المؤلفون: D'Incecco, A, Andreozzi, M., Ludovini, V., Rossi, E., Capodanno, A., Landi, L., Tibaldi, C., Minuti, G., Salvini, J., Coppi, E., Chella, A., Filice, M. E., Tornillo, L., Incensati, R. M., Sani, S., Crinò, L., Terracciano, L., Cappuzzo, F., FONTANINI, GABRIELLA

المساهمون: D'Incecco, A, Andreozzi, M., Ludovini, V., Rossi, E., Capodanno, A., Landi, L., Tibaldi, C., Minuti, G., Salvini, J., Coppi, E., Chella, A., Fontanini, Gabriella, Filice, M. E., Tornillo, L., Incensati, R. M., Sani, S., Crinò, L., Terracciano, L., Cappuzzo, F.

مصطلحات موضوعية: non-small-cell lung cancer, PD-1, PD-L1, tyrosine kinase inhibitor, Adult, Aged, 80 and over, Antigens, CD274, Carcinoma, Non-Small-Cell Lung, Cohort Studie, Female, Human, Immunohistochemistry, Lung Neoplasm, Male, Middle Aged, Programmed Cell Death 1 Receptor, Retrospective Studie, Cancer Research, Oncology, Medicine (all)

الوصف: BACKGROUND: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. METHODS: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. RESULTS: PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01). CONCLUSIONS: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/25349974; info:eu-repo/semantics/altIdentifier/wos/WOS:000348280900015; volume:112; issue:1; firstpage:95; lastpage:102; numberofpages:8; journal:BRITISH JOURNAL OF CANCER; http://hdl.handle.net/11568/759619Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84920655625; http://www.nature.com/bjc/index.htmlTest

الإتاحة: https://doi.org/10.1038/bjc.2014.555Test
http://hdl.handle.net/11568/759619Test
http://www.nature.com/bjc/index.htmlTest

المؤلفون: PETRINI, IACOPO, Meltzer, P. S., Zucali, P. A., Luo, J., Lee, C., Santoro, A., Lee, H. S., Killian, K. J., Wang, Y., Tsokos, M., Roncalli, M., Steinberg, S. M., Giaccone, G.

المساهمون: Petrini, Iacopo, Meltzer, P. S., Zucali, P. A., Luo, J., Lee, C., Santoro, A., Lee, H. S., Killian, K. J., Wang, Y., Tsokos, M., Roncalli, M., Steinberg, S. M., Giaccone, G.

مصطلحات موضوعية: BCL2 anti-apoptotic family member, CDKN2A, comparative genomic hybridization, target therapy, thymic epithelial tumor, Adult, Aged, 80 and over, Algorithm, Aniline Compound, Animal, Apoptosis Regulatory Protein, Autophagy, Benzenesulfonate, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variation, Female, Human, Male, Mice, Nude, Middle Aged, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Glandular and Epithelial, Niacinamide

الوصف: The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/22825469; info:eu-repo/semantics/altIdentifier/wos/WOS:000306786400014; volume:3; issue:7; firstpage:e351; journal:CELL DEATH & DISEASE; http://hdl.handle.net/11568/757337Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84864882707

الإتاحة: https://doi.org/10.1038/cddis.2012.92Test
http://hdl.handle.net/11568/757337Test

المؤلفون: Zucali, Paolo A., Lorenzi, Elena, Merino, Maria, Cao, Liang, Di Tommaso, Luca, Lee, Hye Seung, Incarbone, Matteo, Walter, Beatriz A., Simonelli, Matteo, Roncalli, Massimo, Santoro, Armando, Giaccone, Giuseppe, PETRINI, IACOPO

المساهمون: Zucali, Paolo A., Petrini, Iacopo, Lorenzi, Elena, Merino, Maria, Cao, Liang, Di Tommaso, Luca, Lee, Hye Seung, Incarbone, Matteo, Walter, Beatriz A., Simonelli, Matteo, Roncalli, Massimo, Santoro, Armando, Giaccone, Giuseppe

مصطلحات موضوعية: Expression, Immunohistochemistry, Insulin-like growth factor-1 receptor, Prognosi, Thymoma, Adult, Aged, 80 and over, Female, Human, Male, Middle Aged, Oncogene Protein v-akt, Phosphorylation, Receptor, IGF Type 1, Serine, Thymus Neoplasm, Treatment Outcome, Cancer Research, Oncology

