tbuckley/cabot-search huggingface dataset:
Colorectal cancer (CRC) patients surveyed by <sup>18</sup>FDGPET-CT (PET-CT): An open-label multicenter randomized trial (NCT 00624260).
Authors: Iradj Sobhani, Isabelle Baumgaertner, Emmanuel Itti, Alain Luciani, Richard Layese, Pierre Andre Natella, Jean Marc Gornet, Thierry Andre, Gael Goujon, Thomas Aparicio, Julien Taieb, Jean-Baptiste Bachet, Michel Ducreux, Christophe Tournigand, Francois Hemery, Isabelle Durand-Zaleski, Sylvie Bastuji Garin
Journal: Journal of Clinical Oncology (2017)

3520 Background: Curative surgery is the best therapy of CRC and recurrences. We assessed whether adding semi-annual PET-CT to the usual surveillance would be cost-effective in high risk recurrent CRC patients. Methods: CRC patients (stage II tumor perforated, stages III and IV) in remission after curative surgery were randomly assigned (1:1) to trimester usual surveillance (control) or usual surveillance + semi-annual course PET-CT (intervention) for a 3-yr follow up period. Every 3 months, multidisciplinary committee decided about recurrence by yes/no/doubtful. If yes, curative surgery alone (when relevant), or chemotherapy alone (unresecable recurrence) were conducted; additional exams could be performed if doubtful. Primary composite endpoint (failure) comprised unresectable recurrence &amp; death. The economic assessments according to standards (CHEERS) were performed and costs were compared between groups. Statistical tests for calculation of the relative risk (RR) were used and survival was analyzed using Kaplan-Meier method, Log-Rang test and Cox models. Results: Baseline characteristics of 239 patients (120/119) enrolled in 12 centers were balanced. The failure rate was 29.2% (31 unresectable recurrences &amp; 4 deaths) and 23.5% (27 &amp; 1) in Interventional vs Control, respectively with no significant difference (RR = 1.24, 95% CI: 0.81-1.90; P = .32). Similar results were observed in multivariate analysis (Cox models) adjusted for stage and tumor differentiation (HR = 1.33, 95% CI: 0.8-2.19, P = .27). Period until the unresectable recurrence was significantly shorter in Interventional (median = 7; IQR: 3-20 months) than in Control group (14.3; 7.3-27; P= 0.016). This was consistent with lower elevation (median; IQR) of tumour marker in interventional (3.8; 2.8-19) than in control group (10; 5.2-28.6) at the first recurrence time as compared to the baseline (p = 0.007). Overall (mean; SD) cost (euros)/patient was higher in the PET-Scan (9385; 11658) than in the control group (7027; 7656). Conclusions: Although recurrences were detected earlier in PET-CT group, the strategy was less effective, more expensive. This exam should not be advised routinely. Clinical trial information: NCT 00624260.
Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy
Authors: Terry J Smith, Joseph A M J L Janssen
Journal: Endocrine Reviews (2018)

Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.
Identification of resistance mechanisms for EGFR-targeted therapy in head and neck squamous cell carcinoma: Combining whole-exome sequencing and tumour kinase profiling
Authors: I. de Pauw, A. Wouters, J. Van den Bossche, K. Op de Beeck, M. Beyens, H. Baysal, P. Pauwels, M. Peeters, J.B. Vermorken, F. Lardon
Journal: Annals of Oncology (2018)

Background: The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies such as cetuximab is a major clinical problem. This study aims to unravel resistance mechanisms by combining whole-exome sequencing (WES) and tumour kinase profiling. Based on the genetic and tumour kinase profile, new combination treatments can be designed to overcome therapy resistance. Methods: Acquired cetuximab resistant HNSCC cell lines (SC263-R and SCC22b-R) were generated by chronically exposing initially sensitive cell lines to cetuximab. In parallel, control cell lines (SC263-PBS and SCC22b-PBS) were established by exposing these cells to the vehicle control. DNA samples were sequenced using Illumina's HiSeq 1500 platform and variant calling was performed. Proteome Profiler Human Phospho-Kinase Antibody Array kit (R&D Systems) was used to determine the relative levels of protein kinase phosphorylation in sensitive and acquired resistant cell lines after cetuximab treatment. Results: Variant calling in cetuximab sensitive and acquired resistant cell lines demonstrated 10 and 1 novel single-nucleotide variants (SNVs) in SC263-R and SCC22b-R, respectively. Based on gene functions, these SNVs might be responsible for resistance to cetuximab treatment. Phospho-kinase analysis showed increased phosphorylation of Akt1/2/3 after cetuximab treatment in acquired resistant cells compared to sensitive cells. As such, combining cetuximab with an Akt1/2/3 inhibitor could be an interesting new combination treatment. Results obtained from WES and tumour kinase profiling will be further validated using Sanger sequencing and western blot, respectively. Conclusions: This study demonstrated that resistance mechanisms for EGFR-targeted therapy can be identified through genetic and tumour kinase profiling. Our results showed that SNVs and increased Akt1/2/3 phosphorylation may lead to acquired cetuximab resistance. Personalised therapy using combinations of targeted therapies based on the molecular profile of the tumour may achieve the much-needed progress in HNSCC treatment. Legal entity responsible for the study: University of Antwerp. Funding: Stand Up to Cancer (the Flemish Cancer Society) and University of Antwerp. Disclosure: All authors have declared no conflicts of interest.
miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1
Authors: Yu-Shui Ma, Fei Yu, Xiao-Ming Zhong, Gai-Xia Lu, Xian-Ling Cong, Shao-Bo Xue, Wen-Ting Xie, Li-Kun Hou, Li-Juan Pang, Wei Wu, Wei Zhang, Le-Le Cong, Tie Liu, Hui-Deng Long, Ran Sun, Hong-Yan Sun, Zhong-Wei Lv, Chun-Yan Wu, Da Fu
Journal: Molecular Therapy (2018)

