tbuckley/cabot-search huggingface dataset:
Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2.
Authors: Rita Nanda, Minetta C. Liu, Christina Yau, Smita Asare, Nola Hylton, Laura Van't Veer, Jane Perlmutter, Anne M. Wallace, Amy Jo Chien, Andres Forero-Torres, Erin Ellis, Heather Han, Amy Sanders Clark, Kathy S. Albain, Judy Caroline Boughey, Anthony D. Elias, Donald A. Berry, Douglas Yee, Angela DeMichele, Laura Esserman
Journal: Journal of Clinical Oncology (2017)

506 Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, &amp; MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw &amp; Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, &amp; serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw &amp; estimated pCR rates by &gt;50% &amp; 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis &amp; 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]
Human Papillomavirus DNA Methylation Predicts Response to Treatment Using Cidofovir and Imiquimod in Vulval Intraepithelial Neoplasia 3
Authors: Sadie E.F. Jones, Samantha Hibbitts, Christopher N. Hurt, Dean Bryant, Alison N. Fiander, Ned Powell, Amanda J. Tristram
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting. Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing. Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n = 30), median E2 methylation was significantly higher in patients who responded (P ≤ 0.0001); E2 methylation &amp;gt;4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n = 33), median E2 methylation was lower in patients who responded to treatment (P = 0.03; not significant after Bonferroni correction); E2 methylation &amp;lt;4% predicted response with 70.6% sensitivity and 62.5% specificity. Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. Clin Cancer Res; 23(18); 5460–8. ©2017 AACR.
Phase III randomized, open label study (ARCHER 1050) of first-line dacomitinib (D) versus gefitinib (G) for advanced (adv) non-small cell lung cancer (NSCLC) in patients (pts) with epidermal growth factor receptor (<i>EGFR</i>) activating mutation(s).
Authors: Tony Mok, Kazuhiko Nakagawa, Rafael Rosell, Yi Long Wu, Carl Trygstad, Robert L. Capizzi, Min Young Lee, Fumito Tsuji, Robert DeBenedetto, Zelanna Goldberg, Tao Wang, Jane Q. Liang, Stephen P. Letrent, Joseph P. O'Connell, Vladan Antic
Journal: Journal of Clinical Oncology (2013)

TPS8123 Background: D is an orally available, potent and selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family tyrosine kinases that has shown activity in preclinical studies on EGFR mutant cell lines, including those resistant to G. In a phase II trial of NSCLC pts who received 1 st -line D, 75.6% of 45 pts with confirmed EGFR exon 19 or 21 sensitizing mutations (m) experienced a partial response (PR). The median progression-free survival (PFS) was 18.2 mo, and the PFS rate at 1 yr was 76.5% (preliminary data; Mok et al APLCC 2012). Methods: Based on the phase II data, a phase III randomized, open label trial (ARCHER 1050; NCT01774721) was designed to compare the efficacy of 1 st line D with G in pts with adv EGFR m-positive NSCLC. Eligible pts (N=440) have pathologically confirmed stage IIIB/IV NSCLC with at least one activating EGFR m, either exon 19 deletion or exon 21 L858R m. Concurrent m in exon 20 T790M is permitted. Pts must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Pts will be randomized (1:1) to receive D 45 mg or G 250 mg orally once daily. The primary endpoint is PFS by Independent Radiologic Review. Secondary endpoints include PFS by investigator assessment, overall survival (OS), OS at 30 mo, best overall response, duration of response, and safety and tolerability. Pt-reported outcomes (HRQoL and disease/treatment-related symptoms) were also assessed. Randomization will be stratified by race (Japanese vs mainland Chinese vs other East Asian vs nonEEast Asian), and EGFR m status (exon 19 deletion vs exon 21 L858R m). A minimum of 268 PFS events is required for 90% power to detect a PFS improvement of ≥50% in D vs G recipients using the intent-to-treat (ITT) analysis population (HR ≤0.667). A significant (0.025 significance level) 1-sided stratified log-rank test for PFS at the final PFS analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility. Clinical trial information: NCT01774721.
Abstract NTOC-111: TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS
Authors: Sarah R. Walker, Yixi Zhang, Suhu Liu, Zachary T. Giaccone, David A. Frank
Journal: Clinical Cancer Research (2017)

