tbuckley/cabot-search huggingface dataset:
Induced Pluripotent Stem Cells in Pulmonary Arterial Hypertension
Authors: Rizwan Hamid, Ling Yan
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Pioneering work by Yamanaka's group showed that overexpression of four transcription factors, octamer-binding protein 4 (OCT4), Krüppel-like factor 4 (KLF4), sex determining region Y-box 2 (SOX2), and c-myc avian myelocytomatosis viral oncogene homolog (c-MYC), could reprogram somatic cells into induced pluripotent stem cells (iPSCs), which could then be differentiated into all cell types (1).Since that finding, it has become clear that iPSCs hold great promise as models for diseases, drug discovery, and testing of cell-based therapeutic strategies.Pulmonary diseases are one leading cause of morbidity and mortality worldwide.Currently available treatments can only alleviate symptoms or delay disease progression within a limited time range for patients with end-stage pulmonary diseases.Pulmonary arterial hypertension (PAH) is a complex disorder of pulmonary microvasculature, circulating cells, and right heart, with poor prognosis (2, 3).Animal models of PAH have existed for some time and have provided key insights into disease pathogenesis.Attempts to translate these findings into treatment for patients, however, have been imperfect at best, because at a molecular level animal lungs and lung tissues are different from human lungs and tissues, and thus it has been difficult to recapitulate the disease process in vitro.Use of human lung cells could address some of the deficiencies.However, it is technically difficult to isolate and characterize human cells in enough number to be useful in laboratory studies.iPSCs provide one potential solution to this problem.iPSCs have been used to derive respiratory epithelial cells, vascular endothelial cells, and vascular smooth muscle cells (4-6) and have also been used to study lung development and vascular modeling (4, 7-9).However, whether they can serve as tools to investigate the potential for new therapeutic agents in PAH is unknown.In this issue of the Journal, Sa and colleagues (pp.930-941) present data from proof-of-principle studies that address an important question: whether iPSCs derived from patients with PAH have potential as tools for drug discovery and testing (10).They compared the pulmonary artery endothelial cells isolated from patients with idiopathic or heritable PAH to endothelial cells (ECs) derived from fibroblast-derived iPSCs from the same patients.The authors show that there are many similarities between the iPSC-ECs and native pulmonary artery endothelial cells, including morphology, functional deficits, reduction of bone morphogenetic protein receptor (BMPR)-II signaling, and, importantly, response to bone morphogenetic protein 9 stimulation
The clinical impact of PET/CT with 68Ga-DOTATATE in neuroendocrine tumors (NETs): The experience of a private institution in Brazil.
Authors: Jessica Sayuri Tsukamoto, Noelle Suemi Wassano, Luiza Damian Ribeiro Barbosa, Virginia Moreira Braga, Letícia Rigo, Douglas Jorge Racy, Tercia Tarciane Soares De Souzsa, Marcos Belotto, Renata D'Alpino D'Alpino
Journal: Journal of Clinical Oncology (2017)

271 Background: The introduction of PET/CT with 68Ga-DOTATATE (68Ga-PET) determined an exponential increase of the accuracy in diagnosing and following up NETs. However, this exam is not frequently available in developing countries. Methods: We have retrospectively evaluated the efficacy of 68Ga-PET in patients with NETs and its impact on clinical decision at Hospital São José, Brazil. Results: Between February 2014 and July 2016, 28 patients (15 males) with histologically confirmed NETs underwent Ga68-PET at our hospital. Median age was 57 (range 21 - 82). Primary sites were pancreas (n = 10), small bowel (n = 7), lung (n = 3) and others (n = 8). The Ki-67 index was &lt; 2% in 7 patients and &gt; 20% in 6 patients. Five patients had unknown Ki67 index. There was 68Ga uptake in 82% of the patients (21,4% in patients with Ki67 &gt; 20%). Median SUV was 16,3 (range 1,7- 129,8). Only 32% of the patients underwent concomitant Octreoscan. Results were divergent between both imaging methods in 55% of the patients, which resulted in therapeutic change. The main reason to request the exam was to measure the extent of metastatic disease (n = 14). Other reasons were to access response to therapy (n = 8), to evaluate the possibility of treatment with Lutetium (n = 3), to investigate the primary tumor (n = 2), and others (n = 1). Conclusions: Ga68-PET is an important imaging key to guide therapeutic management in NETs, especially among patients with Ki67 &lt; 20%. When available, Ga68-PET is superior to Octreoscan.
Assessment of overall survival from time of metastastasis in mucosal, uveal, and cutaneous melanoma.
Authors: Michael Andrew Postow, Deborah Kuk, Kita Bogatch, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2014)

