tbuckley/cabot-search huggingface dataset:
ASAMET: A randomized, 2x2 biomarker prevention trial of low-dose aspirin and metformin in colorectal cancer.
Authors: Marilena Petrera, Laura Paleari, Matteo Puntoni, Silvia Caviglia, Matteo Clavarezza, Paola Romagnolli, Michael Gnant, Walter E. Haefeli, Wilfried Roth, Dominique Scherer, Borut Stabuc, Cornelia M Ulrich, Andrea De Censi
Journal: Journal of Clinical Oncology (2017)

TPS1591 Background: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased CRC incidence and mortality in meta-analyses of epidemiological studies in diabetics and has been shown to decrease by 40% colorectal adenoma recurrence in a randomized trial. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism, and that the combination of ASA and MET, another AMPK activator and S6K1 inhibitor, has a striking additive effect on AMPK activation and mTOR inhibition, with increased autophagy and decreased cell growth in CRC cell lines. While both drugs are being tested as single agents, their combination has not been tested in clinical trials. Methods: This is a randomized, placebo-controlled, double-blind, 2x2 biomarker trial of ASA and MET to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC will randomly be assigned in a 4-arm trial to either ASA, 100mg qd, MET 850mg bid, their combination, or placebo for 1 year. The primary endpoint is the change, defined as the difference between pre- and post-treatment expression, of NFκBin the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in paired colonoscopies one year apart. Additional biomarkers will include: 1) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome-wide gene expression arrays; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of mutations and SNPs with treatment response by NGS of primary tumors; 4) the measurement of circulating IL-6, CRP and VEGF, and 5) plasma and colonic MET concentrations and their correlation with biomarker profiles. A favorable biomarker modulation may provide important clues for a subsequent phase III adjuvant trial. Clinical trial information: EudraCT Number: 2015-004824-77.
Marker expression of cancer stem cells (CSC) in malignant pleural effusion (MPE)
Authors: Mysore Veena, Scott Oh, Eri Srivatsan, Sherven Sharma, Raj Batra, Saroj Basak
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5426 

The Cancer Stem Cell (CSC) hypothesis states that tumors arise from    progenitor or stem cells which sustain the growth and spread of tumor.    Various cell markers and differences in phenotype (e.g.: cytotoxic drug    resistance, mesenchymal type morphology and behavior) are    purported to distinguish CSCs from the other tumor cells within    epithelial malignancies. We have begun to evaluate the putative    CSC-marker profile in tumor cells fractionated from MPE, using flow    cytometry. We show that the fractional and temporal expression of the    putative CSC and/or the tumor progression markers    (CD44, CD166, cMET, MDR1, uPAR) in primary MPE-derived lung cancer specimens. Whereas only 20-30%    of primary isolates are CD44+ by immuno-histochemistry upon removal from    subjects, 90-95% of the tumor cells cultured in medium enriched with    autologous effusion cells are CD44+ after one week of culture in vitro .    Of the CD44+ fraction, 60% of the cultured cells also express cMET, and    approximately 50% also co-express CD166, uPAR, or MDR1.    When evaluated for CD44 receptor variants, 35% of the total cells express variant v4/5 and are negative for other variants such as v6, v7/8. Lastly, the cells were also evaluated for Adenoviral entry receptors (CAR, avb3, avb5) for consideration of targeted gene-therapy. Remarkably, over 80% of the CD44+ cells cultured from MPE also co-expressed CAR and avb5, but not avb3.    These results suggest that processes utilized for MPE-specimen fractionation, isolation and primary culture alter the CSC-marker profiles. Additionally, if CD44+ cells are truly enriched for CSCs, our results indicate that this population may well be susceptible to targeted adenoviral gene-delivery/therapy by virtue of their differential expression of Ad-entry receptors.    Study fuded by VA Medical Research Funds to RKB.
Variant classifications in BRCA1 and BRCA2: A systematic analysis of interlaboratory concordance
Authors: Stephen E Lincoln, Melissa Cline, Shan Yang, Yuya Kobayashi, Molly Zhang, Erin O'Leary, Scott Topper, Benedict Paten, Robert Nussbaum
Journal: Journal of Clinical Oncology (2016)