Abstract High grade serous ovarian cancer remains deadly for countless women; therefore, better treatment options are necessary. To identify new targeted therapies for this disease, it is necessary to delineate critical signaling pathways that are driving the pathogenesis of ovarian cancer. Since ovarian cancer in patients grows as three dimensional clusters, particularly within the peritoneum, we examined signaling pathways that were activated with 3D culture in vitro. Comparing the growth of ovarian cancer cell lines in 2D and 3D, we found that the transcription factor STAT3 consistently becomes activated in 3D culture systems. Ovarian cancer cells that lack STAT3 activation when grown in 2D acquire STAT3 activation when grown in 3D. Additionally, ovarian cancer cell lines that have constitutively active STAT3 when grown in 2D display enhanced STAT3 activation when these cells are grown in 3D. STAT3 is often activated through autocrine or paracrine mechanisms via cytokine receptors interacting with the transmembrane signal transducing molecule GP130 and intracellular Jak kinases. Once activated, these kinases tyrosine phosphorylate STAT3, which then translocates to the nucleus, binds to cognate DNA binding sites, and regulates genes that are involved in migration, invasion, and survival. We have found that not only is STAT3 tyrosine phosphorylated in cells grown in 3D, but that STAT3 is functionally active such that STAT3 DNA binding and target gene expression is enhanced in ovarian cancer cells grown in 3D versus 2D. We next determined if STAT3 signaling was necessary for ovarian cancer cell growth in 3D. Using RNA interference directed to STAT3 or GP130, we found that both proteins are necessary for the 3D growth of ovarian cancer cells. In addition, we have found that cells grown in 3D are more resistant to cytotoxic drugs; therefore, we wanted to determine if inhibiting STAT3 would enhance the response to conventional chemotherapy. Using both chemical biology and computational approaches, we have identified small molecule inhibitors of STAT3 that target a number of distinct points in the STAT3 activation pathway. We have found that a subset of these compounds disrupt the morphology of ovarian cancer spheroids. Furthermore, combination of these inhibitors with paclitaxel leads to enhanced loss of viability of cells grown in 3D, raising the possibility of using STAT3 inhibitors alone or in combination with chemotherapeutic drugs for the treatment of ovarian cancer. Citation Format: Sarah R. Walker, Yixi Zhang, Suhu Liu, Zachary T. Giaccone, and David A. Frank. TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-111.
Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial
Authors: Eric Rullier, Philippe Rouanet, Jean-Jacques Tuech, Alain Valverde, Bernard Lelong, Michel Rivoire, Jean-Luc Faucheron, Mehrdad Jafari, Guillaume Portier, Bernard Meunier, Igor Sileznieff, Michel Prudhomme, Frédéric Marchal, Marc Pocard, Denis Pezet, Anne Rullier, Véronique Vendrely, Quentin Denost, Julien Asselineau, Adélaïde Doussau
Journal: The Lancet (2017)
Сравнительное исследование эффективности препарата Прогепар у пациентов с неалкогольным стеатогепатитом
Authors: V.G. Perederii, G.K. Syzenko
Journal: GASTROENTEROLOGY (2020)