9074 Background: Rarer subtypes of melanoma such as mucosal melanoma (MM) and uveal melanoma (UM) are thought to be associated with worse prognoses than cutaneous melanoma (CM). Comparison of OS in pts with MM, UM and CM after diagnosis of stage IV disease, however, has not been rigorously evaluated. Methods: We conducted a single-center, retrospective analysis of 2920 pts diagnosed with stage IV melanoma between 2000 and 2013 identified from a prospectively maintained database. Melanoma subtype, date of diagnosis of stage IV disease and date of death were extracted, as were established prognostic variables including age at diagnosis of metastasis, gender and M-stage. Results: MM (n=237): median (med) age 66 years (yrs; range 26-91); 65% female; M1a/b/c - 8%/21%/71%. UM (n=286): med age 63 yrs (range 16-86); 46% female; M1a/b/c - 5%/8%/87%. CM (n=2397): med age 62 yrs (range 3-97); 34% female; M1a/b/c - 14%/31%/55%. Differences in age, gender and M-stage were significantly different between groups (p=0.002, p<0.0001 and p<0.0001, respectively). With a median followup of 46.6 months (mos) and 2192 deaths, the median OS for MM, UM and CM was 9.0 mos (range 0.4-108.1), 13.4 mos (range 0.4-144.0), and 11.7 mos (range 0.1-139.8), respectively. Pts with UM and CM had similar OS (HR: 1.02, p=0.82), but pts with MM had worse OS compared to pts with UM (HR: 1.41, p<0.001) and CM (HR: 1.44, p<0.001). Pts diagnosed with stage IV melanoma between 2006-2013 (n=1148) had a better OS compared to pts diagnosed between 2000-2005 (n=1773; 13.59 vs. 9.77 mos; p < 0.001). In a multivariate model taking into account year of stage IV diagnosis (2000-2005 vs. 2006-2013), age, gender, and M-stage, pts with MM had inferior OS compared to UM and CM. Conclusions: MM is an independent poor prognostic factor in pts with stage IV melanoma. Despite distinct tumor biology, similar survivals were observed in stage IV UM and CM. Improved OS in pts treated between 2006-2013 may reflect the efficacy of newer therapies. Stratification by melanoma subtype is warranted in trials including MM.
Adjuvant zoledronic acid (ZOL) in postmenopausal women with breast cancer and those rendered postmenopausal: Results of a meta-analysis.
Authors: Walter Gregory, Helen Marshall, Richard Bell, David A. Cameron, Robert Edward Coleman
Journal: Journal of Clinical Oncology (2012)

513 Background: A number of groups have now reported results of randomised trials of adjuvant zoledronic acid (ZOL) for women with early stage breast cancer. Following an interaction effect observed in the AZURE trial, where postmenopausal women appeared to benefit from ZOL, we performed a meta-analysis, from both publications and presented data, of the most recent results from these trials. We also looked at recently reported large studies of clodronate and ibandronate in older or postmenopausal women to further examine this hypothesis. Methods: DFS data from 8735 women in 7 trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN) that included a randomization to ZOL vs. control or clodronate/ibandronate vs. control were examined. Median follow-up was 5 years. 14% of women experienced a DFS event. The ABCSG-12 study was included since, although it included only premenopausal women, they were all treated with goserelin, effectively rendering them postmenopausal, prior to and during treatment with ZOL. We analysed the subgroup of women aged ≥50 in the NSABP-B34 study in the absence of information on menopausal status, and included only postmenopausal women from the AZURE and GAIN trials. Sensitivity analyses confirmed that exclusion of some older, small, clodronate studies that lacked DFS data, or failed to report by age or menopausal status would be unlikely to alter these findings. Results: For the 5 ZOL studies alone, there was a very substantial and highly significant DFS benefit for ZOL, 2P=.0006, with a hazard ratio of 0.76, and therefore a DFS risk reduction of 24% (95% CI 11%-35%). The results were, in the main, extremely consistent, with the exception of the very small E-ZO-FAST study, which had only 30 events. The risk reduction lessened to 18% (95% CI 8%-26%) when adding in the clodronate and ibandronate studies, but the result remained highly significant (2P=.00075). Conclusions: These meta-analysis results, including more than 8000 women in a range of studies, now provide strong evidence that ZOL is an effective adjuvant treatment for postmenopausal women with early stage breast cancer, and that the treatment benefits are substantial.
Genome-wide association study (GWAS) of pazopanib efficacy and safety in patients with ovarian cancer who have not progressed following first-line standard therapy.
Authors: Giovanni Scambia, Toby Johnson, Anne Floquet, Florian Heitz, Sang-Yoon Park, Martin Buck, Rafael ÃƒÂlvarez Gallego, Muneaki Shimada, Ignace Vergote, Elisabeth Avall-Lundqvist, Nicoletta Colombo, Anna Maria Mosconi, Bradley J. Monk, Jianqing Zhu, Lingying Wu, Ionel Mitrica, Pingkuan Zhang, Sandy Stinnett, Chun-fang Xu, Andreas Du Bois
Journal: Journal of Clinical Oncology (2014)

