bluuebunny/crossref_metadata_2025_split huggingface dataset:
CXCR4 is involved in multiple functions of cancer cells and is a compelling target for monoclonal antibody-based therapeutics
Authors: Boynton A. L. 
Published: March 2020

20013 Background: CXCR4 is over-expressed on > 75% of cancers and absent on most non-neoplastic cells. It is a G protein coupled receptor spanning the cell membrane with CXCL-12 as its ligand. It is uniquely involved in 3 vital aspects of cancer: 1) proliferation; 2) motility; and 3) metastasis. Our objective was to assess specific Abs as candidates for clinical development in preclinical models. Methods: Several human cancer cell lines were used to study whether either mAbs specific to the CXCR4 receptor or to CXCL12 could inhibit: 1) proliferation; 2) chemotaxis; and 3) invasion through a reconstituted basement membrane. The ability of anti-CXCR4 Ab to inhibit tumor growth in vivo was also tested. Female Nod/Scid mice were injected IP with 2 × 105 human Namalwa tumor cells with 10 mice per group. Mice were injected with: Group 1) 100μg irrelevant IgG2b isotype control Ab; Group 2) 100μg CX02 anti-CXCR4 Ab; and Group 3) 100 μg CX05 anti-CXCR4 Ab. All mice in each group received an injection of Ab at day 2, 8, 14 and 20. Mice were observed for tumor growth over the following 4–5 months. Results: We originally found that CXCR4 was over expressed in fresh surgical human Glioblastoma, then showing that it was also over expressed in multiple cancer types. Specific anti-CXCR4 monoclonal Abs, CX02 and CX05 as well as anti-CXCL12 Abs demonstrated the ability to block cell proliferation of a variety of human Glioblastoma tumor cells including GB1690, HTB16, and 5GB, but not the proliferation of cells that do not express CXCR4. CX02 and CX05 Abs bind to live tumor cells with high affinity and have an EC50 of 3.2 and 2.7 μg/ml respectively (effective concentration required to provide 50% maximal median fluorescence shift). Both Abs (10 μg/ml) also inhibited by over 90% the motility of HS Sultan cells as demonstrated by the standard chemotaxis assays. In addition, both Abs (10–40 μg/ml) also inhibited the ability of HS Sultan cells to penetrate Matrigel, a reconstituted basement membrane assay used to assess malignant potential of cancer cells. Finally, both Abs were successful in extensively prolonging survival of Nod/Scid mice injected with human Namalwa cells. Conclusions: CXCR4 represents a compelling target for mAb therapy; Phase I clinical trails are pending. [Table: see text]
Imatinib mesylate inhibits the growth of breast cancer cells mediated by PDGF-receptor-β and Akt inactivation
Authors: Mundhenke C. , Weigel M. , Meinhold-Heerlein I. , Schem C. , Bauerschlag D. O. , Jonat W. , Maass N. 
Published: March 2020

20040 Background: The prognosis of patients with progressed breast cancer remains poor after intensive chemotherapy. Therefore new treatment options such as targeted therapies are needed. Imatinib Mesylate is a tyrosin kinase inhibitor targeting growth receptors like PDGF-R α and β, c-kit. These receptors and their downstream effectors trigger a cascade that regulates multiple cellular processes such as proliferation, differentiation and survival. The activity of the important downstream effector Akt leads to cell survival through inhibition of pro-apoptotic signals. We therefore evaluated the effects of Imatinib on of PDGFR β and Akt activity in breast cancer cell lines in vitro. We previously detected that Imatinib inhibits the growth of the breast cancer cell lines MDA MB 231, MCF 7, ZR 75–1 and T 47-D in vitro. Furthermore Imatinib induces apoptosis in these cell lines. Methods: To investigate effects on receptor activation, cells were stimulated with PDGF BB, the physiological ligand of PDGFR β. Phosphorylation of PDGFR β and Akt was examined after incubation with increasing concentrations of Imatinib by immunohistochemical and western blot assays. Imatinib concentrations from 2 μM to 10 μM were applied. Results: Imatinib Mesylate shows a dose dependent inhibitory effect on PDGFR β phosphorylation, determined by immunohistochemistry and western blot analysis. No changes in the expression pattern occured. The phosphorylation of the tyrosine kinase Akt can also be inhibited by Imatinib in a dose dependent manner. The expression of Akt remains also unchanged. Conclusions: It can be suggested that the growth inhibitory effect of Imatinib Mesylate on breast cancer cell lines is caused by a dose dependent decrease of activation in PDGFR β and Akt. The inhibition of Akt phosphorylation by Imatinib explains the induction of apoptosis. These interesting effects should be further validated in vivo in clinical trials. [Table: see text]
Molecular identification, expression and prognostic role of estrogen alpha, beta and progesteron receptors in head and neck cancer
Authors: Timar professor J. , Lukits J. , Rásó E. , Kásler M. , Remenár É. 
Published: March 2020

