tbuckley/cabot-search huggingface dataset:
Ovarian stimulation for infertility treatment and cancer risk: An Italian cohort study.
Authors: Matteo Puntoni, Mauro Costa, Laura Paleari, Paola Anserini, Claudia Casella, Alberto Revelli, Silvia Patriarca, Ivo Noci, Adele Caldarella, Paolo Bruzzi, Nicoletta Provinciali, Andrea De Censi, Alessandra Gennari
Journal: Journal of Clinical Oncology (2016)

534 Background: With the increasing practice of infertility treatments, concerns were raised about the long-term effects of hormonal ovarian stimulation, especially regarding the risk of breast, endometrial and ovarian cancer. We evaluated the long term cancer incidence in women enrolled into fertility programs from 1980 to 2005. Methods: This is a retrospective cohort study of consecutive women entered into fertility programs in 4 italian centers operating in areas covered by Cancer Registries. Eligibility criteria included premenopausal woman aged 20 to 41 years, who received at least 1 cycle of ovarian stimulation in the context of an Assisted Reproductive Technology (ART) treatment. The primary endpoint was breast cancer (BC) incidence; secondary endpoints were incidence of cervical, endometrial and ovarian cancer. Cancer incidence was assessed by linkage with databases of Cancer Registries. The relationship between ovarian stimulation and cancer incidence was assessed using region specific standardized incidence rates (SIR) by comparing the observed and expected number of events. Results: A cohort of 4,586 women treated for infertility between 1980 and 2005 was identified. Of these, 2,888 cases presented all the required informations and were included in this analysis. All women received gonadotropins. Forty-six cancers were observed: among these, 19 BC cases, 6 cervix, 2 endometrium and 1 ovarian, during an overall follow-up of 23,050 person/years. No increased cancer incidence was observed in the cohort. Ever use of gonadotropins was not associated with increased BC risk (24,5 expected versus 19 observed), for an overall SIR = 0.76; 95% CI, 0.5-1.3. A moderately increased risk of cervical cancer was observed, although not significant (SIR = 1.8; 95% CI, 0.8-4.3). Similarly a small increase was observed in the risk of endometrium/ovarian cancer (SIR = 1.6; 95% CI,0.5-4.9). Conclusions: These data showed no significant association between breast, cervix, endometrium or ovarian cancer and the use of gonadotropins in women undergoing ovarian stimulation. We conclude that, in our experience, modern practices of ART with induction of multiple ovulations were not associated with increased cancer risk.
Molecular profiling of cancer outliers.
Authors: Kyungsuk Jung, Marijo Bilusic, Jianming Pei, Michael Slifker, Yan Zhou, Douglas B Flieder, Phillip Gray, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2017)

e13025 Background: A few patients with metastatic cancer survive exceptionally longer than others under the same treatment. We hypothesized that there is a specific biologic signature in genetic profiles of long-term survivors that plays a key role in sensitivity to systemic treatment. Methods: Twenty-six patients with metastatic cancer treated at Fox Chase cancer center with exceptional response were included in the study. Exceptional response was defined as complete response &gt; 1 year or stable disease/partial response &gt; 2 years at any time during the disease course. Archived tumor specimens of 16 patients were sequenced and analyzed using Ambry Genetics 142 gene panel. In addition, genes expressions in tumor tissues from 23 exceptional responders and 23 matched controls (age, sex and tumor type) were analyzed using two NanoString nCounter PanCancer panels (Pathway and Immune Profiling). Results: See Table. Conclusions: Multiple common mutations of NOTCH2, NF1, FANCD2, PIK3CB and EPHA5 were found in tumors that responded exceptionally well to treatments. Additionally, certain genes were significantly over-expressed or under-expressed in these tumors compared to matched controls. Underlying mechanisms that these genetic alterations foster, leading to susceptibility to treatment and prolonged patient survival, should be further studied. [Table: see text]
First-in-human phase I study of an oral HSP90 inhibitor, TAS-116, in advanced solid tumors.
Authors: Noriko Yanagitani, Atsushi Horiike, Satoru Kitazono, Fumiyoshi Ohyanagi, Shunsuke Kondo, Akihiko Shimomura, Yutaka Fujiwara, Toshihiko Doi, Yasutoshi Kuboki, Akihito Kawazoe, Kohei Shitara, Izumi Ohno, Udai Banerji, Raghav Sundar, Shuichi Ohkubo, Jerry M. Huang, Makoto Nishio, Noboru Yamamoto
Journal: Journal of Clinical Oncology (2017)