5574 Background: Pazopanib is an oral multi-kinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit. In the phase III AGO-OVAR16 study (NCT00866697), pazopanib maintenance therapy significantly increased progression free survival (PFS) in patients with ovarian cancer who have not progressed after first line therapy; however such benefit was not observed in a phase II study (NCT01227928) conducted in East Asian countries. In both studies, there is heterogeneity in patient response (safety and efficacy) to pazopanib; we hypothesized that germline genetic variation may contribute to this heterogeneity. Methods: GWAS analyses were conducted using combined patient data from the AGO-OVAR16 study (N=477, pazopanib) and the East Asian phase II study (N=73, pazopanib), which had similar eligibility criteria and treatment schedules. In aggregate N=387 patients receiving pazopanib provided consent for pharmacogenetic research. GWAS were conducted using normal, ordinal, and Cox regression models to test 30M genetic variants (genotyped or imputed) for association with PFS, overall survival, CA-125 change, bilirubin elevation, transaminase elevation, blood pressure change, hand foot syndrome, diarrhoea, fatigue, neutropenia, thrombocytopenia, and dose reduction or dose discontinuation. Results: At the genome wide significance level (P≤5x10-8), common variants near UGT1A1 were associated with bilirubin elevation (P=1.1x10-21), consistent with our previous observations in pazopanib treated patients with renal cell carcinoma. Common variants near a disintegrin and metalloprotease (ADAM) domain family genes ADAM28–ADAM7 were associated with CA-125 change (P=2.9x10-10). No other common variants reached genome-wide significance. Conclusions: Some instances of isolated bilirubin elevation in pazopanib treated patients with ovarian cancer may be benign manifestations of Gilbert's syndrome. We identified a novel association between germline variants in ADAM28–ADAM7 and CA-125 change; further studies of this finding may yield insights into mechanisms underlying differential response to pazopanib in patients with ovarian cancer.
Dissecting the genomic landscape of metastatic bladder cancer using circulating tumor DNA.
Authors: Werner J. Struss, Gillian Vandekerkhove, Matti Annala, Tilman Todenhoefer, Kevin Beja, Bernhard J. Eigl, Alexander William Wyatt, Peter C. Black
Journal: Journal of Clinical Oncology (2017)