20056 Background: Previous data suggested hormone receptor protein expressions in head and neck cancer (HNC), but the molecular identification of the receptors was lacking and the prognostic significance was unclear. Methods: Sixty seven freshly frozen surgical samples of HNC patients were used throughout the study. Sex hormone receptor protein expression (ERa, Erb and PgR) of tumor cells was determined by immunocytochemistry. In case of positive reaction, data have been confirmed at mRNA level by nested-PCR and sequencing. Prognostic significance of the hormone receptor expression was determined by statistical analysis of the 4 year survival of the patients. Results: ER and PgR expressions confirmed by PCR analysis were frequent in HNC: 50.7 and 49.3%, respectively. Concerning the ER isoforms, ERa was predominant (41.8%) over ERb (28.4%) in both of oral as well as glottic cancers. The incidence of functional receptor expression (coexpression of ER and PgR) was relatively frequent in HNC: 41.8% which was independent of the anatomical location of the tumor. A minimum of 3 year follow up data were available for 51 HNC patients. Sex hormone receptor expressions did not affect survival, however, in the glottic cancer subgroup (n = 36) the ER expression was associated with a shortened 4 survival (23.1 versus 65.0%, respectively). Conclusions: ERa,b and PgR expression is frequent in HNC and may affect the prognosis of the disease at least in case of glottic cancer. On the other hand, the frequent coexpression of ER isoforms with PgR in HNC raises the possibility of clinical application of selective estrogen receptor modulators in this cancer type.This work is supported by the grant NKFP1a-0024–05. No significant financial relationships to disclose.
Cancer risk of aged people with HIV infection and of transplant people
Authors: Serraino D. , Piselli P. , Busnach G. , Citterio F. , Fratino L. , Tirelli U. , Burra P. , Arbustini E. , Pradier C. , Giovanni R. , Carrieri P. 
Published: March 2020

20063 Background: Acquired immunesuppression due to HIV-infection or to anti-rejection therapies following organ transplantation is a well known risk factor for cancer. This increased risk has been well documented for young adults, whereas few data are available on older persons. In this study, we assessed the impact of cancer in HIV-positive persons (HIV+) and in transplant persons (TRP) who were 50 years of age or older. Methods: Data from a multi-cohort study conducted in Italy and France were analysed. Individuals ≥50 years of age were selected from the original study group constituted by 2002 HIV+ seroconverters from Italy, 6072 HIV+ from France and 2755 Italian TRP (1844 kidney, 702 heart, 159 liver and 50 lung TRP). Sex- and age-standardized incidence ratios (SIR) and 95% confidence intervals (CI) were computed to quantify the cancer risk as compared to the general population. Among HIV+, the risk of cancer was also assessed according to treatment with highly active antiretroviral therapies (HAART). Results: This analysis was based on 94 cancers diagnosed in 833 HIV+, and on 154 cancers diagnosed in 1558 TRP ≥50 years of age. The SIRs for all cancers decreased with ageing, ranging from 5.1 (95% CI: 4.0–6.5) in HIV+ aged 50–59 to 2.1 (95% CI: 1.4–3.1) in HIV+ aged 60 or older. In TRP, the SIRs for all cancer were 2.5 (95% CI:2.0–3.1) and 1.6 (95% CI: 1.2–2.0), respectively. In HIV+, the protective effect of HAART was more evident in those aged 50–59 (SIR = 6.8 in never treated and SIR = 2.4 in ever treated) than in HIV+ aged ≥60 (SIR = 2.8 and SIR = 1.6, respectively). This pattern of cancer occurrence was peculiar to virus-related cancers (e.g., Kaposi’s sarcoma, non-Hodgkin’s lymphoma, liver cancer). SIRs for lung cancer in both groups were significantly increased but did not significantly differ according to HAART and/or age. The survival of both HIV+ and TRP was significantly reduced by the diagnosis of cancer, but the difference in survival was not associated with ageing (p = 0.20). Conclusions: Aged individuals with acquired immunesuppression have a cancer pattern similar to younger persons with immunosuppression, but the burden of cancer will increase in absolute terms because of the increasing proportion of older individuals among both HIV+ and TRP. No significant financial relationships to disclose.
Gene expression analytics identify tissue of origin of unspecified metastatic cancers
Authors: Rigl T. , Buturovic L. , Pattin A. , Tran Q. , Nguyen L. 
Published: March 2020

