tbuckley/cabot-search huggingface dataset:
Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis
Authors: Jose Miguel Baena-Díez, Judit Peñafiel, Isaac Subirana, Rafel Ramos, Roberto Elosua, Alejandro Marín-Ibañez, María Jesús Guembe, Fernando Rigo, María José Tormo-Díaz, Conchi Moreno-Iribas, Joan Josep Cabré, Antonio Segura, Manel García-Lareo, Agustín Gómez de la Cámara, José Lapetra, Miquel Quesada, Jaume Marrugat, Maria José Medrano, Jesús Berjón, Guiem Frontera, Diana Gavrila, Aurelio Barricarte, Josep Basora, Jose María García, Natalia C. Pavone, David Lora-Pablos, Eduardo Mayoral, Josep Franch, Manel Mata, Conxa Castell, Albert Frances, María Grau
Journal: Diabetes Care (2016)

OBJECTIVE Diabetes is a common cause of shortened life expectancy. We aimed to assess the association between diabetes and cause-specific death. RESEARCH DESIGN AND METHODS We used the pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35–79 years old. Diabetes status was self-reported or defined as glycemia &amp;gt;125 mg/dL at baseline. Vital status and causes of death were ascertained by medical records review and linkage with the official death registry. The hazard ratios and cumulative mortality function were assessed with two approaches, with and without competing risks: proportional subdistribution hazard (PSH) and cause-specific hazard (CSH), respectively. Multivariate analyses were fitted for cardiovascular, cancer, and noncardiovascular noncancer deaths. RESULTS We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63–2.52) and PSH = 1.99 (1.60–2.49) in men; and CSH = 2.28 (1.75–2.97) and PSH = 2.23 (1.70–2.91) in women; 2) cancer death, CSH = 1.37 (1.13–1.67) and PSH = 1.35 (1.10–1.65) in men; and CSH = 1.68 (1.29–2.20) and PSH = 1.66 (1.25–2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23–1.91) and PSH = 1.50 (1.20–1.89) in men; and CSH = 1.89 (1.43–2.48) and PSH = 1.84 (1.39–2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes. CONCLUSIONS Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes. The use of CSH and PSH provides a comprehensive view of mortality dynamics in a population with diabetes.
Abstract 1424: Predicting response to immune checkpoint therapy using an mutation burden threshold
Authors: Anshuman Panda, Anil Betigeri, Kalyanasundaram Subramanian, Kim Hirshfield, Lorna Rodriguez, Shridar Ganesan, Gyan Bhanot
Journal: Cancer Research (2016)

Abstract Treatment with antibodies to PD-1 or CTLA-4 leads to prolonged response in some cancer patients. Patients whose tumors have a high mutational burden have a better response to anti-CTLA-4 treatment with ipilimumab in melanoma5, and to anti-PD-1 treatment with pembrolizumab in non-small cell lung6 and colorectal cancer7. These results suggest that a sufficiently high non-synonymous somatic mutation burden in the tumor may lead to protein alterations that serve as neo-antigens to stimulate CD8 T-cell immune response. This immune response may be blocked by the tumor by engaging the immune checkpoint pathway, making such tumors especially vulnerable to immune checkpoint disruption. However, the specific criteria to identify patients likely to respond to immune checkpoint therapy have remained elusive so far. Using somatic mutation and RNA-Seq data from TCGA, we propose that there exists a mutational threshold, which we call the “Activated Immune Mutational” (AIM) Threshold, which can identify patients likely to respond to immune checkpoint therapy. Compared to AIM- patients (potential non-responders), AIM+ patients (potential responders) have tumors that meet four criteria: (1) a high non-synonymous mutation burden; (2) a high level of immune infiltration in the tumor; (3) a high CD8 T cell fraction in the leukocyte component of the immune infiltrate plus high expression of the T cell marker CD8A; and (4) a high expression of immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA-4. We find that in melanoma, endometrial, colon, cervical and breast cancer, a clear AIM threshold satisfying all four criteria exists. The distribution of mutations in AIM- versus AIM+ tumors for these cancers is very different. In the former, there are high frequency somatic mutations in only a few genes, while in the latter, high frequency somatic mutations are found in many genes distributed over the whole genome. Pathological analysis of high-resolution images from 150 TCGA tumors (30 from each of the five tumor types) validated the presence of significantly higher lymphocytic infiltration in the AIM+ tumors compared to AIM- tumors. We show that AIM+ tumors can be identified using sequencing assays which are currently in clinical use. Finally, survival analysis in melanoma patients from TCGA treated with immunotherapy will be presented. Citation Format: Anshuman Panda, Anil Betigeri, Kalyanasundaram Subramanian, Kim Hirshfield, Lorna Rodriguez, Shridar Ganesan, Gyan Bhanot. Predicting response to immune checkpoint therapy using an mutation burden threshold. [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 1424.
Abstract 5004: APX005M, a humanized anti-CD40 antibody with strong immune-modulatory activities capable of tumor eradication <i>in vivo</i>
Authors: Pia Björck, Erin Filbert, Xiaodong Yang, Ovidiu C. Trifan
Journal: Cancer Research (2016)