2546 Background: TAS-116 is an oral non-ansamycin, non-purine, and non-resorcinol highly selective inhibitor of HSP90α/β. The objective of this FIH study was to determine the MTD and investigate the safety, tolerability, PK, PD (HSP70 protein levels in PBMCs), and antitumor activity of TAS-116. Methods: The study is being conducted in Japan and the UK. Patients with advanced solid tumors received escalating doses of TAS-116 once daily (QD) with an accelerated titration design. After the MTD was determined, safety and tolerability of 5 days on / 2 days off per week administration (QDx5) at the MTD in QD was explored. In parallel, the MTD with every other day administration (QOD) was evaluated by using a 3 + 3 design. Results: As of 20 September 2016, 52 patients were enrolled. TAS-116 was evaluated at doses of 4.8 to 150.5 mg/m 2 /day in the QD schedule and doses of 107.5 to 295.0 mg/m 2 /day in the QOD schedule. The MTD was 107.5 mg/m 2 /day with QD and 210.7 mg/m 2 /day with QOD. QDx5 at the MTD in QD using a flat dose of 160 mg was evaluated. The most common adverse events in all regimens were gastrointestinal disorders and increased creatinine. DLTs were observed in 4 patients in QD (night blindness, visual disorder, AST/ ALT/gamma-GTP elevations, and anorexia) and in 2 patients in QOD (platelet count decreased, febrile neutropenia, pneumonia, respiratory failure, and septic shock). Reversible eye disorders were observed in all schedules, but those observed in QDx5 were limited to grade 1. The PK level demonstrated dose proportionality without unexpected accumulation under repeated administration. Dose-related HSP70 induction of PBMCs was observed. As of 20 September 2016, three confirmed durable PRs by RECIST were observed (239 days in GIST and 173 days in NSCLC with QD; 293 + days in NSCLC with QOD). PR and SD ≥ 12 weeks were observed in 15 out of 47 patients. Conclusions: TAS-116 had an acceptable safety profile under all schedules, especially QDx5. Preliminary antitumor activity was demonstrated with evidence of target engagement. Dose expansion at the MTD in this phase 1 study and the phase 2 study in patients with GIST are ongoing. Parts of this study will be expanded to the US with an amended study protocol. Clinical trial information: NCT02965885.
A systems model of BCL-2 dependent apoptosis to predict stage II CRC patients benefiting from adjuvant chemotherapy and as a prognostic tool for stage III CRC patients with increased risk of recurrence.
Authors: Jochen Prehn, Andreas Ulrich Lindner, Manuela Salvucci, Mattia Cremona, Naser Monsefi, Sarah Curry, Clare Morgan, Alexa Resler, Robert O'Byrne, Orna Bacon, Lorna Flanagan, Richard H. Wilson, Patrick G Johnston, Manuel Salto-Tellez, Sophie Camilleri-Broët, Deborah A McNamara, Bryan T Hennessy, Elaine Kay, Pierre Laurent-Puig, Sandra Van Schaeybroeck
Journal: Journal of Clinical Oncology (2016)