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.
Germline sequencing of advanced prostate cancer patients in the BARCODE2 study.
Authors: Sarah Benafif, Ian Whitmore, Ezequiel Anokian, Clara Cieza-Borrella, Ed Saunders, Zsofia Kote-Jarai, Ros A. Eeles
Journal: Journal of Clinical Oncology (2018)

e13617 Background: The BARCODE2 study is investigating the response to platinum chemotherapy in men with advanced prostate cancer (PrCa) and a germline mutation in a DNA repair gene. We present the germline DNA sequencing results for the initial cohort of men who underwent genetic screening. Methods: Eligible men with advanced PrCa consented to study entry and provided a blood sample for DNA extraction and sequencing. All patients were known to have metastatic castration resistant prostate cancer (mCRPC) and were undergoing treatment with either chemotherapy (docetaxel) or androgen receptor targeted therapy (abiraterone or enzalutamide). Patients were unselected for age, ethnicity or family history. Next generation sequencing (NGS) using a customised 115 gene panel (Agilent Technologies) was carried out on a MiSeq machine. NGS data was processed and analysed using SureCall (Agilent Technologies) software. Only clearly pathogenic variants (i.e. protein truncating variants (PTV)) were considered to yield a positive genetic screening result. PTVs were validated by Sanger sequencing. Results: 41 patients have undergone genetic testing in the study. Patient age at study entry ranged between 51-80 years (median 69). 8 patients (19.5%) carried a heterozygous PTV in a DNA repair gene: 2 mutations in each of BRCA2 and ALKBH3, and 1 in each of: CHEK2, EXO1, MSH5 and PMS1. When comparing age at prostate cancer diagnosis, there was no significant difference between gene mutation carriers and non-carriers (mean age 57.6 years vs 61; t-test p = 0.18). Conclusions: The initial NGS results in the BARCODE2 trial demonstrate a higher frequency of germline mutations in mCRPC patients compared with previously published data. This study is ongoing and aims to sequence 450 patients. If the frequency of germline mutations in men with advanced PrCa is confirmed to be in the range of 15-20%, this would support the roll-out of routine genetic testing in the oncology setting to identify men who may benefit from targeted treatments such as platinum chemotherapy and PARP inhibitors.
The characteristics of ARID1A mutations in colorectal cancer.
Authors: Amir Mehrvarz Sarshekeh, Jonathan M. Loree, Ganiraju C. Manyam, Allan Andresson Lima Pereira, Kanwal Pratap Singh Raghav, Michael Lam, Jennifer S Davis, A. Dasari, Van Karlyle Morris, David Menter, Cathy Eng, Russell Broaddus, Mark Routbort, Rajyalakshmi Luthra, Dipen M. Maru, Michael J. Overman, Funda Meric-Bernstam, Scott Kopetz
Journal: Journal of Clinical Oncology (2018)