Abstract The success of immune checkpoint inhibitors validates the concept that immunotherapy is an effective approach for the treatment of solid tumors. In addition to reversing tumor-induced immune suppression, immune activating antibodies are being explored as the next generation of immuno-oncology therapeutics. CD40, which is expressed on antigen presenting cells such as dendritic and B cells initiates and regulates both innate and adaptive immunity and is essential for the activation of antigen-specific T cells. APX005M is a humanized IgG1 CD40 agonistic antibody developed using Apexigen's APXiMAB™ discovery platform. APX005M binds with high affinity to human (Kd = 0.12nM) and monkey (Kd = 0.37nM) CD40. It recognizes a unique epitope that overlaps with the CD40 ligand binding sites and thus blocks the binding of CD40 to CD40L. APX005M is a potent CD40 agonistic antibody capable of activating antigen presenting B cells (EC50 = 12pM) and dendritic cells (EC50 = 0.49nM). Its CD40 agonistic activity requires crosslinking by Fc-gamma receptors since F(ab)’2 fragment of APX005M loses the agonistic activity. Upon binding to CD40 expressing tumor cells APX005M induces antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In vivo APX005M completely eradicates CD40+ lymphoma tumors and inhibits the growth of rituximab-resistant tumors. The data suggest that a CD40 agonistic mAb such as APX005M, that activates CD40 through binding to the CD40L binding site while being dependent on crosslinking via Fc-gamma receptors, may represent an ideal immune activating antibody drug candidate for stimulating effective immune responses against tumors. APX005M is currently being evaluated in clinical trials for the treatment of patients with solid tumors. Citation Format: Pia Björck, Erin Filbert, Xiaodong Yang, Ovidiu C. Trifan. APX005M, a humanized anti-CD40 antibody with strong immune-modulatory activities capable of tumor eradication in vivo. [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 5004.
Abstract LB-297: Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus cancers
Authors: Joongho Joh, Shinje Ghim, Paula M. Chilton, Jino Park, Sarah A. Wilcher, Mary L. Proctor, Alfred B. Jenson
Journal: Cancer Research (2016)

Abstract Infection by mouse papillomavirus (PV), MmuPV1, of T cell-deficient, B6.Cg-Foxn1nu/J nude mice revealed that four, distinct squamous papilloma phenotypes developed simultaneously after infection of experimental mice. Papillomas appeared on the muzzle, vagina, and tail at or about day 42 days post-inoculation. The dorsal skin developed papillomas and hair follicle tumors (trichoblastomas) as early as 26 days after infection. When this aggressive tumor was transplanted into normal congenic strains, the transplant immediately regressed while the transplanted tumor into B6.Cg-Foxn1nu/J continued to grow. This result suggested that T-cell deficiency is critical to tumor formation. Passive transfer of hyperimmune sera from normal congenic mice immunized with MmuPV1 virus-like particles (VLPs) to T cell-deficient strains of mice prevented infection by virions of experimental mice. A cell adoption study showed that activated CD8+ populations collected during the regression process of MmuPV1 tumor explants efficiently eliminated both growing and established tumors in the model. Consequently, this study will provide an efficient immunotherapeutic strategy that can be employed to HPV-positive patients, who are at a risk of cancer development. Citation Format: Joongho Joh, Shinje Ghim, Paula M. Chilton, Jino Park, Sarah A. Wilcher, Mary L. Proctor, Alfred B. Jenson. Antitumor immune response passively prevents and eliminates skin tumors on the mouse model of human papillomavirus 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 LB-297.
An international, biomarker-directed, randomized, phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, <i>TP53</i>-mutant ovarian cancer.
Authors: Amit M. Oza, Johanne Ingrid Weberpals, Diane M. Provencher, Eva-Maria Grischke, Marcia Hall, Denise Uyar, Maria Del Pilar Estevez-Diz, Frederik Marmé, Alexey Kuzmin, Per Rosenberg, Robert Michael Wenham, Jingjun Qiu, Mark Anthony Lee, Ji Liu, Shelonitda Rose, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2015)