3584 Background: Over the past decades the TNM staging system has remained the best indicator for the clinical outcome of CRC patients, and it is used to stratify patients for adjuvant chemotherapy after surgical resection of the tumor. Currently, adjuvant chemotherapy is not recommended for stage II patients. Previously, we developed a systems model of the BCL2 family of proteins (DR_MOMP) to assess cancer cells’ resistance to induce mitochondrial outer membrane permeabilization (MOMP), based on absolute protein levels and the interaction of pro- and anti-apoptotic BCL2 family proteins. Methods: Reverse Phase Protein Arrays (RPPA) were used to determine BAK, BAX, BCL2, BCL(X)L and MCL1 protein levels in primary tumours collected from two distinct cohorts: 1) 138 stage II CRC patients from a completed clinical trial, randomised to adjuvant 5-FU-based chemotherapy or observation only, 2) 128 stage III CRC patients treated with adjuvant 5-FU-based chemotherapy. DR_MOMP was employed to calculate the amount of cellular stress required to induce MOMP based on tumour protein levels. Protein level (RPPA) and mRNA expression (SeqV2 RSEM) data from the TCGA COAD cohort was used to validate the findings. Results: 1) Stage II patients randomised to observation only and classified as high-risk by DR_MOMP had an approximately 2-fold increased risk of death compared to patients receiving chemotherapy or classified as low-risk (HR 2.4; 95% CI 1.2-4.8; p-value = 0.02). 2) Stage III patients treated with chemotherapy and classified as high-risk had a more than 10-fold increased risk of death compared to low-risk patients (HR 10.6; 95% CI 2.4-46.3; p-value < 0.0001). The hazard ratio (HR) was similar in 261 stage II-IV patients of the TCGA COAD cohort (HR 10.6; 95% CI 1.2-12.5; p-value = 0.01). Conclusions: Our system holds promise as a novel predictive biomarker to stratify stage II CRC patients for adjuvant chemotherapy and as a prognostic biomarker for stage III patients. It could be combined with traditional staging to assess risk and in subsequent clinical management of patients.
Réalisation de la cytoponction dirigée sous échoendoscopie (EE) en ambulatoire: évaluation prospective dans un centre référent
Authors: B Bournet, I Migueres, M Delacroix, D Vigouroux, JL Bornet, J Escourrou, L Buscail
Journal: Endoscopy (2006)

Nous avons précédemment évalué la morbidité de l'EE interventionnelle à 2,6% avec une mortalité nulle (Endoscopy 2005 sous presse). Le délai moyen de survenu des complications étaient de 6 heures suivant le geste amenant à proposer la réalisation du geste en ambulatoire. La présente étude a donc été menée pour évaluer la faisabilité/morbidité de la cytoponction sous EE dans des conditions ambulatoires («sortie le jour même»).
Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice
Authors: Kang Ho Kim, Sungwoo Choi, Ying Zhou, Eun Young Kim, Jae Man Lee, Pradip K. Saha, Sayeepriyadarshini Anakk, David D. Moore
Journal: Hepatology (2017)

The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver-specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy-machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage.Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole-body energy homeostasis. (Hepatology 2017;66:498-509).
Phase 0 trial of AZD1775 in patients with first-recurrence glioblastoma.
Authors: Nader Sanai, Jing Li, Julie Boerner, Harshil Dhruv, Michael E. Berens, Patricia LoRusso
Journal: Journal of Clinical Oncology (2016)

2008 Background: AZD1775 is a first-in-class Wee1 inhibitor with dual-function as a DNA damage sensitizer (via Cdk1-mediated G2-checkpoint arrest) and as a cytotoxic agent (via Cdk2-mediated DNA-destabilization). A Phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain-barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetic (PK) and pharmacodynamics (PD) of AZD1775 in first-recurrence, de novo glioblastoma (GBM) patients. Methods: 20 adult patients received a single dose of AZD1775 prior to brain tumor resection and enrolled in either a dose-escalation arm (100, 200, or 400 mg) or a time-escalation arm at 400 mg (4-, 8-, or 24-hrs). Sparse PK blood sampling was performed. Tumor samples were collected intraoperatively and AZD1775 concentrations in plasma and tumor were determined by a validated LC-MS/MS method. PD endpoints were compared to matched archival tissue. Expression of efflux and uptake transporters in tumor samples were determined by qRT-PCR. Results: AZD1775 plasma exposure increased with increasing dose. AZD1775 tumor concentrations exhibited large inter-individual variability. At all doses and times, AZD1775 tumor concentrations (range, 98 – 4926 ng/g) were higher than the in vitro IC50 (42 ng/mL) for inhibition of cellular Wee1 activity. The tumor-to-plasma ratio was dose- and time-independent, ranging from 3.8 to 40.4 (mean, 11.7 ± 8.5). Tumor-to-plasma ratios appeared to be associated with tumor mRNA levels of transporters ABCC1, ABCC3, and OATP1A2. Wee1 pathway suppression was inferred by abrogation of G2-arrest (phosphohistone-3, p= 0.0085) and intensified double-strand DNA breakage (gamma-H2AX, p= 0.003) following drug exposure. No drug-related adverse events were associated with this study. Conclusions: Within 6 months of study activation, we obtained data to justify a Phase II trial for AZD1775 in GBM. Our findings show good CNS penetration for AZD1775 in humans (in contrast to results in mice), provide the first evidence of clinical biological activity in human GBM, and confirm the utility of Phase 0 trials as part of an accelerated paradigm for early drug development in brain tumor patients. Clinical trial information: NCT02207010.
Locoregional treatment (LRT) and overall survival (OS) of men with T1a,b,cN0M0 breast cancer: a population-based study.
Authors: Jose Pablo Leone, Julieta Leone, Ariel Osvaldo Zwenger, Julian Iturbe, Bernardo Amadeo Leone, Carlos Teodoro Vallejo
Journal: Journal of Clinical Oncology (2016)