20082 Background: Identification of the tissue of origin for unspecified metastatic cancers is associated with improved outcomes. To aid in determining the origin of these cancers, we designed a semi-quantitative test that uses proprietary analytics and a companion genomic microarray to compare the expression signature of a biopsy specimen with those of the following types of cancers: bladder, breast, colorectal, gastroesophageal, germ line, hepatocellular, kidney, lung, lymphoma, melanoma, ovarian, pancreatic, prostate, soft tissue-sarcoma, and thyroid. More than 5,500 human specimens processed on Affymetrix HG U133A microarrays were analyzed to determine the test’s standardization algorithm. Methods: Studies across nine different laboratories were conducted to demonstrate the reproducibility required to support the potential clinical application of the test. Biopsy specimens of 604 metastatic cancers of known origin (by conventional pathological testing) were used to “train” the algorithm. An additional 636 samples then were tested. Diagnostic odds ratio (OR), sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR−) were determined for individual all-against-one tests. Results: Robust standardization, which involves 121 “house-keeping genes”, enabled the tissue of origin test to demonstrate reproducibility across nine different laboratories. Identification of the correct tissue of origin was associated with OR values ranging from 23 to >500, with averages for sensitivity of 83%, specificity of 99%, LR+ of 210, and LR− of 0.17. Conclusions: The PathWork Oncology Suite: Tissue of Origin (POS:TOO) test uses methods that are reproducible across laboratories. By analyzing microarray data with the POS:TOO algorithm, the test can identify the origin of metastatic tumors. Preparations for clinical validation studies are in progress and results will be submitted to FDA for clearance. [Table: see text]
The clinicopathological and socioeconomic features of patients with gastric cancer in Turkey (Turkish Oncology Group)
Authors: Yalcin B. , Aydin F. , Zengin N. , Ilhan M. , Isikdogan A. , Aykan F. , Demir G. , Celik I. , Turhal S. , Icli F. , Akbulut H. 
Published: March 2020

20098 Background: The incidence of gastric cancer has declined dramatically in western countries. However it is the second most common cancer in Turkey, and its mortality rate is still high. The aim of this study was to evaluate the clinicopathological and socioeconomic features of patients with gastric cancer in Turkey. Methods: A questionnaire including the clinicopathological and socioeconomic features of gastric cancer patients diagnosed in 2004, was used in this retrospective multicentre study. The characteristic of patients in economically developed Western Turkey (WT) was compared to those in less developed Eastern Turkey (ET). Results: From sixteen centers, 971 patients with gastric cancer during the year 2004 were included in the study. Male-female ratio was 2/1. Mean age was 57 ± 12.9 years. Of patients, 75.3% had low socioeconomic status. Distal and middle gastric cancers were the most common locations (distal 39%, middle 36.5% vs upper 24.5%). The R0 resectability rate was 54.1% in all patients. There was no statistically significant difference in gender, age, smoking rate, anemia, the location of tumor and the frequency of atrophic gastritis between WT and ET. The rate of cancer resectability was lower in Eastern Turkey (ET) than Western Turkey (WT) (31.6% vs. 63.4%, p = 0.0001). Also, socioeconomic status of patients was lower in ET than those in WT (53.6% vs. 32.3%, p = 0.0001). H. pylori associated gastritis and intestinal metaplasia were more common in ET when compared with WT (75.0% vs. 40.5%, P = 0.003, and 68.4% vs. 18.1%, respectively, P = 0.0001). Conclusions: Lower socioeconomic status and lower resectability rate of gastric cancer in ET is considerable. Further epidemiological study of gastric cancer is warranted in Turkey. No significant financial relationships to disclose.
Promising targets in renal cell cancer: Met and ron-beta
Authors: Lambea J. J. , Alvarez I. , Lastra R. , Ortega M. , Aguirre E. , Ruiz-Echarri M. , Millastre E. , Mayordomo J. I. , Escudero P. , Storkus W. , Tres A. 
Published: March 2020