Неалкогольная жировая болезнь печени (НАЖБП) является одним из самых распространенных заболеваний печени в развитых странах. В среднем ее частота достигает 20 %. У части пациентов ­НАЖБП протекает с наличием воспаления, вакуолизации гепатоцитов и последующим развитием фиброза и цирроза. Такой вариант течения НАЖБП называют неалкогольным стеатогепатитом (НАСГ). Пациенты с НАСГ подвержены более высокому риску развития осложнений, например возникновению гепатоцеллюлярной карциномы или варикозного расширения вен пищевода. Специфическая терапия НАСГ на сегодняшний день еще не разработана. Основные рекомендации для пациентов заключаются в изменении стиля жизни, что имеет определенную эффективность в снижении уровня стеатоза и активности воспаления. Однако быстро прогрессирующее течение НАСГ не всегда возможно контролировать одним только снижением калорийности диеты и увеличением уровня физической активности. Для лечения пациентов с НАСГ также используется неспецифическая терапия, которая способна замедлять прогрессирование заболевания и снижать уровень воспаления. Так как основным механизмом патогенеза НАСГ является оксидативный стресс, исследователи активно изучают действие различных антиоксидантов и их комбинаций. На сегодняшний день представлено большое количество результатов исследований подобных препаратов. Существенным ограничением большой части данных исследований является отсутствие тщательного мониторинга комплайенса и длительности выполнения пациентами рекомендаций по изменению образа жизни. Ведь в данной ситуации особый интерес должны представлять именно те пациенты, у которых высокая степень активности НАСГ сохраняется, несмотря на строгую приверженность к рекомендациям по изменению стиля жизни. В связи с этим требуется проведение дополнительных исследований по оценке эффективности фармакологической терапии у пациентов с НАСГ на фоне длительного изменения образа жизни. В этой статье мы приведем описание и результаты одноцентрового контролируемого исследования по оценке эффективности препарата Прогепар у пациентов с НАСГ с персистенцией активности воспалительного процесса на фоне модификации образа жизни.
Abstract NTOC-114: ARID1A DEFICIENCY IN OVARIAN CLEAR CELL CARCINOMAS UP–REGULATES OXIDATIVE STRESS AND SENSITIZES CELLS TO ROS–INDUCING AGENTS
Authors: Suet-Yan Kwan, Xuanjin Cheng, Suet-Ying Kwan, Daisy I. Izaguirre, Yvonne T.M. Tsang, Jong-Sun Choi, Hoi-Shan Kwan, David M. Gershenson, Kwong-Kwok Wong
Journal: Clinical Cancer Research (2017)

Abstract Inactivating mutations in AT-rich interaction domain 1A (ARID1A) are most frequently found in ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant cancers. In this study, drug responses between ARID1A-wildtype and ARID1A-mutant cell lines were compared using the ‘Genomics of Drug Sensitivities in Cancer’ database. From this analysis, we found that ARID1A-mutant cell lines are more sensitive to elesclomol, which is a reactive oxygen species (ROS)-inducing agent. This finding was validated using a panel of well-characterized ovarian and endometrial cancer cell lines. ARID1A-mutant OCCC cell lines exhibited lower IC50 values and higher apoptotic rates when treated with elesclomol. Knockdown and re-expression of ARID1A in ovarian cancer cells showed that ARID1A is required to protect cancer cells from oxidative stress. In the absence of ARID1A, intracellular ROS levels were increased as determined by flow cytometry. Immunostaining of 4-hydroxy-2-nonenals (4-HNE), one of the products from lipid peroxidation induced by ROS, in OCCC patient samples indicated an up-regulation of oxidative stress in the tumor. We also found that ARID1A negatively regulates the expression of NRF2 which is the major regulator of the antioxidant response in the cell. Knockdown of NRF2 in ovarian cancer cell lines revealed that NRF2 expression may be preferentially required for protection from oxidative stress and cell proliferation in ARID1A-mutant cells. Analysis using The Cancer Genome Atlas (TCGA) UCEC dataset revealed that ARID1A-mutant tumor samples have higher expression of NRF2 and NRF2-target genes. In summary, this study revealed novel roles of ARID1A in protecting ovarian cancer cells against oxidative stress. In the absence of ARID1A, NRF2 is up-regulated and may be required to compensate for ARID1A deficiency. These findings suggest that ARID1A-mutant ovarian cancer cells may be targeted for treatment with ROS-inducing agents and NRF2 inhibitors. Citation Format: Suet-Yan Kwan, Xuanjin Cheng, Suet-Ying Kwan, Daisy I. Izaguirre, Yvonne T.M. Tsang, Jong-Sun Choi, Hoi-Shan Kwan, David M. Gershenson and Kwong-Kwok Wong. ARID1A DEFICIENCY IN OVARIAN CLEAR CELL CARCINOMAS UP–REGULATES OXIDATIVE STRESS AND SENSITIZES CELLS TO ROS–INDUCING AGENTS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-114.
SMRP in screening of mesothelioma in asbestos-exposed workers: A study of 1,704 subjects.
Authors: Manlio Mencoboni, Alex Cioe, Luigi Michelazzi, Andrea Bruzzone, Lisette DelCorso, Claudio Simonassi, Virginia Mortara, Rosangela Filiberti, Paola Marroni, Fabio Spigno
Journal: Journal of Clinical Oncology (2013)

