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  • American Association for Cancer Research (AACR)  (73)
  • 1
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    Abstract 6120: The effect of chronic stress in T-cell population and function in ovarian cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6120-6120
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6120-6120
    Abstract: Ovarian cancer (OC) is the deadliest form of gynecological malignancies highlighted by a five-year survival rate of less than 49%. Late diagnosis and chemoresistance represent the main hurdle in the effort to improve OC patient outcomes. Currently, immunotherapy is studied as an alternative to front-line therapy, but its use in the clinic remains limited due to its modest impact on patient outcomes. It is well known that the neuroendocrine system can modulate immune cell behavior. This study aims to determine how behavioral factors, such as chronic stress and an associated increase in stress hormone levels, impact T-cell infiltration and function in ovarian cancer. As T-cells play a central role in cancer recognition and killing, we hypothesize that stress hormones could decrease the efficacy of checkpoint blockade by inducing changes in T-cell populations and contribute to T-cell exhaustion (determined by the expression of PD-1, TIM-3, FOXP3, and CTLA-4). We obtained tumor samples from C57/BL6 ID8 tumor-bearing mice subjected to daily restraint stress to dissect the interaction between the neuroendocrine system and tumor-associated T-cells. Unstressed mice were used as controls. Tumors from both groups were collected and preserved with paraffin for histological assessments. Immunohistochemistry analyses were used to evaluate the presence of CD4+ and CD8+ T-cells. To measure specific CD4+ T-cell subtype, regulatory T-cells (T-reg), FOXP3 was used as a marker. In addition, we assessed for T-cell surface markers PD-1, CTLA-4, and TIM-3. Results show a significant increase in PD1+ expressing cells (2.35x-fold; p= 0.0173) in tumors from the stress group. On the other hand, there was a non-significant decrease in CD4+ T-cells (0.78x-fold; p=0.4286) and non-significant increase in CD8+ T-cells (1.75x-fold; p= 0.1833) between groups. Although we did not observe significant differences in FOX-P3 (1.4x-fold; p=0.3152), we did observe a trend towards increased expression of this transcription factor, suggesting a predominance of T-regs in the tumor microenvironment. When comparing the presence of surface markers, there was a non-significant increase in TIM-3 (1.56x-fold; p=0.5273) and CTLA-4 (1.32x-fold; p=0.5303) positive cells in the tumor microenvironment of samples from the stress group. These data suggest that the neuroendocrine system may modulate T-cell activity, specifically the expression of PD-1 ligand. Furthermore, sustained release of stress hormones may promote an immunosuppressive tumor microenvironment, leading to T-cell exhaustion, immune evasion, and tumor progression. Citation Format: Camily Morales-López, Alexandra Aquino-Acevedo, Melanie E. Cruz-Robles, Melanie Ortiz-León, Elvin R. Hernández-Cordero, Yadiel A. Rivera-López, Margarita Rivera-Bonilla, Rebecca A. Previs, Guillermo N. Armaiz-Pena. The effect of chronic stress in T-cell population and function in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6120.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6120
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    CD34+ Cells from Acute Myeloid Leukemia, Myelodysplastic Syndromes, and Normal Bone Marrow Display Different Apoptosis and Drug Resistance–Associated Phenotypes
    American Association for Cancer Research (AACR) ; 2004
    In:  Clinical Cancer Research Vol. 10, No. 22 ( 2004-11-15), p. 7599-7606
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 22 ( 2004-11-15), p. 7599-7606
    Abstract: Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32−/dim and CD32+ subsets, in de novo AML (n = 90), high-risk myelodysplastic syndrome (n = 9), and low-risk myelodysplastic syndrome (n = 21) patients at diagnosis, and compared with normal BM CD34+ cells (n = 6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P & lt; 0.0001) and lower reactivity for APO2.7 (P = 0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P & lt; 0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P = 0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34− cell compartments.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-0598