1592 Background: Most laboratories use publicly available literature, databases, and expertise to determine the pathogenicity of genetic variants. Recently, discordances between public databases have been raised as a concern, most prominently by those who use proprietary data in their classification processes. However, the clinical impact of these differences is unclear, as experienced and responsible lab directors never simply copy variant classifications from any public database. Instead, they critically evaluate underlying evidence and determine classifications following established guidelines (i.e., ACMG 2015). In prior work, we observed 99.8% concordance between two labs in 975 prospectively accrued patients (Lincoln et al., JMD 2015). Here we evaluated classification concordance among multiple labs in a much larger patient population. Methods: We analyzed the BRCA Exchange dataset, based on ClinVar and under development by the Global Alliance for Genomics and Health's BRCA Challenge collaboration. We compared classifications from 7 established clinical laboratories in variants from roughly 20,000 patients. Classification discordances were defined as those that change potential actionability. Results: On a per-variant basis, concordance between labs is high: 97.9% to 99.7%. However, this greatly underestimates concordance on a per-patient basis. Most discordant classifications are in rare variants that, by definition, are present in very few patients. Based on observed prevalence, we calculate that 99.8% of patients would receive concordant reports, similar to our prior study’s result. Conclusions: While classification differences are seen in few patients, it is important to analyze and resolve them collaboratively, not competitively, as is done in all other areas of medicine. Thorough peer review of classifications in public databases both supports laboratory quality control efforts and helps improve evolving practice guidelines.
Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis
Authors: Teresa M. Ribeiro-Rodrigues, Tiago L. Laundos, Rita Pereira-Carvalho, Daniela Batista-Almeida, Ricardo Pereira, Vanessa Coelho-Santos, Ana P. Silva, Rosa Fernandes, Monica Zuzarte, Francisco J. Enguita, Marina C. Costa, Perpetua Pinto-do-Ó, Marta T. Pinto, Pedro Gouveia, Lino Ferreira, Justin C. Mason, Paulo Pereira, Brenda R. Kwak, Diana S. Nascimento, Henrique Girão
Journal: Cardiovascular Research (2017)

Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs).Exosomes secreted by H9c2 myocardial cells and primary cardiomyocytes, cultured either in control or ischaemic conditions were isolated and added to ECs. We show that ischaemic exosomes, in comparison with control exosomes, confer protection against oxidative-induced lesion, promote proliferation, and sprouting of ECs, stimulate the formation of capillary-like structures and strengthen adhesion complexes and barrier properties. Moreover, ischaemic exosomes display higher levels of metalloproteases (MMP) and promote the secretion of MMP by ECs. We demonstrate that miR-222 and miR-143, the relatively most abundant miRs in ischaemic exosomes, partially recapitulate the angiogenic effect of exosomes. Additionally, we show that ischaemic exosomes stimulate the formation of new functional vessels in vivo using in ovo and Matrigel plug assays. Finally, we demonstrate that intramyocardial delivery of ischaemic exosomes improves neovascularization following MI.This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply.
Mucosectomie pour tumeur superficielle du rectum et du colon: résultats à 6 mois
Authors: P Bulois, V Maunoury, P Houcke, E Vaillant, P Desurmont, P Gallais, E Leteurtre, A Cortot
Journal: Endoscopy (2006)

La mucosectomie endoscopique est devenue le traitement de référence des tumeurs rectocoliques superficielles. Elle permet l'obtention d'une pièce opératoire dont l'analyse conditionne la conduite à tenir ultérieure. Le but de ce travail était d'évaluer les résultats de la mucosectomie colorectale, ses complications et d'évaluer la qualité des pièces opératoires obtenues.
Analysis of chemo-predictive assay for targeting cancer stem cells in 41 glioblastoma patients.
Authors: Candace M Howard, Anthony Alberico, Jagan Valluri, Michael Griswold, Pier Paolo Claudio
Journal: Journal of Clinical Oncology (2017)

e13544 Background: We have developed a drug response assay (ChemoID) that identifies effective chemotherapy against cancer stem cells (CSCs) vs. bulk of tumor cells from of a panel of potential treatments. A prospective study was conducted evaluating the use of the CSC drug response assay in glioblastoma patients treated with standard-of-care. Methods: 41 glioblastoma patients were enrolled in an IRB-approved protocol. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Results: For every 5% increase in in-vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR=2.2 (p=0.016). Similar associations with the bulk tumor test were seen, OR=2.75 (p=0.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (p=0.036) but a much attenuated remaining bulk tumor association, OR=1.46 (p=0.472). Areas under the curve (AUC) and [sensitivity/specificity] at optimal outpoints (&gt;40% CSC cell kill and &gt;55% bulk tumor cell kill) were AUC=0.989 [Sens=100/Spec=97], 0.972 [100/89] and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification non-event NRI and overall NRI = 0.111, p=0.030). Median recurrence time was 20 months for patients with a positive (&gt;40% cell kill) CSC test versus only 3 months with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (&gt;55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS. Results across 14 potential other treatments indicated that 34/41 (83%) and 27/41 (66%) potentially more optimal alternative therapies may have been chosen using CSC results and Bulk results, respectively. Conclusions: The ChemoID assay has the potential to increase the accuracy of bulk tumor assays.
First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3: Final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC).
Authors: Maria Alsina, Valentina Boni, Jan H.M. Schellens, Victor Moreno, Kees Bol, Martine Westendorp, L. Andres Sirulnik, Josep Tabernero, Emiliano Calvo
Journal: Journal of Clinical Oncology (2017)