3595 Background: AT-rich interactive domain 1A (ARID1A) is a component of the SWI/SNF chromatin remodeling complex that regulates gene expression. Inactivating mutations of ARID1A have been reported in a variety of cancers but data on characteristics and associated clinicopathologic features in colorectal cancer (CRC) are limited. Methods: Data for patients (pts) with CRC whose tumors underwent comprehensive genomic profiling were reviewed using the Cancer Genome Atlas (TCGA), Nurses' Health Study and Health Professionals' Follow-up Study (NHS/HPFS), AACR Project GENIE and MD Anderson Cancer Center databases. Results: Among 3127 pts, 196 (6.2%) had a mutation in ARID1A. Across the datasets, 249 mutations in ARID1A were identified. Mutations were more likely to be frameshift or nonsense as compared with mutations in other genes (64.0% vs. 9.1%, OR = 7.0, 95% CI 5.6-8.7; p< .001) and the majority were considered clonal by allele frequency (defined as > 25%). The mutation locations were broadly distributed, although 10 recurrent (hot-spot) regions were identified. ARID1A mutations were associated with MSI-H status (OR = 8.1, 95% CI 4.4-14.8; p< .001), with PIK3CA mutations (OR = 2.8, 95% CI 2.1-3.9; p< .001), and BRAF mutations (OR = 3.1, 95% CI 2.2-4.4; p< .001) but had inverse correlation with TP53 mutations (OR = 0.5, 95% CI 0.4-0.7; p< .001). Of note, 18/23 (74%) of tumors with ARID1A mutations were classified as consensus molecular subtype-1 (CMS-1) with OR of 17 (95% CI 4.8-63.7; p< .001). The mutations were associated with PPAR and HNF4 transcription factor activity. ARID1A mutations were more common in early stages (OR = 1.83, 95% CI 1.09-3.07; p= 0.019) and right-sided tumors (OR = 1.66, 95% CI 1.01-2.71; p= 0.034). There was no association between ARID1A mutation and race, gender, age at the time of diagnosis, grade, or presence of distant metastases. Conclusions: This is the largest study evaluating ARID1A mutations in CRC. The majority of mutations appear to be truncating and clonal, suggesting that they have functional significance. ARID1A-mutated tumors demonstrate enrichment of wild-type TP53 but they are more likely to have MSI-H, PIK3CA and BRAF mutations. The transcriptional signature may indicate future therapeutic strategies for this subgroup.
Management of Acute Myeloid Leukemia Patients Old than 60 Years in Casablanca: A Great Challenge in Developing Countries
Authors: Romaric Mahutondji Massi, Mouna Lamchahab, Bienvenu Houssou, Nheza Hda, Nisrine Khoubila, Siham Cherkaoui, Bouchra Oukkache, Asmaa Quessar
Journal: Cancer Research (2018)

Introduction: AML is the most common form of acute leukemia in adults, accounting for 25% of leukemias in this population in the Western world. The characteristics of AML in the elder patients are different from those in young patients characterized by a high prevalence of poor prognosis cytogenetic abnormalities. All these factors make AML in patients older than 60 years to be an particular entity wich management is very difficult in developing countries. Data on this group of AML patients are rare in our context and the Morocco national AML-MA 2011 protocol wich is use for the treatement of AML is limited for patients aged less than 60 years. The aim of our study was to describe the epidemiological, clinical, biological characteristics of AML patients aged over 60 in the departement and to highlight the dificulties wich occurred in their management. Patients and method: A retrospective study was conducted from 1 January 2003 to 1 January 2016 including, all cases of AML patients olders than 60 years, diagnosed according to WHO criteria. Conventional cytogenetics was made in RGH band on medullary or blood samples. Results: 266/1741 (15.28%) cases were recorded during the study. The median age was 70 years (61-98ans) and the sex ratio was 1.12. The median leukocyte count at diagnosis was 33,891 / mm3 (450-347000). 52/266 (20%) patients had hyperleucocytosis more than 50G/L at diagnosis. The mean hemoglobin level at diagnosis was 6.4 g / dl (3-10.3d / dl), the mean platelet count was 76525mm3 (5000-262000) 52/266 (20%) had hyperleucocytosis. 140 patients (52.6%) had a karyotype of which 3% favorable prognosis, 67% intermediate prognosis, and 30% unfavorable prognosis. Conclusion: AML patients old than 60 years represent an important part of AML patients in the departement. Their characteristics are the same like in literature with a dominance of intermediate prognosis group. Very few are treated with intensive chemotherapy in our series.
Delayed PSA responses in metastatic castration resistant prostate cancer (mCRPC) patients (pts) treated with sipuleucel-T.
Authors: Xiao X. Wei, Anis Hamid, Monica He, Lauren Christine Harshman, Toni K. Choueiri, Guru Sonpavde, Mark Pomerantz, Mary-Ellen Taplin, Christopher Sweeney, Atish Dipankar Choudhury
Journal: Journal of Clinical Oncology (2018)