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
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  • 3
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    Abstract 937: Molecular dynamics of SrcS17 activation in chronic stress-induced tumor growth
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 937-937
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 937-937
    Abstract: Clinical studies have demonstrated that chronic stress can influence cancer progression. However, the underlying mechanisms are not fully understood. To determine the molecular drivers of downstream signaling networks activated in response to chronic stress, we performed a phosphoproteomic analysis and determined that the non-receptor tyrosine kinase, Src, was the key regulator of these networks. Since Src plays an important role in cancer biology, we examined the biological and clinical significance of Src in stress-mediated tumor growth. Norepinephrine (NE) rapidly activated SrcY419 in β-adrenergic receptor (ADRB) positive ovarian cancer cell lines, but not in ADRB-null cells. Confocal microscopy showed that Src was rapidly recruited to the cellular membrane after NE exposure in ADRB positive ovarian cancer cells. Furthermore, treatment with different ADRB agonists and blockers determined that ADRB2 is required for SrcY419 phosphorylation. Treatment with a cAMP agonist or PKA agonist/antagonists demonstrated that cAMP/PKA signaling is required for NE-induced Src activation. The unexpected Src activation via cAMP/PKA was found to be mediated by direct phosphorylation of SrcS17 following NE treatment. In Src-/- cells transiently expressing WT Src, NE caused SrcY419 phosphorylation, which was not observed when cells were transfected with a Src S17A construct. In order to investigate how S17 phosphorylation leads to Src activation, we performed molecular dynamic simulations and observed that upon SrcS17 phosphorylation, Src undergoes significant structural changes that expose its Y419 residue. To understand the functional consequences of stress-induced Src activation, we performed migration and invasion assays. Exposure to NE resulted in an increase in ovarian cancer cell migration and invasion that was completely abrogated by Src-targeted siRNA (P & lt; 0.01). In various orthotopic mouse models of ovarian carcinoma, chronic restraint stress significantly increased tumor weights (P & lt; 0.05). Increased tumor growth was completely blocked by Src silencing with Src siRNA-DOPC or by the non-specific beta-blocker, propranolol (P & lt; 0.05). To test the clinical significance of our biological findings, we examined 91 epithelial ovarian cancer samples. Elevated pSrcY419 was associated with worse patient survival (P & lt; 0.001), high tumoral NE levels (P & lt; 0.001) and high scores on the Center for Epidemiologic Studies Depression Scale (P = 0.008). To examine the potential clinical impact of our findings, we investigated whether beta-blocker usage by patients affected cancer-related mortality. This analysis revealed that beta-blockers reduced mortality by 17% across all major cancer types and 14.6% among patients with ovarian and other gynecologic cancers. This work is the first to demonstrate that an ADRB-PKA-Src axis mediates the effect of chronic stress on tumor growth and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 937. doi:10.1158/1538-7445.AM2011-937
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-937
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract 6610: Increasing blood volumes to detect minimal residual disease in neoadjuvant-treated early breast cancer patients
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6610-6610
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6610-6610