2522 Background: MCLA-128 is a novel IgG1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity targeting HER2 and HER3 receptors. We report final phase 1 single agent escalation data, and safety and preliminary activity at the recommended phase 2 dose (RP2D). Methods: In the phase 1 part, patients (pts) with advanced solid tumors received MCLA-128 every 3 weeks (q3w) IV over 1-2 hr from 40 to 900 mg. In the phase 2 part, pts with selected metastatic indications were treated at the RP2D. Antitumor activity was assessed as per RECIST 1.1. Clinical benefit rate (CBR) was defined as CR + PR + SD ≥12 weeks. Results: As of January 2017, 28 advanced solid tumor pts were treated in the escalation part. No dose limiting toxicities were seen. The RP2D was established as 750 mg q3w (flat dose, corticosteroid premedication) based on safety and PK data. Fifteen pts with HER2 amplified tumors were treated at the RP2D (8 MBC, 4 gastric, 2 ovarian, 1 colorectal). Median age was 52 years (range 33-71), ECOG PS 0/1: 3/12, all ≥2 metastatic sites. The safety profile at the RP2D confirmed dose escalation data; the most common AEs were infusion related reactions in 6 pts (40%; G1-2 in 5 pts, G4 in 1 pt), and G1-2 diarrhea, rash, fatigue in 2 pts each (13%). No congestive heart failure or significant LVEF decreases occurred. The 8 MBC pts had a median 5.5 prior lines of metastatic therapy (range 4-14), all had progressed on 3 prior Her2 inhibitor therapies and received a median of 4.5 MCLA-128 cycles (range 2-12); 1 had a confirmed PR, 5 had SD (including 2 sustained, 11 and 12 cycles). SD was also seen in 2 evaluable MBC pts treated at 480 mg in the phase 1 part (7 and 4 cycles). Overall, CBR in these 10 MBC pts was 70%. Evaluation of other indications is ongoing. Conclusions: MCLA-128 showed a well tolerated safety profile. Consistent antitumor activity was seen in heavily pretreated MBC patients progressing on HER2 therapies. Further exploration of MCLA-128 based combinations with chemotherapy or trastuzumab in less pretreated MBC patients progressing after ≥2 prior Her2 inhibitors including TDM-1 is planned. Clinical trial information: NCT02912949.
A multicenter, 3-arm, open-label, phase IIa clinical trial to evaluate the safety and efficacy of tanibirumab (VEGFR2 mAb), in patients with recurrent glioblastoma (GBM).
Authors: Lawrence Cher, Anna K. Nowak, George Iatropoulos, Weon Sup Lee, Seon Young Lee, Sang Ryeol Shim, Jin San Yoo
Journal: Journal of Clinical Oncology (2017)

e13522 Background: Treatment of recurrent GBM remains a challenge. The VEGF signal transduction pathway is upregulated in GBM. We evaluated Tanibirumab, a mAb to VEGFR2, in an open-label, dose-escalation, 3-arm, Phase 2a clinical trial. Primary and secondary endpoints were determining safety and efficacy (6-month PFS, ORR, DCR and OS). Methods: Eligibility criteria included age ≥19 yrs at 1 st or 2 nd recurrence of GBM, measurable disease, KPS≥80, and no prior bevacizumab. Patients were enrolled in 3 arms: Arm 1 (8mg/kg d1,8,15/q28 days); Arm 2 (12mg/kg d1,8,15/q28 days) and Arm 3 (12mg/kg weekly). Response evaluation with MRI (RANO criteria) including DCE, was performed every 2 cycles. Results: 12 patients were enrolled over 10 months from 2 sites: 3 patients each in Arms 1 &amp; 2; 6 in Arm 3. The median age was 50 years and 8 were male. 6 patients had second recurrence. At 1 st infusion, 8 out of 12 were on baseline corticosteroids. 10 patients have progressed. No dose limiting toxicities (DLT) were observed. Cutaneous hemangiomas (CH) were frequent (83% of patients) and all G2 or less. No drug-related G3 or 4 AEs were observed. All SAEs were unrelated to the study drug apart from G2 bleeding haemangioma and G2 cerebral haemorrhage. Expected AEs with anti-angiogenic drugs (hypertension; impaired wound healing) were not observed. Among 12 patients allocated to Arm 1, 2 and 3, no objective radiological responses were observed. 3 patients demonstrated stable disease (SD); 2 patients had SD beyond 4 cycles and are still receiving treatment at weeks 45 (Arm 1) &amp; 20 (3). This was correlated with the highest expression of VEGFR2 using immunohistochemistry on archival tumour and blood vessels. Only 2 patients needed to initiate or increase corticosteroids for control of tumor edema while on treatment. Current data are immature to determine time to event efficacy endpoints (PFS,OS). Conclusions: Tanibirumab can be safely administered to patients with recurrent GBM, with CH being common. SD was seen in 2 patients up to 10+ months, with some indication that VEGFR2 expression may be a response biomarker. Clinical trial information: NCT03033524.
Correlation of mutation status between tissue and blood-drop liquid biopsies from ovarian cancer patients following chemotherapy.
Authors: Angelina I Londono, Chen-Hsiung Yeh, Ronald David Alvarez, Charles A. Leath, John Michael Straughn, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2016)

