and regulatory approval. Information and results from consortium projects will be used broadly by researchers to promote the appropriate use of biomarkers to improve the public health worldwide. Methods: N/A Results: Promising project concepts that have been approved in principle for further development by The Biomarkers Consortium include the Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Lung Cancer and Non-Hodgkin’s Lymphoma Projects and projects in metabolic disorders and neuroscience. Steering Committees in cancer, metabolic disorders, and neuroscience have been created to evaluate and develop project concepts approved for further development. Conclusions: The Biomarkers Consortium is an important avenue to facilitate the search and validation of a variety of biomarkers projects. No significant financial relationships to disclose.
Induction of gemcitabine (GCB)-related genes by pemetrexed (MTA): Assessment of the best time interval between MTA and GCB administration
Authors: De Pas T. M. , Danesi R. , Toffalorio F. , Milani A. , Giovannetti E. , Mey V. , Nannizzi S. , Pelosi G. , Manzotti M. , de Braud F. 
Published: March 2020

14145 Background: Both MTA and GCB are active drugs in non-small cell lung cancer (NSCLC). Many molecular events induced by MTA support the synergic interaction between the two drugs and explain why the sequence MTA ? GCB is more active than GCB ? MTA. Of major interest, MTA induces the expression of deoxycytidine kinase (dCK), the rate-limiting enzyme of GCB activation, and of the human equilibrative nucleoside transporter-1 (hENT1), the key transporter for the intracellular penetration of GCB. Even if the optimal sequence is well established, no information on the best administration time between the two drugs is available. Methods: To evaluate if there is a reproducible timing of maximum dCK and hENT1 expression by MTA, we measured these targets in patients with advanced NSCLC after administration of MTA 500 mg/m2 q2wks. All patients were not pre-treated with MTA or GCB. Gene-expression was measured in normal lymphocytes by quantitative real-time PCR (qRT-PCR), at various interval (up to 48 hrs) at each of the first 3 chemotherapy cycles. Results: Between September and December 2006, 8 out of the 19 planned patients were enrolled in the present study. At the time of this analysis, dosages from 63 samples / 9 cycles of chemotherapy are available. In all treatment cycles, qRT-PCR analysis revealed an increase of hENT1 and/or dCK genes at least in one time-point. With respect to gene expression levels at basal time, dCK increased both early (+1h: 3 out of 9 valuable cycles; + 4–6 hrs: 4 out of 9 cycles) and late (+ 24–48 hrs: 5 out of 9 cycles); hENT1 increased poorly at +1h (1 out of 6 valuable cycles) but consistently at + 4–6 hrs (5 out of 6 cycles) and late (+24–48 hrs: 6 out of 6 cycles). The increase of dCK and hENT1 gene expression was from + 15% to 285% and from 21% to + 380%, respectively. Conclusions: MTA induces GCB- related genes both at early and late time points with an inter-patients variability. The most rationale time interval between the two drugs administration will be valuated at the completion of the study. No significant financial relationships to disclose.
Preliminary phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Beslija S. , Banjin M. , Jungic S. , Obralic N. , Kecman-Malcic G. , Rakita I. , Salkic B. , Pasic A. , Tinjic L. , Ajanovic E. 
Published: March 2020

14502 Background: The oral fluoropyrimidine X (Xeloda®) has improved efficacy, safety and convenience compared with 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A (Avastin®) targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) results in significant improvements in survival among pts with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175 mg/m2 i.v. d1, X 1000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x12 cycles in the absence of disease progression or unacceptable toxicity. Pts without progressive disease after 12 cycles of XIA continued on the same dose of A + X 1500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate (RECIST), overall survival (OS), safety, and quality of life. Results: 24 out of a planned total of 32 pts have been enrolled. Baseline characteristics are: M/F 50%/50%; median age 53 years (range 30–70); disease stage at initial diagnosis IIIA/IIIB/IV 29%/21%/50%; no. of metastatic sites 1/>1 50%/50%; most common metastatic site liver; prior adjuvant therapy 33% (Mayo 5-FU/LV). Pts received a median of 12 cycles (range 1–18) of XIA. All 24 pts are evaluable for safety and 22 for efficacy. The overall response rate is 77% (4 CR, 13 PR); 2 pts (9%) have stable disease and 3 have progressed. One pt has died. Median PFS and median OS have not yet been reached. The only grade 3 adverse events are diarrhea (13%), fatigue (4%), mucositis (4%), enteritis (4%), ileus (4%); there is one report of grade 4 leucopenia. All other adverse events are mild-to-moderate. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC, providing support for further evaluation of this combination. No significant financial relationships to disclose.
UGT1As polymorphisms predict toxicity in colorectal cancer patients treated with different recommended doses of irinotecan oriented by UGT1A1*28 polymorphism based on previous phase I study
Authors: Hazama S. , Koudo H. , Yoshida S. , Shimizu R. , Ozasa H. , Yamamoto T. , Araki A. , Yoshino S. , Okayama N. , Hinoda Y. , Oka M. 
Published: March 2020