    Abstract: Breast cancer (BC) is the most frequent neoplasia affecting women worldwide normally detected at early stages. In this regard, early diagnosis drastically decreases mortality, however, around 20% of these patients will later relapse. This is mainly caused by undetectable molecular residual disease (MRD) not eliminated by standard primary treatments. Therefore, it is crucial to detect the after-treatment MRD to stratify the patients by their risk of relapse. Liquid biopsies have emerged as non-invasive method to obtain information about tumors and improve clinical cancer management. Regarding this, much has been hypothesized about utilizing high blood volumes to overcome the necessity of complex and resource-intensive next generation sequencing (NGS) methodologies to detect highly diluted blood tumor components in localized cancers. Herein, we employed a combined analysis of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) together with high blood volumes and single-assay droplet digital PCR (ddPCR) to detect MRD with ultra-high sensitivity. We prospectively assayed 124 samples extracted at baseline, post-neoadjuvant therapy (NAT), post-surgery and a follow-up on a six-monthly basis. A median of 76.40 mL of blood to detect CTCs and 40 mL of plasma to detect ctDNA per patient from 19 BC women were used in this study. ddPCR assays were performed with a median of 14 partitions per determination to detect ctDNA and 12 partitions for CTCs. Overall, ctDNA, CTCs and ctDNA and/or CTCs were detected in 84.21%, 66.66% and 89.47% respectively in the pre-treatment blood samples. MRD (ctDNA and/or CTCs) was detected in 73.68% of the after NAT blood samples. On the other hand, it was detected in 46.66% and 70.00% of the post-surgery and follow-up samples respectively. Post-NAT MRD was detected in 57.14% (4/7) and 83.33% (10/12) of patients with and without pathological complete response pCR respectively. To note, the discordant patients achieving pCR in tissue with detectable MRD in blood were high-risk BC. Importantly, in one of the two patients without pCR and no MRD detected, not enough sample were available to complete the analysis. The other discordant patient presented a localized disease with residual cancer burden value of 1 and no lymph nodes affected. In 1 out of 19 (5.26%) patient clinically relapsed with a positive MRD detection 6 months earlier. Applying this methodology, we observed a sensitivity of 0.004% in ctDNA detection and 0.224 CTCs per mL of blood. Overall, this novel methodology greatly improves sensitivity for ctDNA and CTCs detection in treatment-naïve early BC. In addition, MRD was successfully detected in post-treatment samples antedating clinical relapse by 6 months in one patient. This prospective study is potentially demonstrating that using high blood volumes and a single-assay ddPCR is a cost-effective strategy to monitor localized BC and predict relapses. Citation Format: Alfonso Alba-Bernal, Ana Godoy-Ortiz, María Emilia Domínguez-Recio, Begoña Jimenez-Rodriguez, María Elena Quirós-Ortega, Esperanza López-López, Guillermo Carbajosa-Antona, Jesús Peralta-Linero, Luis Vicioso, Estefanía Bellagarza-García, Guadalupe Dolores Garrido-Ruiz, Cynthia Robles-Podadera, Alicia Garrido-Aranda, María Dunia Roldán-Díaz, Jesús Velasco-Suelto, Rocío Lavado-Valenzuela, Martina Álvarez, Nuria Ribelles, Javier Pascual, Emilio Alba, Iñaki Comino-Méndez. Increasing blood volumes to detect minimal residual disease in neoadjuvant-treated early breast cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6610.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6610
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 3795: Early seeding of Richter transformation in chronic lymphocytic leukemia
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3795-3795
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3795-3795
    Abstract: Introduction: Clonal evolution drives cancer development due to the emergence and/or selection of proliferatively advantageous subclones. Its understanding may facilitate the design of anticipation-based management strategies. Richter transformation (RT) is a paradigmatic tumor evolution in which chronic lymphocytic leukemia (CLL), an indolent neoplasia of mature B-cells, transforms into a high-grade lymphoma, usually diffuse large B-cell lymphoma (DLBCL), conferring a dismal prognosis. The evolutionary trajectories of RT and its driving (epi)genomic mechanisms remain largely unknown. Aims: To reconstruct the evolutionary history of RT and to reveal the molecular processes underlying this transformation. Methods: We characterized the whole genome (WGS), epigenome (DNA methylation, H3K27ac, ATAC-seq), and transcriptome (RNA-seq), combined with single-cell DNA and RNA sequencing analyses, of 19 CLL patients developing RT before (n=3) or after treatment with chemoimmunotherapy (n=6) and targeted therapies (BCR or BCL2 inhibitors, n=10). We analyzed 54 longitudinal samples covering up to 19 