tbuckley/cabot-search huggingface dataset:
Abstract PL04-03: Heterogeneity, drug resistance, and clonal evolution in colorectal cancers
Authors: Alberto Bardelli
Journal: Cancer Research (2016)

Abstract When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? To address this question a deeper understanding of the evolutive nature of cancer cells is necessary. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor's evolution the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that manipulation of the mutational loads can trigger prolonged therapeutic responses that are not observed when cancer cells are challenged with targeted drugs alone. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses. Citation Format: Alberto Bardelli. Heterogeneity, drug resistance, and clonal evolution in colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL04-03.
Randomized phase II study of first-line FOLFOX plus panitumumab (pan) versus 5FU plus pan in elderly RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts): The PANDA study.
Authors: Roberto Moretto, Francesca Battaglin, Carlotta Antoniotti, Federica Buggin, Laura Delliponti, Francesca Bergamo, Chiara Cremolini, Antonella Brunello, Marta Schirripa, Alice Menichetti, Lisa Salvatore, Valentina Angela Marsico, Daniele Rossini, Laura Rumano', Federica Marmorino, Alfredo Falcone, Vittorina Zagonel, Fotios Loupakis, Sara Lonardi
Journal: Journal of Clinical Oncology (2016)

TPS3627 Background: Based on available data, a reasonable upfront treatment for elderly mCRC pts is a fluoropyrimidine-based monotherapy plus bevacizumab, irrespectively of RAS status. Up today, data about the treatment of elderly mCRC pts with chemotherapy plus anti-EGFRs are scarce. FOLFOX plus pan is a standard first-line option for RAS wt mCRC. Adjustments of chemo-dosage are commonly applied in routinary practice to elderly pts, while evidences about the combination of an anti-EGFR with a fluoropyrimidine-based monotherapy are lacking. On the basis of these considerations, we designed the present randomized phase II trial of upfront pan in combination with FOLFOX or 5FU (both at adjusted dosage) in elderly RAS and BRAFwt unresectable mCRC pts. Methods: This is a prospective, open-label, multicenter phase II trial in which initially unresectable and previously untreated elderly (≥ 70 years) RAS and BRAF wt mCRC pts are randomized to pan (6 mg/kg) plus simplified FOLFOX (oxaliplatin 85 mg/sqm, L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion) or 5FU (L-leucovorin 200 mg/sqm, 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion) every 14 days up to 12 cycles, followed by pan alone until disease progression. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 screening tool and CRASH score is scheduled at baseline. Primary endpoint is progression-free survival (PFS). Secondary endpoints are response rate, overall survival, safety profile, early response, association of G8 score with clinical outcome and treatment-related toxicity, association of CRASH score risk categories with treatment-related toxicity. Assuming an expected median PFS time ≥ 9.65 months with one or both experimental regimens, a sample size of 90 patients in each arm will guarantee a power of 90% for a one-sided Brookmeyer-Crowley test, with a type I error rate of 5%, against the null hypothesis of a median PFS time ≤ 6 months. A pick-the-winner strategy will drive further experimental developments for one or both the two combinations. The study is sponsored by GONO Cooperative Group. EUDRACT 2015-003888-10. Clinical trial information: 2015-003888-10.
Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients
Authors: Guillermo Drelichman, Nicolás Fernández Escobar, Nora Basack, Luis Aversa, María Silvia Larroude, Gabriela Aguilar, Marina Szlago, Andrea Schenone, Alcyra Fynn, María Fernanda Cuello, Marcela Aznar, Ramiro Fernández, Alba Ruiz, Paola Reichel, Norberto Guelbert, Hugo Robledo, Nora Watman, Moira Bolesina, Graciela Elena, S. Ernesto Veber, Graciela Pujal, Graciela Galván, Juan José Chain, Adriana Arizo, Julieta Bietti, Daniel Bar, Marta Dragosky, Marisa Marquez, Leonardo Feldman, Katja Muller, Sandra Zirone, Greogorio Buchovsky, Victoria Lanza, Alba Sanabria, Ignacio Fernández, Rossana Jaureguiberry, Marcelo Contte, Angie Barbieri María, Alejandra Maro, Graciela Zárate, Gabriel Fernández, María Cristina Rapetti, Hugo Donato, Adriana Degano, Gustavo Kantor, Roberto Albina, María Á;lvarez Bollea, María Brun, Viviana Bacciedoni, Francis Del Río, Bárbara Soberón, Nazario Boido, Maya Schweri, Sandra Borchichi, Victoria Welsh, Marcela Corrales, Alejandra Cedola, Analía Carvani, Blanca Diez, Lucía Richard, Ccecilia Baduel, Gabriela Nuñez, Rubén Colimodio, Lucía Barazzutti, Hugo Medici, Susana Meschengieser, Germán Damiani, María Nucifora, Beatriz Girardi, Sergio Gómez, Maura Papucci, David Verón, Luis Quiroga, Gustavo Carro, Patricia De Ambrosio, José Ferro, Marcelo Pujol, Cristina Cabral Castella, Liliana Franco, Gisela Nisnovich, María Veloso, Isabel Pacheco, Mario Savarino, Andrés Marino, José Luis Saavedra
Journal: American Journal of Hematology (2016)

Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc.
Cul4A Is Required for Cell Viability and Its Deficiency in Hematopoietic Cells Causes Apoptosis and Is Fatal.
Authors: Kristin T. Chun, David L. Waning, Binghui Li, Nan Jia, Yahaira M. Naaldijk, W. Scott Goebl, Harm HogenEsch
Journal: Blood (2007)
Prognostic impact of local treatment against postoperative oligometastases in non-small cell lung cancer.
Authors: T. Yano, A. Haro, T. Yoshida, Y. Morodomi, K. Ito, F. Shoji, Y. Maehara
Journal: Journal of Clinical Oncology (2010)

e18020 Background: Prognostic factors for recurrent non-small cell lung cancer (NSCLC) after a complete resection have not been well elucidated, nor have therapeutic guidelines for postoperative recurrence been established. In this study, we investigated prognostic factors associated with survival after recurrence in surgically resected NSCLC, and clarified the influence of local treatment on the prognosis for oligometastatic recurrence. Methods: In Kyushu University Hospital from January 1994 through December 2004, 418 consecutive patients with NSCLC underwent complete resection; 138 experienced a postoperative recurrence by December 2005. The first recurrent site was locoregional in 36 patients, distant in 93 patients, and combined in 9 patients. Of the 138 patients with recurrence, we reviewed 93 patients with only distant metastases for clinicopathological information, treatment modality, and survival. We also analyzed the prognostic factors for postrecurrence survival. Results: For the 93 patients with distant metastasis alone, the 2- and 5-year survival rates after recurrence were 43.9% and 38.7%, respectively. Of those patients, 44 first received local treatment, including radiotherapy or surgical resection. Their recurrent disease (‘oligometastases') was limited, with the potential to be controlled with local treatment. Significant prognostic factors for postoperative survival after the appearance of distant metastases include adenocarcinoma histology, long disease-free interval (DFI) (≥ 1 year), and the performance of local treatment for the limited distant oligometastases. Of the 44 patients who received local therapy, the 24 with a DFI ≥ 1 year had significantly better postrecurrence survival than the 20 patients with DFI < 1 year (72.4% vs. 45.9% for 2-year survival rate, and 66.8% vs. 32.8% for 5-year survival). Conclusions: Local therapy, such as radiotherapy and surgery, might be considered first-line treatment in patients with postoperative oligometastatic recurrence of NSCLC, especially those with a DFI ≥ 1 year. No significant financial relationships to disclose.
Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients
Authors: Tariq Shafi, Neil R. Powe, Timothy W. Meyer, Seungyoung Hwang, Xin Hai, Michal L. Melamed, Tanushree Banerjee, Josef Coresh, Thomas H. Hostetter
Journal: Journal of the American Society of Nephrology (2016)

Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N -oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3–6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μ M) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.
Abstract 7: LKB1 deficiency is associated with a unique metabolic signature in Kras mutant non-small cell lung cancer (NSCLC)
Authors: Tingyu Liu, Erin Sennott, Zhengjie Zhong, Mya Steadman, Kelly Marsh, Jonathan Hurov, Cyril Benes, Jeffrey A. Engelman
Journal: Cancer Research (2016)