20119 Background: The activation of Tyrosin Kinase Receptors (RTKs) produces several effects about cellular response. These are membrane receptors that bind differentiation signals, grow factors and cellular mediators. The interaction with their ligand causes the phosphorilation and internalization in the endosome. By a metabolic way, these receptors are degradated into the proteasome to small peptides that are expressed over the cellular surface joined to MHC class I mollecules, getting a better immunogenic recognition of the tumor cells. It is known that the bigger expression of the tyrosin kinase receptors in tumors is associated with an aggressive phenotype. For example overexpression of ephA2 or EGFR. Our study is based in the demostration of the overexpression of other receptors in renal cell cancer, a tumour with a disappointing response with treatment in advanced stages. On this way we can use them as targets for monoclonal antibodies and for citotoxic lymphocites CD8 stimulated that will join to peptides presented in MHC class I after the proteasomic degradation. Methods: We use Western-Blot for identifying the overexpressed RTKs in relation to normal tissue and as a reference the expression of beta-actin, that is present in every cells. The cells are from 5 murine renal cell cancer lines, (thanks to Hillman Cancer Center Institute, University of Pittsburgh. Pennsylvania. USA). The control is a murine cell line that is very similar to normal renal tissue (HK). We calculate the ratio of expression compared with the expression of normal tissue with an statistical analysis. Results: HER-2, VEGFR-2, Met, Ron-beta are overexpresed in renal cell cancer in a murine model, as EGFR (epidermic growing factor receptor). Conclusions: Met may be excellent therapeutic and inmunologic target and in selected cases of renal cell cancer. It’s known that EGFR and VEGFR are also good targets. Future research about these targets will get new options of combined immunotherapy (vaccines and monoclonal antibodies). No significant financial relationships to disclose.
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced cancers
Authors: Beeram M. , Saif W. M. , Sarantopoulos J. , Schwartz G. , Patnaik A. , Tolcher A. W. , Mehdi F. , Feit K. , Takimoto C. H. 
Published: March 2020

2016 Background: DJ-927, an oral microtubule stabilizer, has impressive cytotoxic activity in taxane-resistant tumors and an acceptable toxicity profile. C and Taxane combinations are active in solid tumors such as breast cancer. Non-overlapping mechanism of action and toxicity profiles and the convenience of an orally administered therapy have prompted a phase I evaluation of the combination. D was given orally once on day 1 and C for 14-days (D1–14), every three weeks. Methods: Eligible pts had evaluable cancer, minimal prior therapy and PS 0 - 2 ECOG. D was started at 18 mg/m2 on day 1 along with 1,250 mg/m2 of C orally B.I.D for 14 days, of a 21-day cycle. Incremental doses of both drugs were explored until the maximum tolerated dose (MTD) was reached. PK samples were collected during cycles 1 and 2, for assays of C and for D when given concurrently with C during cycle 1 and D given alone during cycle 2. Results: Twenty-seven pts [18 Male/ 9 Female; median age (range)- 58 yrs (33–70); PS 0 (n=8) ; PS 1 (n=19)] received 81 cycles [median (range)- 3 (1–8)] in 5 cohorts, with D and C 18/ 1250 mg/m2 (n = 3), 27/ 1250 mg/m2 (n = 7), 27/ 1900 mg/m2 (n = 7), 35/ 1900 mg/m2 (n = 3),and 27/ 2500 mg/m2 (n = 7). Dose-limiting toxicity (DLT) was grade 4 neutropenia in 2 of 3 pts at 35/ 1900 mg/m2 dose. Other common drug-related toxicities were leukopenia, nausea & vomiting (12 pts each, 44.4%), neutropenia, diarrhea and hand-foot syndrome (11 pts each, 40.7%), and fatigue (7 pts, 25.9%). A pt with hepatocellular carcinoma had an unconfirmed partial response at cycle 2 and 10 pts experienced disease stabilization lasting ≥ 12 weeks. The median elimination half-life (t½) of D was 182 hrs for cycle 1 (with C) and 204 hrs for cycle 2 (without C). Median tmax values for D with and without C occurred at 2 hours. Median clearance values (CL/F) for D in plasma were similar with and without C at 18.4 L/h/m2 and 19.8 L/h/m2, respectively. Conclusions: The combination of D and C is feasible and safe at the MTD of 27 mg/m2 and 2500 mg/m2, respectively. Co-administering C with D did not alter the PK of either drug. Preliminary evidence of antitumor activity suggests that further studies of this combination are warranted. [Table: see text]
Hand-foot syndrome (HFS) in patients receiving capecitabine: A pharmacological explanation
Authors: Ferrero J. M. , Lassalle S. , Mari M. , Formento J. L. , Francoual M. , Lacour J. P. , Etienne-Grimaldi M. C. , Hofman P. , Milano G. 
Published: March 2020