years of disease course. Results: Our WGS analyses uncovered that RT is characterized by a remarkable structural complexity. We also identified a novel treatment-independent RT-specific mutational process, which we named SBS-RT. The genetic driver landscape of RT is a compendium of alterations in genes involved in cell cycle, MYC, and NF-κB pathways, frequently targeted in single catastrophic events including chromothripsis and chromoplexy. The WGS-based phylogenic reconstruction and single-cell DNA/RNA-seq analyses identified a very early diversification of CLL leading to emergence of RT-cells carrying specific genetic drivers and transcriptomic profiles of RT already at CLL diagnosis. These small subclones were dormant for 6-19 years until rapid expansion associated with the clinical transformation. While the DNA methylome kept track of the cell of origin and proliferative history of RT cells, their chromatin configuration and transcriptional program converged into the overexpression of cell cycle regulators, Toll-like receptors, MYC, MTORC1, and OXPHOS related transcripts, as well as downregulation of BCR pathway. This phenotypic shift was related to de novo activation of key transcription factors. In vitro experiments confirmed that RT cells have a 4-fold higher oxygen consumption at routine respiration and electron transfer system capacity compared to CLL. The resistance of RT to BCR inhibition is consistent with its high OXPHOS and low BCR signaling, which mimics de novo DLBCL-OXPHOS insensitive to BCR inhibition. This OXPHOShigh-BCRlow transcriptional axis of RT can be exploited therapeutically. Conclusions: These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover therapeutic targets for the, once expanded, lethal Richter transformation. Citation Format: Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa, Beatriz Garcia-Torre, Martí Duran-Ferrer, Kevin J. Dawson, Marta Kulis, Ander Diaz-Navarro, Neus Villamor, Juan L. Melero, Vicente Chapaprieta, Ana Dueso-Barroso, Julio Delgado, Riccardo Moia, Sara Ruiz-Gil, Domenica Marchese, Núria Verdaguer-Dot, Mónica Romo, Maria Rozman, Gerard Frigola, Alfredo Rivas-Delgado, Tycho Baumann, Miguel Alcoceba, Marcos González, Fina Climent, Pau Abrisqueta, Josep Castellví, Francesc Bosch, Marta Aymerich, Anna Enjuanes, Sílvia Ruiz-Gaspà, Armando López-Guillermo, Pedro Jares, Sílvia Beà, Dolors Colomer, Núria López-Bigas, Josep LlGelpí, David Torrents, Peter J. Campbell, Ivo Gut, Pablo M. Garcia-Roves, Davide Rossi, Gianluca Gaidano, Xose S. Puente, Holger Heyn, Francesco Maura, José I. Martín-Subero, Elías Campo. Early seeding of Richter transformation in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3795.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3795
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract OT2-08-02: SOLTI-1907 ATREZZO: Targeting hormonal receptor negative (HR-) or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive metastatic breast cancer (MBC)
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. OT2-08-02-OT2-08-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. OT2-08-02-OT2-08-02
    Abstract: Background Today, there is no clear therapeutic algorithm for patients with metastatic HER2-positive (HER2+) breast cancer (BC) who have progressed to trastuzumab, pertuzumab, tyrosine kinase inhibitors and antibody-drug conjugates (ADC). Among the emerging strategies, the use of immune checkpoint inhibitors in combination therapy is showing promising clinical benefit in the advanced setting of HER2+ BC by overcoming immune resistance and enhancing antitumor cellular immunity. The intrinsic subtypes Basal-like and HER2-enriched (i.e PAM50 non-luminal tumors) represent approximately the 60% of HER2+ BC and are associated with higher expression of immune-related genes, tumor-infiltrating lymphocytes (TILs) presence and high tumor mutational burden (TMB), compared to luminal subtypes. Additionally, immune infiltration and TMB in HER2+ BC are associated with chemo/antiHER2 responsiveness and with potential benefit from anti-PD-1/PD-L1 inhibitors. We hypothesize that combining atezolizumab with trastuzumab and vinorelbine may improve outcomes in HR- or PAM50 non-luminal/HR-positive (HR+) disease within HER2+ MBC. Methods ATREZZO is an open-label, single-arm, Simon 2-stage, multicenter phase II study. The trial will include 55 pre- or post-menopausal female or male patients with