5506 Background: Data suggest synthetic lethality when TP53-deficient cells are exposed to genotoxic drugs plus the Wee1 inhibitor AZD1775 (MK-1775). AZD1775 plus C was well tolerated in patients (pts) with advanced solid tumors (NCT00648648). This current two-part study (NCT01357161) evaluated the efficacy of AZD1775 plus P/C compared with P/C alone in women with TP53-mutant OC. Methods: After confirming a dose of AZD1775 (225 mg bid; capsules) in 15 pts in part 1, pts in part 2 received AZD1775 or placebo bid for 2.5 days plus P (175 mg/m2; IV) and C (AUC5; IV) on day 1 per 21-day treatment cycle, until progression or the completion of six cycles. Primary objectives: PFS (enhanced [volumetric] RECIST v1.1, criterion for superiority = P< 0.1), safety and tolerability (CTCAE v4.0). Secondary objectives: PFS (RECIST v1.1), ORR (enhanced RECIST v1.1, CA-125 levels) and OS. Results: 121 pts with confirmed TP53 mutations were randomized, 59 and 62 to AZD1775/P/C and P/C, respectively. PFS by independent central review (~57% maturity) was greater with AZD1775/P/C compared with P/C alone (enhanced RECIST: HR 0.63, 80% CI 0.45, 0.89, 95% CI 0.38, 1.06, P= 0.080, median 34.14 vs 31.86 weeks; RECIST: HR 0.55, 80% CI 0.39, 0.79, 95% CI 0.32, 0.95, P= 0.030, median 42.86 vs 34.86 weeks). ORRs were 81.4% vs 75.8% (difference 5.6%, 95% CI for difference –9.4, 20.2, P= 0.459) with AZD1775/P/C vs P/C, respectively. Best response rates based on CA-125 criteria were 81.35% vs 74.19% with AZD1775/P/C vs P/C, respectively. OS data are immature. Most common adverse events (AEs) were nausea (78.0% vs 60.0% for AZD1775/P/C vs P/C, respectively), diarrhea (74.6% vs 36.7%), alopecia (54.2% vs 66.7%) and fatigue (54.2% vs 55.0%). 85 pts had grade ≥ 3 AEs (78.0% vs 65.0% for AZD1775/P/C vs P/C, respectively), 36 pts had serious AEs (40.7% vs 20.0%) and 25 pts had AEs resulting in discontinuation (20.3% vs 21.7%). Conclusions: AZD1775/P/C was associated with a significant increase in PFS when compared with P/C alone, met the preset primary and secondary PFS efficacy bar for clinical importance, and showed acceptable tolerability in women with TP53-mutant OC. Clinical trial information: NCT01357161.
Expression of gemcitabine and cisplatin-related genes according to histology and stage in non-small-cell lung cancer (NSCLC)
Authors: T. M. De Pas, E. Giovannetti, F. Toffalorio, M. Manzotti, G. Pelosi, G. Spitaleri, D. Minocci, L. Spaggiari, M. Del Tacca, F. G. de Braud, R. Danesi
Journal: Journal of Clinical Oncology (2008)