14511 Background: We have presented at 2006 ASCO annual meeting about a genetic UGT1A1 polymorphism oriented phase (P) I study of Irinotecan and 5’-DFUR for metastatic colorectal cancer (MCRC) to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 *1/*1 and *1/*28 genotypes. The RD of biweekly Irinotecan administration was 150 mg/m2 for patients (pts) with wild *1/*1 genotype and 70 mg/m2 of Irinotecan for mutated *1/*28. Now we are carrying out a *28 oriented P II study based on this RD. Here we report the profiles of toxicities in the P II study of irinotecan and 5’-DFUR to analyze other kinds of UGT1As polymorphisms in relation to irinotecan toxicities. Patients & Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–1, age<76, adequate organ functions, and written informed consent. Twenty one pts with wild type genotype and 9 pts with mutated genotype were enrolled. Irinotecan was infused 150 mg/m2 for pts with *1/*1 genotype and 70 mg/m2 for *1/*28. Hematological and non-hematological toxicities were graded, and UGT1As polymorphisms (UGT1A1*6 and *7, UGT1A7*1*2*3*4, UGT1A9*22) were analyzed. Results: Grade (G)3 & 4 toxicities were observed in 6 of 22 (27%) wild type pts and in 3 of 9 (33%) mutated pts, and in 9 of 31 (29%) all pts. There was no significant difference on the profiles of toxicities between the pts with wild genotype and mutated genotype, irrespective of the difference of the quantity of irinotecan. So, the RD was thought to be adequate. In pts with UGT1A1*6 allele, G3 & 4 toxicities were observed 6/11 (55%), on the other hand 3/20 (15%) in pts without *6 allele (p=0.038). G3 & 4 toxicities were also more frequent in pts with UGT1A7*3 alleles than pts without *3 allele (p<0.10). Conclusions: The profiles of toxicities of pts with *1/*1 or *1/*28 genotypes were similar irrespective of the difference of the quantity of irinotecan. The result indicated that the RD of latest PI for each group was adequate, and this P II study is suitable to analyze other kinds of polymorphisms that have correlation to irinotecan toxicities. UGT1A1*6 and UGT1A7*3 allele will be a novel predictor for toxicity of irinotecan. No significant financial relationships to disclose.
Prognostic markers in stage II/III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiotherapy
Authors: Pinto C. , Di Fabio F. , Longobardi C. , Ceccarelli C. , Cuicchi D. , Iacopino B. , Ugolini G. , Minni F. , Cola B. , Martoni A. A. 
Published: March 2020