unresectable locally advanced or metastatic HR- or PAM50 non-luminal/HR+ HER2+ BC and progressed to trastuzumab-based chemotherapy and anti-HER2 ADC. Prior pertuzumab is allowed, but not required. Treatment consists of atezolizumab IV 1200 mg every 3 weeks combined with trastuzumab and vinorelbine. Patients with stable, progressing, or untreated brain metastasis not requiring immediate local therapy are eligible. The primary objective is to evaluate the Overall Response Rate (ORR) according to RECIST v 1.1 and secondary endpoints include ORR in patients with PD-L1 positive breast cancer, clinical benefit rate, overall survival and progression-free survival. The final recruited population will contain no more than 60 % of patients with PD-L1 negative tumors. Tumor assessments will be performed every 9 weeks. Incidence, duration and severity of adverse events, and further correlative molecular analyses will be also evaluated. An interim analysis will be conducted when 19 patients are evaluable for ORR and if the number of responses is ≥ 3, 36 additional patients will be included. As of July 15th, 2022, 48 patients were screened and 15 were included in sixteen Spanish sites. This study was funded by Roche Farma SA. Trial identification: NCT04759248 Citation Format: Eva Ciruelos, Antonia Perelló, Santiago González-Santiago, Ana López, Francisco Javier Salvador Bofill, Cinta Albacar, Juan Miguel Cejalvo, Santiago Escrivá-de-Romani, Isabel Blancas, Sonia Pernas, Olga Martínez-Sáez, Josefina Cruz, Jose Ponce, Sonia Servitja, Maria-Eva Perez-Lopez, Juan A Guerra, Esther Sanfeliu, Cesar A Rodríguez, Guillermo Villacampa, Lorea Villanueva, Pablo Tolosa, Tomás Pascual, Aleix Prat. SOLTI-1907 ATREZZO: Targeting hormonal receptor negative (HR-) or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-08-02.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-OT2-08-02
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    CDK4 and MDM2 Gene Alterations Mainly Occur in Highly Proliferative and Aggressive Mantle Cell Lymphomas with Wild-type INK4a/ARF Locus
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 6 ( 2005-03-15), p. 2199-2206
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 6 ( 2005-03-15), p. 2199-2206
    Abstract: Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes. To determine the role of these genes in MCL, we have examined their gene status and expression and their relationship to INK4a/ARF and p53 gene aberrations in 69 tumors. Increased CDK4 gene copy number was detected in 4 of 19 (21%) highly proliferative blastoid variants and was associated with mRNA and protein overexpression. Three additional cases showed mRNA overexpression with no structural alterations of the gene. MDM2 gene overexpression was detected in three blastoid tumors (16%) with no relationship to gene copy gains. INK4a/ARF and p53 aberrations were observed in 13 and 12 tumors, respectively. Four of the seven lymphomas with CDK4 aberrations had concurrent inactivation of p53 gene, whereas only one case had a concomitant homozygous deletion of INK4a/ARF. No other gene alterations were found in the three cases with MDM2 overexpression. Patients with INK4a/ARF deletions or simultaneous aberrations of p53 and CDK4 had a significantly shorter median survival (17 months) than patients with isolated alterations of p53, MDM2, or CDK4 (32 months) and patients with no alterations in any of these genes (77 months). The prognostic impact of the concomitant oncogenic alterations of the p14ARF/p53 and p16INK4a/CDK4 pathways was independent of the proliferation of the tumors. These findings indicate that CDK4 and MDM2 gene alterations mainly occur in MCL with a wild-type INK4a/ARF locus and may contribute to the higher proliferation and more aggressive behavior of the tumors.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-04-1526
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 8
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    Abstract A36: Catching up: Building sustainable community-academic alliance to increase human papillomavirus vaccination uptake among college students
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 25, No. 3_Supplement ( 2016-03-01), p. A36-A36
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 3_Supplement ( 2016-03-01), p. A36-A36