Abstract LKB1 deficiency is found in approximately 10% of non-small cell lung cancer harboring Kras mutation. Loss of LKB1 has been associated with increased metastatic rates and decreased survival in patients. Currently, no effective therapy has been developed against this subtype of lung cancer. LKB1 can regulate multiple cellular activities. One of the most well-studied functions is its regulation on cell metabolism through AMPK signaling pathway. How LKB1 loss globally impacts NSCLC metabolism has not been well understood yet. Using isotope-labeled substrate tracing approach, we found an increase of specially-labeled intermediates in pentose phosphate pathway (PPP) that may suggest upregulation of PPP activity. In addition, we also performed an unbiased drug screen that showed higher sensitivity to an mTOR inhibitor in Kras and LKB1 double mutant lung cancer cells relative to cancer cells under other genetic background. These data suggest that loss of LKB1 may upregulate biosynthetic reactions in Kras mutant NSCLC and render these cells sensitive to inhibitors in biosynthesis. These findings may provide new insights in developing therapeutic agents targeting KrasMT/LKB1MT NSCLC. Citation Format: Tingyu Liu, Erin Sennott, Zhengjie Zhong, Mya Steadman, Kelly Marsh, Jonathan Hurov, Cyril Benes, Jeffrey A. Engelman. LKB1 deficiency is associated with a unique metabolic signature in Kras mutant non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 7.
RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis
Authors: Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül
Journal: Journal of Clinical Investigation (2016)

Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
Blood-based predictive biomarkers for overall survival (OS) in patients (pts) receiving the immunotherapy sipuleucel-T (sip-T).
Authors: William K. Oh, Harini Kandadi, Nadeem Anwar Sheikh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2017)

36 Background: Sip-T is an FDA-approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). While baseline prostate-specific antigen level correlates with prolonged OS in pts treated with sip-T, biomarkers predictive of OS remain elusive. Gene expression signatures in peripheral blood (PB) correlate with prognosis in mCRPC (Ross et al, Lancet Oncol. 2012). This study sought to identify a candidate PB gene signature predictive of OS benefit with sip-T. Methods: PB mononuclear cells from sip-T or control (CN) mCRPC pts in the IMPACT trial (NCT00065442) were collected prior to leukapheresis. Affymetrix gene chip (HGU133P2) screening evaluated gene expression; association of gene expression with OS was performed using a multivariate Cox proportional hazards regression model, where OS was fit to gene expression and the 2003 baseline Halabi prognostic variables. The top 50 gene candidates were selected for qPCR confirmation. Results: Out of the 50 gene candidates selected for qPCR confirmation, 5 genes were associated with OS. High expression of SNTB1 and CHI3L2 and low expression of SYNGR3, AURKC, and ZNF268 were associated with improved OS in sip-T–treated pts but not in CN arm pts. A composite gene score (CGS) was calculated incorporating expression of these genes. In a CGS tertile analysis, OS in the top and middle sip-T tertiles was significantly better compared with the corresponding CN groups (Table). The lowest sip-T tertile had a median OS similar to that of the CN arm. Conclusions: CGS based on baseline gene expression may predict OS outcomes for mCRPC pts receiving sip-T. Compared with the CN arm, OS was significantly improved in the top two tertiles of sip-T–treated pts; OS in the bottom tertile was similar to the CN arm. Clinical trial information: NCT00065442. [Table: see text]
Clinical performance of the DigniCap system, a scalp hypothermia system, in preventing chemotherapy-induced alopecia.
Authors: Hope S. Rugo, Paula Klein, Susan Anitra Melin, Sara A. Hurvitz, Michelle E. Melisko, Anne Moore, Glen D Park, Erika Bageman, Ralph D'Agostino, Elizabeth Shea Ver Hoeve, Tessa Cigler
Journal: Journal of Clinical Oncology (2015)