e12518 Background: The soluble mesothelin-related peptide (SMRP) is a marker in the diagnosis for mesothelioma. The role of SMRP as a potential screening tool in subjects with a past asbestos exposure is being debated. Objective: to evaluate SMRP and incidence of malignant mesothelioma in an asbestos exposed cohort. Methods: 1,704 subjects (Median Age 62) occupationally exposed to asbestos were enrolled in the study. A questionnaire on individual characteristics, disease history, and occupational or non-occupational exposure to asbestos was administered. All subjectsunderwent clinical examination and collection of serum sample for SMRP measurement that were repeated after 1 and 2 years. The samples were stored at -80 °C until assayed. Results: Median baseline SMRP was 0.45 nmol/l (range 0.1-4.45). SMRP was higher than 1.5 nmol/l (defined as cut-off) in 40 participants. 9 subjects had recognized lung cancer at the time of screening (median baseline SMRP 0.65 nmo/l, range 0.1-1.7) and 109 had recognized tumors at other sites (median 0.52 nmol/l, range 0.1-3.0). Overall, median follow-up of all subjects was 31.5 months During follow-up, recurrent or metastatic tumors were observed in 23 out of 118 tumors. Sixty-one subjects developed a new tumor. An epithelioid pleural mesothelioma occurred in two subjects, 13 and 17 months after the last SMRP evaluation, respectively. Baseline SMRP was 0.52 nmol/l and 0.17 nmol/l, respectively. In subjects with tumor, SMRP increased of 20-50% in 13 subjects (15%), two of them with abnormal SMRP (1 bladder and 1 prostate cancer). An increase greater than 50% was found in 19 subjects (22%). SMRP was higher than the threshold value in 3 tumors (1 lung, 1 colon and 1 prostate, diagnosed 2 months from last SMRP measure). Overall, mesothelin was above the cut-off in 58 subjects without any evidence of neoplastic disease. Conclusions: we cannot confirm the predictive role of SMRP for mesothelioma because we found two cases with low mesothelin levels 13 and 17 months before the diagnosis. The low number of mesotheliomas could be due to the low median age of our population. It will be intriguing to follow up in the future the subjects that showed an increase of SMRP.
Metabolism and the Evolution of Social Behavior
Authors: Kerry E. Boyle, Hilary T. Monaco, Maxime Deforet, Jinyuan Yan, Zhe Wang, Kyu Rhee, Joao B. Xavier
Journal: Molecular Biology and Evolution (2017)

How does metabolism influence social behavior? This fundamental question at the interface of molecular biology and social evolution is hard to address with experiments in animals, and therefore, we turned to a simple microbial system: swarming in the bacterium Pseudomonas aeruginosa. Using genetic engineering, we excised a locus encoding a key metabolic regulator and disrupted P. aeruginosa's metabolic prudence, the regulatory mechanism that controls expression of swarming public goods and protects this social behavior from exploitation by cheaters. Then, using experimental evolution, we followed the joint evolution of the genome, the metabolome and the social behavior as swarming re-evolved. New variants emerged spontaneously with mutations that reorganized the metabolome and compensated in distinct ways for the disrupted metabolic prudence. These experiments with a unicellular organism provide a detailed view of how metabolism-currency of all physiological processes-can determine the costs and benefits of a social behavior and ultimately influence how an organism behaves towards other organisms of the same species.
Effect of the 21-gene RT-PCR assay on treatment administered in early-stage, node-positive (N+) breast cancer.
Authors: Jennifer Reichert, Jeffrey Patton, Calvin Y. Chao
Journal: Journal of Clinical Oncology (2015)