14644 Background: A number of pharmacogenomic studies have been recently carried out to find out a possible relationship between gene expression and treatment outcome in NSCLC; however, to our knowledge, no data are available on the possible influence of tumor histology and tumor stage on gene expression profile. The aim of this study was the characterization of the expression pattern of genes involved in gemcitabine and cisplatin activity in primary or metastatic adenocarcinoma or squamous carcinoma NSCLC specimens. Methods: Excision repair cross-complementing 1 (ERCC1), 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) were analyzed by quantitative RT-PCR in 89 laser microdissected lung tissues (52 primary tumors, 23 metastatic lymph nodes and 14 normal lung tissues), from 69 patients. β-actin was used as housekeeping gene. Results: The quantitative expression analysis in patients’ samples demonstrated that these target genes were detectable in most surgical specimens. hENT1, CDA and dCK expression was significantly lower in normal than in tumor tissues (p<0.05). A difference in mean CDA expression was also found between tumor (1.015±0.015) and node metastasis (0.965±0.019). Furthermore, a significant (p<0.05) variability of mean gene expression was observed between adenocarcinoma and squamous cell carcinoma with respect to 5’-NT, RRM1 and RRM2. In particular, the mean gene expression values of both RRM1 and RRM2 were significantly higher in squamous cell carcinomas with respect to adenocarcinomas, while 5’-NT expression values were significantly higher in adenocarcinomas. Conclusions: We have identified the differences in expression of gemcitabine and cisplatin-related genes due to tumor stage and histology. The knowledge of these variations in gene profiles should be be taken into account for pharmacogenomic data interpretation and must be considered in predicting gemcitabine/cisplatin efficacy and in personalizing treatment for lung cancer patients. No significant financial relationships to disclose.
Abstract 3148: Clinical validation of a next-generation sequencing assay specifically for blood-drop liquid biopsy
Authors: Chen-Hsiung Yeh, Jonathan Spurgin, Andrew Ford, John Athanasuleas, Upender Manne
Journal: Cancer Research (2016)

Abstract Next-generation sequencing (NGS) technology enables rapid analysis and turnaround of multiple genes for clinically actionable somatic variants. Genetic sequencing on tumor biopsy tissue to inform treatment decisions is the hallmark of precision medicine. However, a one-time, single-site tissue sample may not be a true representation of tumor dynamic profile. A liquid biopsy, based on circulating cell-free DNA (cfDNA), can capture the entire heterogeneity of the disease, and offer what tissue biopsies can’t, the opportunity to take serial samples in order to monitor tumor genomic evolution in real time. We have recently developed a proprietary cfDNA enrichment process that requires only droplet volumes of blood. Here, we presented clinical validation of the blood-drop liquid biopsy NGS assay interrogating 2855 mutation hotspots in 50 cancer-associated genes using the AmpliSeq cancer panel and Ion Torrent Proton sequencer. One nanogram of cfDNA prepared from 20 uL of plasma/serum was used as template to amplify 207 mutation hotspot amplicons. Deep sequencing of total 95 clinical specimens (≥ 1000× average coverage across the capture regions) achieved high sensitivity for detecting somatic variants at low allele fraction (AF). The variants at AF of ≥ 10% in most samples (90/95), except 5 cases, were confirmed by another laboratory. Repeated sequencing of 15 samples, and progressively diluted samples from two reference standard DNAs with known mutations and AF demonstrated reliable detection sensitivity at 1% for most single nucleotide variants (SNV) with high within-run and between-run reproducibility. Validation also revealed sensitivity and specificity for detecting variants at 5% AF was 100% (95% CI = 95.7-100.0) using Tru-Q 4 NGS reference standard DNA, and NA19240 or NA12878 HapMap individual, respectively. Overall, our new-generation liquid biopsy NGS assay, with the capability to multiplex and simultaneously sequence multiple patient samples using finger-stick blood, is a robust and sensitive method for mutation analysis of clinical significance, further expedite treatment decision-making and identify targeted therapies for eligible patients in a time- and cost-efficient manner. Citation Format: Chen-Hsiung Yeh, Jonathan Spurgin, Andrew Ford, John Athanasuleas, Upender Manne. Clinical validation of a next-generation sequencing assay specifically for blood-drop liquid biopsy. [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 3148.
A phase I/II study of telomerase peptide vaccination of patients with non-small cell lung cancer
Authors: P. F. Brunsvig, M. K. Gjertsen, G. Kvalheim, S. Aamdal, C. J. Markowski-Grimsrud, I. Sve, M. Dyrhaug, S. Trachsel, M. Møller, J. Eriksen, G. Gaudernack
Journal: Journal of Clinical Oncology (2005)