378 Background: To date, only limited data are available on genomic alterations present in metastatic lesions of patients with metastatic urothelial carcinoma (mUC). The constant release of cell free DNA (cfDNA) from tumor cells into the peripheral blood stream may provide a valuable source for detection of cancer associated somatic copy number variations and mutations. The aim of this project was to evaluate the feasibility of detecting clinically relevant genomic alterations in mUC by next-generation sequencing (NGS) of circulating cfDNA. Methods: Peripheral blood (20ml) was collected from 15 patients with mUC before chemotherapy. Plasma cfDNA was isolated using the QIAAmp Circulating Nucleic Acid Kit. Germline control DNA was extracted from peripheral blood mononuclear cells (PBMCs) using the DNEasy Kit (Qiagen). We performed deep (&gt;500X) targeted DNA sequencing on cfDNA and germline DNA using a custom NimbleGen SeqCap EZ Choice Library and Illumina sequencers. Our custom panel included 50 bladder cancer-relevant genes, including key tumor suppressors (e.g. TP53, RB1, CDKN2A), cell cycle drivers (e.g. CCND1, CCNE1), DNA repair genes (e.g. ATM, BAP1, ERCC2), PI3K pathway genes (e.g. PIK3CA, PTEN, AKT1), and other oncogenic pathways (e.g. RAS/RAF, EGFR, ERBB2, PPARG, FGFR3). Results: Somatic mutations and/or copy number changes were detected in 14/15 samples, with a median variant allele frequency &gt;5%. The overall mutational landscape was highly consistent with bladder cancer, including mutations in TP53 and ARID1A (and other chromatin modifiers), as well as hotspot activating mutations in PIK3CA. Typical copy number changes, including focal amplifications of ERBB2, KRAS, and CCNE1 were detected. We identified complex gene rearrangements, including an activating FGFR3 fusion in one case. Extended analyses with a larger patient population are currently pending. Conclusions: Non-invasive characterization of genomic changes in peripheral blood of patients with mUC using NGS of plasma cfDNA is feasible in a high proportion of patients. Analysis of cfDNA might therefore provide an improved understanding of genomic changes in mUC and could be developed as a biomarker to help guide the use of targeted therapies.
Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), in previously treated patients with hepatocellular carcinoma (HCC)
Authors: A. Santoro, G. Citterio, T. Pressiani, F. G. De Braud, V. Gregorc, G. Rossoni, G. Donadoni, F. Caligaris-Cappio, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2009)

e15500 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with recurrent or metastatic HCC were treated with NGR-hTNF given intravenously at 0.8 μg/m 2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary endpoint with reassessment performed q6w according to WHO criteria. Results: 27 patients with progressive disease following prior loco- regional treatment (59%), systemic therapy (56%), or both (33%) were evaluated over 86 cycles (range, 1 to 14). Patient characteristics were: median age 67 years (range, 53 to 79); M/F 21/6; PS 0/1 18/9; Child-Pugh class A/B: 21/6. No grade 3–4 treatment-related adverse events were observed. Main grade 1–2 toxicities were short-lasting infusion-related constitutional symptoms, including chills (55%). Median PFS was 2.3 months (95% CI, 1.7–2.9 months). One complete response (4%) lasting 9.0+ months was observed in a sorafenib-refractory patient and one partial response (4%) was reported in a Child-Pugh class B patient. Additionally, a 28% tumor shrinkage was detected in one out of six patients (22%) experiencing stable disease. The median PFS duration in stable or responder patients was 4.3 months (95% CI, 2.7–5.8 months). With a median follow-up of 7.6 months, the overall survival rates at 3 and 6 months were 82% and 60%, respectively. Conclusions: NGR-hTNF given at 0.8 μg/m 2 every 3 weeks is well tolerated and appears to have promising antitumor activity in previously treated patients with advanced HCC. The drug will be further developed in this setting and, currently, an additional cohort of 12 patients has been enrolled and treated at same dose with a weekly schedule. [Table: see text]
Neoadjuvant erlotinib in stage III NSCLC patients (pts) with activating EGFR mutations (EVENT trial).
Authors: Cengiz Inal, Bilal Piperdi, Steven M. Keller, Balazs Halmos, Mark Stoopler, Sewanti Atul Limaye, Benjamin Philip Levy, Bryan J. Schneider, Mimi Kim, Jessica Sides, Roman Perez-Soler, Haiying Cheng
Journal: Journal of Clinical Oncology (2015)