    Abstract: Background: Human Papillomavirus (HPV) is a common sexually transmitted infection among college students, a group still eligible for HPV vaccination. The President's Cancer Panel has identified missed opportunities in the promotion for catch-up vaccination for older adolescents and young adults, a group identified for cancer prevention. Community-academic alliances targeting college students can be used to improve HPV vaccination rates in those who have not initiated or completed the 3-doses series. Objective: The purpose of this ongoing effort is to build a community-academic alliance aiming to promote a sustainable infrastructure of research, outreach and service for HPV vaccination among college students. Methods: A multilevel approach consisting of a series of research and outreach activities; training, as well as vaccination clinics targeting college students or parents, has been implemented since December 2014. Our group, the Puerto Rico Community Cancer Control Outreach Program (PRCCCOP) from the U54 University of Puerto Rico (UPR) and the MD Anderson Cancer Center Partnership for Excellence in Cancer Research, established alliances with the Puerto Rico Comprehensive Cancer Control Program, the Puerto Rico Breast and Cervical Early Detection Program and the HPV Committee from the Puerto Rico Cancer Coalition. A new alliance with the UPR system served as the foundation to conduct these activities. Results: Research activities entitled ¡Habla de VPH! educated a total of 40 students and 468 parents. Both groups, significantly increased their HPV and HPV vaccine knowledge (from an average score of 66% and 72% up to an average score 95% and 93%, respectively) (p-value & lt;0.05). Outreach activities reached over 500 students; 34% of them want to receive notifications for future vaccination clinics. To this date, training activities such as capacity building of health professionals and train-the-trainers for peers reached a total of 71 participants. A total of 137 students attended to at least one of the 5 vaccination clinics held in two campuses, where more than half (61%; mean age=20 years old) received their first dose of the HPV vaccine. Conclusion: College students represent a captive community that can benefit from multiple activities, designed in partnerships, aiming to increase HPV vaccination uptake. Existing alliances of PRCCCOP were a facilitator in the design and development of those activities. Another facilitator for these effort was having a contact-person in campus, as part of the alliance, who helped navigate through the administrative process within campus, resulting in less time and resources involved by other alliance members. This ongoing alliance have various milestones: (1) the addition of new partners in the efforts of HPV vaccination uptake; (2) over one-thousand people reached with research, outreach or training activities; and (3) the effectiveness of the educational intervention ¡Habla de VPH! in increasing HPV knowledge. Despite these achievements, and understanding that our educational activities alone does not increase HPV vaccination, we developed a new plan to promote vaccination, with the implementation of vaccination clinics on campus. During the implementation of HPV vaccine clinics, other challenges emerged such as campus size, complexity and diversity of the groups within the university. To address these challenges, future activities will aim at specific targets within the campus, such as faculty or schools, and to engage more professors and students-groups in those specific targets. Citation Format: Aleli M. Ayala-Marin, Vivian Colon-Lopez, Camille Velez-Alamo, Hernan Rosado-Carpena, Marievelisse Soto-Salgado, Marta Sanchez-Aracil, Omayra Salgado-Cruz, VOCES Puerto Rico Vaccination Coalition, Dianedis Toro, Shelciy Collazo-Castro, Maria Figueroa-Gonzalez, Willmar Contreras, Guillermo Tortolero-Luna, Maria E. Fernandez. Catching up: Building sustainable community-academic alliance to increase human papillomavirus vaccination uptake among college students. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A36.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP15-A36
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 9
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    Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 12 ( 2018-06-15), p. 3233-3242
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 12 ( 2018-06-15), p. 3233-3242