1056 Background: Male breast cancer (MaBC) is an understudied disease, information about LRT and outcomes in patients (pts) with T1a,b,cN0M0 tumors is unknown. The aim of this study was to analyze pt characteristics, LRT and OS of T1a,b,cN0M0 MaBC. Methods: We evaluated men with T1a,b,cN0M0 microscopically confirmed invasive breast cancer reported to the Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2012. Pts with other primary either before or after breast cancer were excluded. Characteristics of pts with different tumor sizes were compared. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Results: We included 1263 pts. Median age was 66 years (range 27-103). Median follow-up was 62 months (range 1-294). OS at 5 and 10 years were 85% and 66%, respectively. 83% were ductal, 95.3% ER positive, 87.2% PR positive and 21.9% grade 1. Distribution according to tumor substage was: T1a 6.5%, T1b 20.7% and T1c 72.8%. Mastectomy was performed in > 70% of pts of each tumor size group and overall 44.1% had ≥ 6 lymph nodes examined (LNE). Only 12.7% of pts received adjuvant radiotherapy. Pts with T1c tumors were older (p = 0.01), had higher grade (p < 0.0001), were more likely to have mastectomy (p = 0.003) and to die from breast cancer (p = 0.01). Univariate analysis showed that pts with T1c (p = 0.0003), no surgery (p < 0.0001) and 0 LNE (p < 0.0001) had worse prognosis. In multivariate analysis, older age (HR 11.2; p < 0.0001), grade 3/4 tumors (HR 1.8; p = 0.01), no surgery (HR 3.1; p = 0.04), 0 LNE (HR 4.8; p < 0.0001) and unmarried pts (HR 1.7; p = 0.02) had shorter OS. Race, ER, PR and radiotherapy were not associated with OS. There were no differences in OS between pts who underwent breast conservation vs mastectomy and pts who had 1-5 LNE vs ≥ 6 LNE. Conclusions: In this cohort of male pts with early breast cancer, a favorable OS rate at 10 years was observed. However, older age, higher tumor grade, no breast surgery, no LNE and unmarried status emerged as poor prognostic characteristics. Efforts to decrease the high rates of mastectomy and extensive LNE should be taken given similar OS observed with breast conservation and 1-5 LNE, respectively.
Résection muco-sous-muqueuse oesophagienne circonférentielle en monobloc chez le porc
Authors: F Prat, A Chryssostalis, L Mangialavori, S Chaussade
Journal: Endoscopy (2006)

Les techniques actuelles de surveillance et de mucosectomie endoscopique sont mal adaptées en particulier à la problématique des EBO longs en dysplasie. Cette vidéo est une démonstration chez le porc d'une nouvelle technique de résection endoscopique emportant la muqueuse et la sousmuqueuse de l'oesophage en monobloc, de façon circonférentielle, et pouvant être étendue sur la hauteur désirée.
Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer
Authors: Sadiq M.I. Saleh, Nicholas Bertos, Tina Gruosso, Mathieu Gigoux, Margarita Souleimanova, Hong Zhao, Atilla Omeroglu, Michael T. Hallett, Morag Park
Journal: Cancer Research (2017)

Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673-83. ©2017 AACR.
Exercise and pregnancy in recreational and elite athletes: 2016/17 evidence summary from the IOC Expert Group Meeting, Lausanne. Part 3—exercise in the postpartum period
Authors: Kari Bø, Raul Artal, Ruben Barakat, Wendy J Brown, Gregory A L Davies, Michael Dooley, Kelly R Evenson, Lene A H Haakstad, Bengt Kayser, Tarja I Kinnunen, Karin Larsén, Michelle F Mottola, Ingrid Nygaard, Mireille van Poppel, Britt Stuge, Karim M Khan
Journal: British Journal of Sports Medicine (2017)

Exercise and pregnancy in recreational and elite athletes : 2016/17 evidence summary from the IOC Expert Group Meeting, Lausanne. Part 3-exercise in the postpartum period.
The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?
Authors: Sarab Lizard, Marie Eliade, Jeremy Skrzypski, Amandine Baurand, Caroline Jacquot, Geoffrey Bertolone, Catherine Loustalot, Charles Coutant, France Guy, Pierre Fumoleau, Yannis Duffourd, Laurent Arnould, Marie-Martine Padeano, Come Lepage, Sandy Chevrier, Frédérique Végran, Nicolas Sevenet, Francois Ghiringhelli, Romain Boidot, Laurence Faivre
Journal: Journal of Clinical Oncology (2016)

e13116 Background: Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1 and 2 testing. The advent of next generation sequencing technologies and the recent discovery of new genes involved in HBOC progressively permitted the transfer of genomic capture targeting multiple candidate genes from research to diagnosis. However, the implication for the management of patients and their families has not been extensively studied. Methods: We studied 583 consecutive patients originated from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-gene panel including 20 candidate predisposition genes for breast and/or ovarian cancer. Results: A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2 %), ATM (n = 9; 1.5 %), and PALB2 (n = 4; 0.6%). Three double-hits were found. Four mutations were found in MMR genes, and family history of Lynch syndrome could be found in 1/4 case only. Most of mutations were consistent with the spectrum of cancer(s) observed in the patient and/or family (89%), and at least one of them could be considered as an incidental finding. The analysis of clinical actionability performed among the 38 mutation-positive individuals other than BRCA enrolled in our clinics revealed that additional disease specific screening and/or prevention measurers beyond those based on personal and family history alone have been recommended in most of cases (84%). Conclusions: In conclusion, multigene panel testing is a powerful tool for identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancer associated to these other genes remain sometimes undefined, and further collaborative work is crucially needed to address this question. The possibility of double hits should lead to careful genetic counseling.
Genomic Analysis of Childhood Brain Tumors: Methods for Genome-Wide Discovery and Precision Medicine Become Mainstream
Authors: Stephen C. Mack, Paul A. Northcott
Journal: Journal of Clinical Oncology (2017)

Recent breakthroughs in next-generation sequencing technology and complementary genomic platforms have transformed our capacity to interrogate the molecular landscapes of human cancers, including childhood brain tumors. Numerous high-throughput genomic studies have been reported for the major histologic brain tumor entities diagnosed in children, including interrogations at the level of the genome, epigenome, and transcriptome, many of which have yielded essential new insights into disease biology. The nature of these discoveries has been largely platform dependent, exemplifying the usefulness of applying different genomic and computational strategies, or integrative approaches, to address specific biologic and/or clinical questions. The goal of this article is to summarize the spectrum of molecular profiling methods available for investigating genomic aspects of childhood brain tumors in both the research and the clinical setting. We provide an overview of the main next-generation sequencing and array-based technologies currently being applied in this field and draw from key examples in the recent neuro-oncology literature to illustrate how these genomic approaches have profoundly advanced our understanding of individual tumor entities. Moreover, we discuss the current status of genomic profiling in the clinic and how different platforms are being used to improve patient diagnosis and stratification, as well as to identify actionable targets for informing molecularly guided therapies, especially for patients for whom conventional standard-of-care treatments have failed. Both the demand for genomic testing and the main challenges associated with incorporating genomics into the clinical management of pediatric patients with brain tumors are discussed, as are recommendations for incorporating these assays into future clinical trials.