TPS7584 Background: Results with standard chemoradiotherapy for stage III NSCLC pts have plateaued and systemic relapse remains the biggest challenge. Genomic driven strategies are desperately needed as there is yet to be an approved targeted agent for locally advanced disease. Erlotinib improved objective response rate (ORR) and prolonged progression free survival (PFS) compared with chemotherapy in pts with EGFR-mutated advanced NSCLC. Mediastinal nodal clearance (pN0) after neoadjuvant therapy is a consistent surrogate marker for long term survival.We aim to evaluate rates of pN0 following neoadjuvant erlotinib in stage III NSCLC pts with activating EGFR mutation. Methods: 3 out of 55 planned pts have been enrolled in this single arm, open label phase II study. Based on historical data, pN0 rate of ≥ 30% will justify further study and the rate of ≤ 15% will be considered ineffective. With optimal two-stage design, if ≥ 3 out of initial 19 pts have pN0, additional 36 pts will be accrued in the second stage. Neoadjuvant erlotinib will be considered for further studies if pN0 is observed in ≥ 12 among total 55 pts. With 80% power and type I error of 0.05, the probability of early stopping at the first stage is 68.4% if the true response rate (TR) is 15% and 13.3% if TR is 30%. Total of 55 pts will ensure that the 95% CI for the estimated TR will be within +/- 15.7% by the end of this study. Stage IIIA/B NSCLC patients with N2 disease, activating EGFR mutations, ECOG PS 0-2, preserved organ function and no prior chemotherapy or radiation are eligible. Pts are treated with neoadjuvant erlotinib 150 mg PO daily for two months and then restaged. Pts with significant clinical down staging and deemed medically fit for surgery will have surgical resection. Pts with non-progressive disease who do not undergo surgery will have mediastinal restaging. Therapy after surgery or mediastinal restaging is at the discretion of the treating physician. The primary objective is to estimate the rate of pN0 after neoadjuvant erlotinib. Secondary objectives include PFS, OS, ORR from neoadjuvant erlotinib, and surgical resection rate. The translational studies in pre and post erlotinib tumor biopsy are also planned. Clinical trial information: NCT01857271. Clinical trial information: NCT01857271.
The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level
Authors: Wiley Barton, Nicholas C Penney, Owen Cronin, Isabel Garcia-Perez, Michael G Molloy, Elaine Holmes, Fergus Shanahan, Paul D Cotter, Orla O'Sullivan
Journal: Gut (2017)

It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state.Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively).Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups.Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet-exercise-gut microbiota paradigm.
Identifying actionable targets in advanced cancer patients: Preliminary results from the Profiler program.
Authors: Philippe Cassier, Olivier Trédan, Christelle Seigne, Emilie Lavergne, Jerome Fayette, Françoise Desseigne, Pierre Biron, Christelle De La Fouchardiere, Isabelle Laure Ray-Coquard, Maurice Pérol, Didier Frappaz, Mathilde Bernardin, Qing Wang, Valéry Attignon, Daniel Pissaloux, Valérie Combaret, Vincent Agrapart, Marie-Eve Fondrevelle, David Pérol, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2014)

2621 Background: The ProfiLER study was designed to characterize tumor genomic alterations (GAs) in a panel of selected genes in patients (pts) with advanced malignancies. Whether the presence of GAs may guide treatment (trt) decision regardless of histological subtype remains unclear. Methods: Pts with advanced solid and hematologic cancers were offered a genetic profiling of their tumor. DNA extracted from archival or freshly collected tumor samples was analyzed by sequencing of 59 cancer-related genes (NGS, Ion Torrent PGM system) and whole genome CGH array (Agilent platform). A multidisciplinary panel of clinicians and scientists reviewed results to determine the relevance of GAs and recommended molecular targeted therapies (MTT) when relevant. Results: From March to October 2013, 431 pts from a single center were consented and 283 (66%) had their tumor analyzed, either by NGS+CGH (186 pts, 66%), NGS alone (86, 30%) or CGH alone (11, 4%). 137 (48%) had at least one actionable target (AT) with a recommended MTT: 20% were breast cancers, 17% head and neck, 15% lung, 9% sarcoma, 8% colon and 31% other tumor types. NGS was conclusive for 132 pts, identifying actionable mutations (hot spot or described in COSMIC database) mainly in PIK3CA (15% of pts), EGFR (9%), MET (4%), MTOR (4%), ALK (4%), PTEN (4%), ERBB2 (3%), BRAF (2%) (median nb of mutations/pt: 1 [range: 0-11]). Main ATs identified with CGH (n=105 pts) were amplifications of CCND1 (17%), FGFR1 (11%), MDM2 (7%), EGFR (5%), ERBB2 (5%), CDK4 (4%), CDK6 (3%), homozygous deletion of CDKN2A (21%) and PTEN (5%) (median nb of copy number variations/pt: 1 [0-6]). 19/137 pts (14%) have so far received an MTT, mainly mTOR inhibitors (7 pts, 37%), ALK/MET inhibitors, anti-HER2, FGFR inhibitors or anti-VEGF (2 pts each, 10%). Best responses were PR (2/19, 10%), SD (6/19, 32 %), PD (9/19, 47%) and not evaluable in 2 pts. Median trt duration was 2.2 months [0.8–7.5] (Data, censored on December 1st2013, will be updated). Conclusions: Systematic tumor profiling is feasible in routine practice, highly attractive for pts with advanced malignancies and identifies ATs in nearly 50% of the pts. Clinical trial information: NCT01774409.