14514 Background: The aim of this study was to evaluate the prognostic value of histologic tumor regression grade (TRG) and pathological biomarkers after neoadjuvant chemoradiotherapy (CT/RT) in rectal cancer pts. Methods: Pts entering the study had rectal adenocarcinoma and stage uT3-T4 N-/+ with location <12 cm from the anal margin. CT consisted of 5-fluorouracil (5FU) 225 mg/m2/die continuous infusion IV d1–38 with/without oxaliplatin (OXA) 60 mg/m2 weekly infusion IV for 6 times. RT was delivered up to a dose of 50.4 Gy in daily fractions of 1.8 Gy. Rectal surgery with TME was performed 6–8 weeks after neoadjuvant therapy. Eight courses of adjuvant CT (LV5FU2) were given after surgery. Immunohistochemical determination of Ki67, p53, bcl2, TS, EGFR, MLH1, MSH2 was performed in pre-treatment biopsy and operative specimen; TRG (Dworak) response (0=none, 1=low, 2–3= intermediate, 4=complete) and circumferential resection margin (CRM) were evaluated on surgical specimens. Results: Between March 2002 and December 2006, 56 pts had completed the integrated treatment. Pt characteristics were: 39M/17F; stage uT3N- 32(57.1%), uT3N+ 15(26.8%), uT3Nx 4(7.1%), uT4N+ 4(7.1%), uT4Nx 1(1.8%). CT was 5FU in 15(26.8%) pts, 5FU/OXA in 41(73.2%) pts. Pathological downstaging was achieved in 31(55.4%) pts, including 9(16.1%) pCR. After a median follow-up of 28.5(6–58) months, 7(12.5%) pts had disease recurrence. TRG evaluation was: no TRG0, 9(16.1%) TRG1, 21(37.5%) TRG2, 17(30.4%) TRG3, 9(16.1%) TRG4. CRM was negative in 91% of pts. By means of univariate analysis, TRG was found to be significantly correlated with DFS (estimated median DFS was 23 months in TRG1 pts, not achieved in TRG2–4 pts; p<0.0001). Other factors correlating significantly with a better DFS by univariate analysis included ypT0–2 (p=0.013) and pN- (p=0.002) categories, CRM- (p=0.024) and lower Ki67 expression post-CT/RT (p=0.012). Using multivariate analysis, we found that TRG2–4 was the strongest DFS prognostic factor (HR=0.0312; 95% CI: 0.003–0.40, p=0.008). Conclusions: In this analysis complete (TRG4) and intermediate (TRG2+3) pathological response produced improved DFS. Significant favorable prognostic factors were the ypT0–2/pN- categories, CRM- status and lower Ki67 expression after CT/RT. No significant financial relationships to disclose.
Prognostic significance of pathological biomarkers in patients with stage II-III colorectal cancer
Authors: Funaioli C. , Pinto C. , Ceccarelli C. , Di Fabio F. , Cuicchi D. , Rojas Llimpe F. L. , Lombardi R. , Longobardi C. , Bottazzi M. , Martoni A. A. 
Published: March 2020

14518 Background: Biopathological colorectal cancer (CRC) studies have provided information on pathogenesis, but it is unclear how important biomarkers actually are in predicting prognosis. The aim of our study was to define the prognostic significance of biomarkers and a biopathological profile that could predict an increase in the disease relapse risk in stage II-III CRC patients (pts). Methods: The primary tumor of the CRC pts treated with surgery was immunohistochemically evaluated on the Ki67, p53, bcl-2, TS, EGFR, MLH1 and MSH2 expressions. All 7 markers were measured using standard immunohistochemical techniques. The biomarker evaluations were scored by just one pathologist. Results: Between March 2001 and October 2006 the primary tumor of 242 consecutive pts was investigated. Pt characteristics were: males 141(58.3%), females 101(41.7%); median age 68.5 (24–88); primary tumor site: right colon 94(38.8%), left colon 148(61.2%); stage II 102(42.1%), stage III 81(33.5%), stage IV 59(24.4%). 5-fluorouracil based adjuvant chemotherapy was performed in 121 (66.1%) pts. After a median follow up of 30 months (1–80), 34 pts (10 pts stage II, 24 pts stage III) of 183 stage II-III pts (18.6%) had a disease recurrence. In a univariate analysis of stage II-III pts, a higher expression of Ki67 (= 50% positive cells) was significantly associated with an improved DFS (p= 0.014) and overall survival (OS) (p=0.010). Expression of p53, bcl-2, TS, EGFR, MLH1 and MSH2 were not significantly associated with DFS and OS. In a multivariate analysis adjusted for the impact of the disease stage and adjuvant chemotherapy, a higher expression of Ki67 was significantly associated with diminished risk of recurrence (HR: 0.395; 95% CI: 0.183–0.855, p=0.018) and death (HR: 0.179; 95% CI: 0.046–0.696, p=0.013). The evaluation of DNA mismatch repair status (MLH1, MSH2) demonstrated that the lack of MLH1 is more frequent in non-relapsed II-III stage pts than in IV stage pts (p= 0.024). Conclusions: This analysis showed a significant correlation between higher Ki67 expression and better DFS and OS in pts with stage II-III CRC. An higher frequency of MLH1 deficiency was observed in non-relapsed pts with stage II-III than in advanced disease. No significant financial relationships to disclose.