2019 Background: Use of the oral fluoropyrimidine capecitabine, which generates 5FU in tumor tissues, is currently expanding. HFS is frequently associated with administration of capecitabine. However, the underlying pharmacological mechanism of HFS is still not elucidated. In a previous experimental study, we ruled out a possible implication of 5FU catabolites (FUH2 and FBAL) in the etiology of HFS (Anti-Cancer Drugs 15: 969, 2004). The aim of this study was to investigate expression levels of thymidine phosphorylase (TP, the main activating enzyme of capecitabine) and dihydropyrimidine dehydrogenase (DPD, the rate-limiting enzyme of 5FU catabolism) in skin samples from the palm area of the hand (target zone) and from the back (control zone). Methods: Paired-skin biopsies have been planned in 12 healthy volunteers, in agreement with the local ethical committee. Expressions of TP, DPD, and Ki67 (cell proliferation marker) were analyzed by a two-step immunohistochemical method using specific monoclonal antibodies (from Calbiochem for TP, Roche for DPD and Dako for Ki67) and immunoperoxydase revelation (kit ABC Vectastain). Results: Data from the first four subjects indicate no significant difference in the strong Ki67 staining between control and target zones. TP was markedly expressed in the basal layer of the epidermis (BLE), with similar staining in control and target zones. Interestingly, in 3 cases out of 4, DPD was strongly expressed (2+, 3+) in the BLE of the control zone and much less (0, 1+) in the paired-target zone. Definitive data on 12 subjects will be presented. Conclusions: This preliminary original observation suggests that capecitabine may be locally activated in the skin due to high TP expression. The relative absence of DPD expression in the palm area may explain the specificity of HFS, which may result from a lack of local 5FU catabolism. These new data open the way to a possible pharmacological approach to limit HFS. No significant financial relationships to disclose.
Prognostic and predictive significance of 5-fluorouracil metabolic enzymes in colorectal cancer
Authors: Soong R. C. , Shah N. , Salto-Tellez M. , Han H. C. , Ng S. S. , Zeps N. , Joseph D. , Diasio R. B. , Iacopetta B. J. 
Published: March 2020

2021 Background: Low levels of the 5-Fluorouracil (5-FU) metabolic enzymes, thymidylate synthase (TS), dihydropyrimdine dehydrogenase (DPD) and thymidine phosphorylase (TP) are linked to improved survival in colorectal cancer (CRC) patients receiving 5-FU chemotherapy. However, whether they are prognostic (related to tumor biology) or predictive (drug sensitivity) indicators is not clarified. This study aimed to (1) discriminate the prognostic and predictive significance of TS, DPD and TP and (2) ascertain the clinical and molecular subtype associations of the proteins in a large sample series. Methods: Tissue arrays containing sections from 956 stage 2/3 CRC cases were stained immunohistochemically for TS, DPD and TP. Associations with clinical and molecular characteristics and survival according to treatment status were assessed by Kruskall-Wallis and Kaplan-Meier analysis. Results: Low TS levels were associated with late stage, proximal tumor location and absence of microsatellite instability, low DPD with younger age and late stage and low TP with proximal tumor location. Low levels of all three enzymes associated with absence of tumor infiltrating lymphocytes. There were no associations with gender, grade or ras and p53 mutation. In stage 2 patients treated by surgery alone, those with low DPD levels had a worse survival than those with high levels (p<0.01). Stage 3 patients treated with chemotherapy had a better survival than those without in subgroups of patients with low TS (p=0.05), DPD (p<0.01) and TP (p=0.03) but not high levels of the proteins. Conclusions: Our results suggest the improved outcome of 5FU-treated patients with low tumor TS, DPD and TP levels may be due primarily to a benefit from adjuvant treatment rather than a favorable prognosis. TS, DPD and TP levels may be useful indicators for identifying CRC patients likely to benefit from 5-FU treatment. No significant financial relationships to disclose.