e11510 Background: Guidelines for treatment of ER+, HER2- breast cancer (BC) recommend the 21-gene RT-PCR assay in node-negative (N-) disease, but remain silent on use of the assay in node-positive (N+) disease since chemotherapy (CT) is recommended for all N+ patients. The assay has been validated for prognosis and prediction of CT benefit in both N- and N+ patients. Influence of the assay on treatment decisions in N- disease has been frequently reported, but there are fewer reports of its effects on CT usage patterns in N+ disease. RainTree Oncology Services evaluated the effect of the assay on CT usage in early-stage, N+ BC at Tennessee Oncology, one of its member practices. Methods: Patients who received the 21-gene assay (Cohort A) were identified by Genomic Health. Patients who had not received the assay (Cohort B) were identified from RainTree’s electronic database. Inclusion criteria were BC surgery between 2009 and 2013, inclusive, for early stage, ER+, HER2- disease with 1-3 positive nodes. Patient demographics, BC metrics, and use of CT were recorded. Results: In Cohort A (N = 119), 62% of patients who received the assay had a Low Recurrence Score (RS) result. Of those, 82% avoided CT. Patients in Cohort A were less likely to receive CT than those in Cohort B (N = 70); 35% versus 60%, respectively. Conclusions: The 21-gene assay identifies many N+ patients to have low risk and low expected benefit from CT. CT usage rates are lower among ER+, HER2- N+ patients receiving the 21-gene assay; however patient selection factors may have contributed to clinicians’ decisions to use the assay for individual patients. The utility of the assay is supported by the large proportion of tested N+ patients who had Low RS results, 82% of whom avoided CT. Cohort A recurrence scores and CT use. Recurrence Score CT n (%) Y n (%) N n (%) Low (≤ 17) 74 (62) 13 (18) 61 (82) Intermediate (18-30) 35 (30) 19 (54) 16 (46) High (≥ 31) 10 (8) 10 (100) 0 (0) Total 119 42 (35) 77 (65)
WHO targets antimicrobial resistance in new essential medicines list
Authors: Anne Gulland
Journal: BMJ (2017)

The antibiotics colistin and some cephalosporins should only be used when all other treatments have failed, the World Health Organization has said, in a bid to combat anti-microbial resistance.1

In the latest edition of its essential medicines list, updated every two years, WHO has grouped antibiotics into three groups—access, watch, and reserve—indicating which can be used for common infections and which should only be used in rare circumstances.

WHO recommends that antibiotics in the access group, which includes amoxicillin, be available at all times to treat common conditions.

The watch group includes antibiotics that are recommended as first or second choice treatments for a small number of infections. In this group are …
Role of T1 Mapping As a Complementary Tool to T2* for Cardiac Iron Overload Assessment
Authors: Camilla Torlasco, Elena Cassinerio, Patrizia Pedrotti, Andrea Faini, Marco Capecchi, Amna Abdel-Gadir, Gianfranco Parati, James C Moon, Maria Domenica Cappellini, Alberto Roghi
Journal: Blood (2016)
In Reply
Authors: Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2007)

respectively), and that infections were the main cause of toxic deaths in both treatment arms, caution is required when using DCF in a standard (elderly) population of patients with advanced gastric cancer.We do not know what the rate of toxic deaths would have been for DCF if the patients included in this trial would have met the median age of 70 years, as in the average population of gastric cancer patients.Thus, results of V325 are only valid for a patient population similar to that of the trial cohort.Further data to evaluate the risk/benefit ratio for the use of DCF in elderly patients with advanced gastric cancer is required.