2580 Background: A phase I/II study was conducted to investigate the safety, tolerability and clinical response to vaccination with a combination of telomerase peptides GV1001 (hTERT: 611–626) and HR2822 (hTERT: 540–548).Methods: Twenty-six patients with non-small cell lung cancerreceived intradermal administrations of either 112 μg or 560 μg GV1001 in combination with 68.4 μg HR2822 and granulocyte macrophage-colony stimulating factor. The treatment period was ten weeks. Booster vaccinations with 560 μg GV1001 were offered as follow-up. Monitoring of blood samples, clinical examination and radiological staging were performed regularly. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T-cell proliferation. Bone marrow function was monitored in long time survivors. Our regional medical research ethics committee has approved the study and signed informed consent was obtained in all subjects. Results: The treatment was well tolerated with minor side effects. Immune responses against GV1001 were detected in 11 of 24 evaluable patients during the primary regimen and in an additional two patients following booster injections. Two patients responded to HR2822. Cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile and recognized autologous antigen presenting cells pulsed with recombinant telomerase protein. No bone marrow toxicities were observed in long time survivors with immune responses. A complete tumor response was observed in one patient who developed GV1001-specific cytotoxic T cells that could be cloned from peripheral blood. Conclusions: Telomerase vaccination of patients with advanced treatment resistant NSCL cancer is feasible and results in potentially beneficial immune responses in about 50% of vaccinated patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GemVax GemVax
Abstract LB-008: KRAS engages AGO2 to enhance cellular transformation
Authors: Sunita Shankar, Sethuramasundaram Pitchiaya, Rohit Malik, Vishal Kothari, Yasuyuki Hosono, Anastasia K. Yocum, Harika Gundlapalli, Yasmine White, Ari Firestone, Xuhong Cao, Saravana M. Dhanasekaran, Jeanne Stuckey, Gideon Bollag, Kevin Shannon, Nils Walter, Chandan Kumar-Sinha, Arul M. Chinnaiyan
Journal: Cancer Research (2016)

Abstract Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Approximately 30% of all cancers harbor activating mutations in the RAS family of small GTPase proteins, making it one of the most common oncogenic aberrations in humans. Normal RAS proteins (H, K or N-RAS) localize to the inner cell membrane and transduce extracellular growth signals by cycling between an “active” GTP-bound state and “inactive” GDP-bound state. Our understanding of RAS biology is primarily from RAS protein-effector interactions that activate a variety of effectors at the plasma membrane like RAF/PI3K/RalGDS. Yet, targeting mutant RAS proteins or its effectors / pathways remains a challenging endeavor for treating RAS driven cancers. For a comprehensive identification of RAS interactors, we recently performed co-immunoprecipitation (Co-IP) Mass Spectrometric analysis of RAS immunoprecipitates from multiple cancer cell lines with differing KRAS mutation status. In all the cell lines studies, we uncovered an interaction between RAS and the core component of the RNA silencing machinery, Argonaute 2 (AGO2). Endogenously expressed RAS and AGO2 co-sediment and co-localize in intracellular membrane bound endoplasmic reticulum. AGO2 binds the Switch II region in KRAS, irrespective of GDP/GTP bound to RAS. Both endogenous and overexpressed mutant forms of KRAS, attenuate AGO2 related gene silencing function. Using NIH3T3 AGO2-/- cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Overall, our studies suggest that through its interaction with AGO2, RAS function extends well beyond its canonical role in intracellular signaling. We will present detailed characterization of the RAS-AGO2 interaction and its functional aspects that we have discovered so far. Citation Format: Sunita Shankar, Sethuramasundaram Pitchiaya, Rohit Malik, Vishal Kothari, Yasuyuki Hosono, Anastasia K. Yocum, Harika Gundlapalli, Yasmine White, Ari Firestone, Xuhong Cao, Saravana M. Dhanasekaran, Jeanne Stuckey, Gideon Bollag, Kevin Shannon, Nils Walter, Chandan Kumar-Sinha, Arul M. Chinnaiyan. KRAS engages AGO2 to enhance cellular transformation. [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 LB-008.