e13108 Background: Peripheral circulating cell-free DNA (cfDNA) has great promise for targeted therapy and monitoring tumor clonal evolution during treatment, thus overcoming the limitations of invasive tissue biopsy. However, the requirement of large sample input, low extraction efficiency, and poor yield, coupled with a labor-intensive and time-consuming procedure in order to obtain a liquid biopsy presents a major challenge. Methods: Circulogene has developed a highly efficient and high yield cfDNA enrichment technology from only 20ul of blood. We were able to sequence cfDNA and tumor DNA from 14 de-identified plasma and tumor tissue samples pre- and post- chemotherapy for a total of 56 samples. We ascertained the mutation status of five therapeutically targetable genes implicated in ovarian cancer: TP53, PIK3CA, PTEN, KRAS, and BRAF. These genes were interrogated by deep next-generation sequencing, and concordance was determined between matched tissue and plasma, and pre- and post-treatment samples. Results: 13 out of 14 of the samples, either tissue or plasma, contained at least 1 mutation. Overall, more mutations were detected in plasma than the corresponding tissue samples at baseline, and much less dramatic mutation changes were observed in tissue than plasma following therapy, indicating that a more complete tumor heterogeneity landscape was captured from the blood. The genomic response to chemotherapy was consistent in both tissue and plasma samples. The overall frequency of TP53, PIK3CA, PTEN, KRAS, BRAF mutations in both patient cohorts (pre and post chemotherapy) were 100%, 16.7%, 6.7%, 6.7%, 0% in tissue, and 70%, 30%, 20%, 0%, 0% in plasma, respectively. The concordance of TP53, PIK3CA, PTEN, KRAS, BRAF mutation status between matched tissue and plasma was 33.3%, 86.7%, 73.3%, 93.3%, 100%, respectively. Conclusions: These results illustrate the potential utility of our blood-drop liquid biopsy as a non-invasive, real-time and longitudinal means for monitoring treatment response, outcomes and disease progression, and could become an invaluable tool clinical decision-making.
Immunological targeting of CD133 in recurrent glioblastoma: A multi-center phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy.
Authors: Jeremy David Rudnick, Karen L. Fink, Joseph C. Landolfi, James Markert, David Eric Piccioni, Michael J. Glantz, Steven J. Swanson, Anthony Gringeri, John Yu
Journal: Journal of Clinical Oncology (2017)

2059 Background: A hallmark of glioblastoma is the high incidence of tumor recurrence, thought to be triggered by cancer stem cells. These tumorigenic cells are resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, was chosen because it has been reported as a cancer stem cell antigen overexpressed in glioblastoma tumors and associated with shorter survival. Recent clinical trials suggest that the mean overall survival for these patients is roughly 5-9 months, emphasizing the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies such as ICT-121 could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease. Methods: This Phase I multi-center trial of ICT-121 targeting CD133 was designed to assess safety and tolerability (primary endpoint) and to monitor overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. CD133 is overexpressed on glioblastoma cancer stem cells. The HLA-A2 patients that had undergone resection for recurrence of glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. Results: A total of 20 patients were treated and eight of these patients are still alive. Immune response data with cytokine mRNA expression demonstrated a response to the CD133 epitopes. A total of 20 patients were treated and eight of these patients are still alive. Conclusions: The results from this Phase I trial suggest that ICT-121 is both safe and well-tolerated with an immune response seen in a subset of patients. Clinical trial information: NCT02049489.