9518 Background: Alopecia is an emotionally traumatic side effect for breast cancer (BC) patients (pts) undergoing adjuvant chemotherapy (CTX). The DigniCap System is the first scalp cooling system studied under a clinical trial approved by the Food and Drug Administration (FDA) to minimize alopecia. Methods: This prospective trial evaluated the clinical performance of the DigniCap System in women with early stage BC receiving adjuvant CTX. The primary endpoint was efficacy evaluated by pt self-assessment of 5 photographs of the head using the Dean scale to estimate hair loss one month after the end of chemotherapy. A score of 0-2 ( ≤ 50% hair loss) was defined as treatment success. Tolerability was defined as the percentage of patients who completed all planned CTX cycles using the DigniCap System and by the Patient Symptoms Survey. Eligibility included women with stage I/II BC scheduled to receive adjuvant CTX, excluding sequential anthracycline/taxane regimens. With 100 pts enrolled, there was 90% power to detect the difference between the null hypothesis treatment success proportion of less than 40% versus an alternative proportion of 56%. Pts who chose not to undergo scalp cooling were enrolled in a control group. Results: 101 pts used the DigniCap System and were evaluable for the primary endpoint. CTX regimens included docetaxel (D)/ cyclophosphamide (76%), D/carboplatin (12%) & weekly paclitaxel (12%); trastuzumab and pertuzumab were allowed. Treatment success was seen in 71 (70.3%; 95% CI, 60.4 - 79.0%; p < 0.001), compared to 0/16 in the control group. Minimal or no hair loss (Dean score 0-1) was seen in 39 pts (39%). Toxicity included grade 1/2 headache (4), pruritus (1), pain of skin (1) and head discomfort (1). Three pts discontinued cooling, primarily from feeling cold. Conclusions: Use of the DigniCap System prevented significant hair loss in 70.3% of pts with breast cancer receiving adjuvant CTX, compared to control where 94% had > 75% hair loss. Treatment was well tolerated and there has been no evidence of scalp metastases. Pts will be followed for long-term safety. The DigniCap System is highly effective in reducing chemotherapy-induced alopecia with a clinically meaningful benefit. Clinical trial information: NCT01831024.
MET as a prognostic biomarker of survival in a large cohort of patients with gastroesophageal cancer (GEC).
Authors: Daniel Virgil Thomas Catenacci, Rui Tang, Kelly Smith Oliner, Agnes Ang, Robert D. Loberg, Emily O'Day, Peng Xu, Les Henderson, Annamaria Ruzzo, Francesco Graziano
Journal: Journal of Clinical Oncology (2015)

4034 Background: Estimates of the frequency of genomic/proteomic alterations in MET in solid tumors vary widely, but a growing body of evidence suggests that MET amplification and/or Met expression are biomarkers for poor prognosis. We examined both MET gene copy number and Met protein expression as potential prognostic biomarkers for survival in a large set of GEC samples with full clinical annotations (staging, HER2 status, treatment, and overall survival). Methods: Formalin-fixed, paraffin-embedded (FFPE) GEC samples (N = 394) primarily from early-stage tumors were collected in the United States and Italy. Samples were analyzed by fluorescence in situ hybridization (FISH) for MET gene amplification (Dako MET IQFISH probe mix, research use only) and by immunohistochemistry (IHC) for Met protein expression (Dako Met IHC assay, MET4 antibody, investigational use only). All assays were performed according to the manufacturer’s instructions. Samples with a MET/CEP 7 ratio ≥ 2.0 were considered amplified, whereas samples with ≥ 25% Met tumor membrane staining by IHC ( ≥ 1+ intensity) were considered Met positive. Spearman’s rank correlation coefficient was used to assess correlations between parameters. Cox proportional hazards models and Kaplan-Meier estimates were applied to explore relationships between MET, overall survival, and other clinical characteristics. Results: MET gene copy number variation ( ≥ 5 copies) was observed in 18 of 344 samples (5.2%), and MET gene amplification (MET/CEP 7 ≥ 2.0) was observed in 16 of 344 samples (4.7%). Of the 332 evaluable IHC samples, 117 (35.2%) were positive for Met protein expression. There was considerable overlap between MET amplification and Met expression; 12 of 15 MET-amplified samples (80.0%) were positive for Met expression. Survival analyses showed that both MET gene amplification and Met IHC positivity were prognostic of poor outcomes. Conclusions: MET amplification was observed in ~5% of this large set of GEC samples. Prevalence of MET amplification and Met expression were similar to those found in previously published studies. Our results indicate that MET gene amplification and Met protein expression are prognostic of poor outcomes in GEC.