الوصف: BACKGROUND: Thymic malignancies are rare tumors. The insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) system is involved in the development of the thymus. IGF-1R expression in thymic epithelial malignancies is unknown. METHODS: The authors investigated the expression of IGF-1R and phosphorylated AKT serine 473 (p-AKT) by using immunohistochemistry and examined the clinicopathologic correlations in a retrospective, single-institution surgical series of 132 patients with thymic epithelial malignancies. RESULTS: Earlier disease stage, less aggressive histologic types, and complete resection were significant positive prognostic factors for disease-related survival and progression-free survival, and being a woman was a better prognostic factor for disease-related survival. IGF-1R and p-AKT protein levels were expressed in 20% and 36% of thymic tumors, respectively. Both markers were expressed more commonly in recurrent disease than in primary tumors, in more aggressive subtypes, and in more advanced disease stages. There was a trend toward better survival and progression-free survival in patients who were negative for IGF-1R or p-AKT expression in the whole series. When only the 91 primary tumors, IGF1R expression was associated with worse progression-free survival (P < .001). CONCLUSIONS: The current retrospective analysis demonstrated that disease stage, tumor histology, sex, and resection type were major prognostic factors in the survival of patients with thymic malignancies. The expression levels of IGF-1R and p-AKT in thymic tumors suggested that IGF-1R is a potential target for treatment.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/20597130; info:eu-repo/semantics/altIdentifier/wos/WOS:000282910800008; volume:116; issue:20; firstpage:4686; lastpage:4695; numberofpages:10; journal:CANCER; http://hdl.handle.net/11568/757344Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-77957569631

الإتاحة: https://doi.org/10.1002/cncr.25367Test
http://hdl.handle.net/11568/757344Test

المؤلفون: E. Giovannetti, M. Del Tacca, V. Mey, N. Funel, S. Nannizzi, S. Ricci, C. Orlandini, BOGGI, UGO, CAMPANI, DANIELA, M. Del Chiaro, M. Iannopollo, BEVILACQUA, GENEROSO, F. Mosca, DANESI, ROMANO

المساهمون: E., Giovannetti, M., Del Tacca, V., Mey, N., Funel, S., Nannizzi, S., Ricci, C., Orlandini, Boggi, Ugo, Campani, Daniela, M., Del Chiaro, M., Iannopollo, Bevilacqua, Generoso, F., Mosca, Danesi, Romano

مصطلحات موضوعية: 5'-Nucleotidase, biosynthesis/genetics, Adult, Aged, 80 and over, Cell Line, Tumor, Cytidine Deaminase, Deoxycytidine Kinase, Deoxycytidine, analogs /&/ derivatives/therapeutic use, Equilibrative Nucleoside Transporter 1, Female, Gene Expression, Humans, Male, Middle Aged, Pancreatic Neoplasm, drug therapy/genetics/metabolism, Predictive Value of Tests, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleoside Diphosphate Reductase, Transcriptional Activation, Treatment Outcome, Tumor Suppressor Protein

الوصف: Gene expression analysis may help the management of cancer patients, allowing the selection of subjects responding to treatment. The aim of this study was the characterization of expression pattern of genes involved in gemcitabine activity in pancreas tumor specimens and its correlation with treatment outcome. The role of drug transport and metabolism on gemcitabine cytotoxicity was examined with specific inhibitors, whereas transcription analysis of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) was done by quantitative reverse transcription-PCR in tumor tissue isolated by laser microdissection from surgical or biopsy samples of 102 patients. Association between clinical outcome and gene expression levels was estimated using Kaplan-Meier method and Cox's proportional hazards model. Transport and metabolism had a key role on gemcitabine sensitivity in vitro; moreover, hENT1, dCK, 5'-NT, CDA, RRM1, and RRM2 were detectable in most tumor specimens. hENT1 expression was significantly correlated with clinical outcome. Patients with high levels of hENT1 had a significantly longer overall survival [median, 25.7; 95\% confidence interval (95\% CI), 17.6-33.7 months in the higher expression tertile versus median, 8.5; 95\% CI, 7.0-9.9 months in the lower expression tertile]. Similar results were obtained with disease-free survival and time to disease progression, and the multivariate analysis confirmed the prognostic significance of hENT1. This study suggests that the expression levels of hENT1 may allow the stratification of patients based on their likelihood of survival, thus offering a potential new tool for treatment optimization.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/16585222; info:eu-repo/semantics/altIdentifier/wos/WOS:000236657800075; volume:66; issue:7; firstpage:3928; lastpage:3935; numberofpages:7; journal:CANCER RESEARCH; http://hdl.handle.net/11568/237206Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-33645731188; http://dx.doi.org/10.1158/0008-5472.CAN-05-4203Test

الإتاحة: https://doi.org/10.1158/0008-5472.CAN-05-4203Test
http://hdl.handle.net/11568/237206Test