e17041 Background: Sipuleucel-T (Provenge) received FDA approval in April 2010 for pts with asymptomatic or minimally symptomatic mCRPC based on prolongation of overall survival. However, its adoption is hindered by a lack of tangible treatment effects such as PSA decline (2.6% in phase III IMPACT trial). We hypothesize that PSA decline after sipuleucel-T may be delayed due to a longer time required to mount an immunological response than that seen with cytotoxic agents. Methods: We conducted a retrospective review of consecutive mCRPC pts treated with sipuleucel-T at Dana-Farber Cancer Institute between 4/2010 and 4/2017. Only pts who were not initiated on a new mCRPC-directed therapy until ≥6 months after completing sipuleucel-T were included. Pre-treatment PSA ≥0.1 was required. Pts who had evidence of antiandrogen withdrawal response or received radiation or mCRPC-directed therapy immediately before or during sipuleucel-T that may influence PSA response were excluded. Concurrent therapy was allowed if PSA was rising prior to initiation of sipuleucel-T. PSA decline (≥10% and ≥50%) and PSADT prolongation by ≥50% were the primary and secondary endpoints, respectively. Results: Of 255 pts who received sipuleucel-T, 31 pts were included in the analysis. Median age was 71, and median baseline PSA was 3ng/mL (range: 0.12-94.5). Nine (29%) pts had node-only metastasis, and 22 (71%) pts had bone metastasis. Twenty-three (41%) pts had received prior mCRPC directed therapy, of whom 5 had received prior abiraterone or enzalutamide. Nine (29%) and four (13%) pts had ≥10% and ≥50% PSA decline below baseline, respectively. The median PSA decline was -31% (range: -10 to -92). Median time to maximum PSA decline was 5.2 months (range: 2.1-6.8). Of the 22 pts who did not experience ≥10% PSA decline, 20 were evaluable for pre- and post-treatment PSADT and 7 (35%) had prolongation of pre-treatment PSADT by ≥50% after sipuleucel-T. Conclusions: In this cohort of mCRPC pts who did not require immediate initiation of next line of therapy, vaccination with sipuleucel-T appeared to induce delayed PSA responses and modulate PSA kinetics in a subset of patients.
Predictive impact of complete molecular response in plasma: A phase II, liquid biopsy study in <i>EGFR</i> mutated NSCLC patients treated with afatinib (WJOG 8114LTR).
Authors: Kohei Otsubo, Hiroaki Akamatsu, Yasuhiro Koh, Satoshi Morita, Daichi Fujimoto, Akihiro Bessho, Koichi Azuma, Kazuhiko Nakagawa, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2017)

9027 Background: Liquid biopsy has been approved as an alternative method to detect clinically relevant EGFR mutations in NSCLC. However, it is unknown whether the early assessment of molecular response in plasma could be a surrogate of clinical response and/or longer efficacy. Here, we conducted a prospective, multi-institutional study of liquid biopsy in EGFRmutated NSCLC patients (WJOG 8114LTR). Methods: Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFRmutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop system, RainDance Technologies, Billerica, MA). Complete molecular response (CMR) was defined as mutant allele event/frequency of exon 19 deletion or exon 21 L858R below the cutoff for the positivity by digital PCR in plasma. This study was registered at UMIN (ID: 000015847). Results: Fifty-seven patients were registered in the study. Efficacy of afatinib was comparable to previous reports (overall response rate: 78.6%, and median progression-free survival (mPFS): 14.2 months). At baseline, 62.5% of patients were positive for EGFR mutation in plasma. Plasma positive patients had slightly shorter PFS than plasma negative patients, but not significant (p = 0.24, log-rank). Among those who were positive at baseline, CMR was achieved in 60.6% of patients at two weeks, and 87.5% at four weeks, respectively. Patients with CMR at two weeks had significantly longer PFS than those without one (13.6 versus 7.5 months, p = 0.0001). Patients with CMR at four weeks also demonstrated longer PFS than those without one (13.6 versus 5.1 months, p &lt; 0.0001). Among patients who achieved CMR by week four, time to achieve CMR did not affect PFS ( p= 0.59). Conclusions: This is the first report on the predictive impact of early CMR in plasma for longer therapeutic efficacy of afatinib in EGFR mutated NSCLC patients. Clinical trial information: 000015847.
Abstract 14933: Il-6 in Aortic Stenosis: Amplification Loop Between Inflammation and Calcification
Authors: Diala El Husseini, Marie-Chloe Boulanger, Dominique Fournier, Phillippe Pibarot, Yohan Bosse, Patrick Mathieu
Journal: Circulation (2013)

BACKGROUND: Calcific aortic valve disease (CAVD) is the most common valvular heart disease and aortic valve replacement is the only available cure. CAVD is a disorder characterized by a calcification and a fibrosis of aortic valve. Inflammatory infiltrates mainly consists in macrophages, leukocytes and T cells. Our goal was to study the role of IL6 during calcification and explore molecular mechanism associated with its action. METHODS AND RESULTS: A microarray analysis of IL6 gene expression profile in CAVD, compared with control valves, showed that IL6 is increased during mineralization. QPCR results confirmed that IL6 transcripts are increased by 8.9 fold in CAVD. Immunohistochemistry assays demonstrated that IL6 is present in vicinity of calcium nodules in CAVD. In vitro experiments, in human valve interstitial cells (VICs), revealed that exposure to a phosphate-rich medium (Pi) increased IL6 mRNA and protein. In addition, cells transfected with siRNA directed against IL6 have a reduced level of miner...