    Abstract: Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233–42. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-1701
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract P2-12-16: Exploratory post hoc analyses of patient-reported outcomes (PROs) in the IMELDA randomized phase III trial: Maintenance bevacizumab (BEV) ± capecitabine (CAP) after initial first-line BEV plus docetaxel (DOC) for HER2-negative metastatic breast can
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P2-12-16-P2-12-16
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P2-12-16-P2-12-16
    Abstract: BACKGROUND The addition of CAP to maintenance BEV demonstrated statistically significant and clinically relevant improvements in progression-free survival (PFS [primary endpoint]; HR 0.38 [95% CI 0.27–0.55] ; log-rank p & lt;0.001) and overall survival (OS [secondary endpoint]; HR 0.43 [95% CI 0.26–0.69] ; log-rank p & lt;0.001) in patients (pts) without disease progression (PD) on initial first-line BEV–DOC for HER2-negative mBC in the IMELDA trial. This benefit was achieved despite the smaller than planned sample size due to premature recruitment discontinuation because of regulatory withdrawal of BEV–DOC. METHODS Pts with HER2-negative measurable mBC, ECOG PS & lt;2, and no prior chemotherapy for mBC were eligible. After 3–6 cycles of BEV–DOC, pts without PD were randomized to either BEV alone or BEV–CAP (BEV 15 mg/kg q3w; CAP 1000 mg/m2 bid d1–14 q3w) until PD. PROs (secondary endpoint) were assessed using the EORTC QLQ-C30 completed at screening (before BEV–DOC), at randomization to CAP vs no CAP, then every 3 cycles until PD, and at (but not beyond) PD. Analyses of mean change from randomization were prespecified. A 28-day window around the scheduled timepoints from randomization was applied to maximize the number of questionnaires available for analysis. Exploratory post hoc analyses included mixed-model repeated measures (MMRM; modeling weighted treatment effect from randomization across all available timepoints) and responder analyses using the global health status/QoL subscale. Pts were categorized as having improved (≥10-point increase), stable (change of & lt;10 points), or worsened (≥10-point decrease) scores from randomization [Osoba, 2005]. RESULTS Adherence with questionnaire completion was 65–85% for all assessment timepoints during the first year of maintenance therapy. MMRM analysis of the global health status/QoL subscale showed no difference between the treatment arms in change from randomization (least squares mean estimate 0.40 [95% CI –6.07 to 6.87]). Similar results were observed for other subscales, including the diarrhea symptom subscale. No. of pts (%)BEV (N=94)BEV–CAP (N=91)Week 9aN=51N=59Improved15 (29.4)17 (28.8)Stable26 (51.0)34 (57.6)Week 18aN=29N=57Improved11 (37.9)12 (21.1)Stable12 (41.4)30 (52.6)Week 27aN=23N=43Improved7 (30.4)16 (37.2)Stable12 (52.2)20 (46.5)Week 36aN=15N=35Improved4 (26.7)14 (40.0)Stable9 (60.0)17 (48.6)aNo. of patients with completed questionnaires at both randomization and the respective week. Only weeks with ≥10 pts in both arms shown. CONCLUSIONS The IMELDA sample size was smaller than planned but protocol adherence with PRO completion was relatively high. Prespecified change from randomization and exploratory post hoc MMRM analyses of PROs suggest that the clinically meaningful PFS and OS benefit from adding CAP to BEV is achieved while maintaining QoL, with no difference between BEV and BEV–CAP treatments. Responder analyses over time showed improved or stable global health status/QoL scores in the majority of pts at each timepoint in both treatment arms. Citation Format: Dinesh Doval, Saverio Cinieri, Hakan Bozcuk, Jean-Yves Pierga, Kadri Altundag, Xiaojia Wang, Sudeep Gupta, Guillermo Lopez Vivanco, Vineet Gupta, Ewa Chmielowska, Jose Bines, Philippe Montcuquet, Alfred Namour, Emilio Alba, Giorgio Mustacchi, Paulo Cortes, Sabine de Ducla, Ulrich Freudensprung, Lesley Fallowfield, Joseph Gligorov. Exploratory post hoc analyses of patient-reported outcomes (PROs) in the IMELDA randomized phase III trial: Maintenance bevacizumab (BEV) ± capecitabine (CAP) after initial first-line BEV plus docetaxel (DOC) for HER2-negative metastatic breast can [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-12-16.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P2-12-16
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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