tbuckley/cabot-search huggingface dataset:
An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated <i>BRAF</i> V600E–mutant advanced non-small cell lung cancer (NSCLC; BRF113928).
Authors: David Planchard, Benjamin Besse, Harry J.M. Groen, Pierre Jean Souquet, Elisabeth A. Quoix, Christina S. Baik, Fabrice Barlesi, Tae Min Kim, Julien Mazieres, Silvia Novello, James R. Rigas, Allison Upalawanna, Anthony Michael D'amelio, Pingkuan Zhang, Bijoyesh Mookerjee, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2016)

107 Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as an oncogenic driver. The BRAF inhibitor D has demonstrated clinical activity (33% overall response rate [ORR], with a median progression-free survival [PFS] of 5.5 months as monotherapy in 78 previously treated pts with metastatic BRAFV600E–mutant NSCLC (cohort A). The combination of D + T has demonstrated significant improvements in efficacy vs BRAF inhibitor monotherapy in BRAF V600–mutant metastatic melanoma. Here, the primary analysis of pts with NSCLC who experienced failure of ≥ 1 prior platinum-based therapy for advanced disease and were treated with combination D + T is presented (cohort B). Methods: This is a multicohort, sequentially enrolled phase 2 trial in pts with metastatic BRAF V600E–mutant NSCLC. The primary endpoint was investigator-assessed ORR according to RECIST v1.1. Secondary efficacy endpoints included PFS and duration of response [DOR]. D was dosed at 150 mg orally twice daily and T at 2 mg orally once daily. Results: Between December 2013 and January 2015, 57 pts received D + T as ≥ second-line treatment and were evaluable for response. Median age was 64 y (range, 41–88 y). Most pts were female (51%), white (86%), adenocarcinoma (95%), and current or former smokers (73%). All pts had nonsquamous histology. 22 pts (37%) remain on therapy, and 37 have stopped (28 with disease progression, 8 due to adverse events [AEs], 1 due to pt decision). 52 pts were evaluable for efficacy (confirmed response). The ORR was 63% (95% CI, 49%-75%), with a disease control rate (ORR + ≥ 12 weeks of stable disease) of 79% (95% CI, 66%-89%). The median PFS was 9.7 mo (95% CI, 6.9-19.6 mo) and the median DOR was 9.0 mo (95% CI, 6.9-18.3 mo). Of the pts with a confirmed response, 50% remained in response at the time of analysis. The most common AEs (> 25%) included pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, and dry skin. Conclusions: D + T was highly efficacious in BRAF V600E–mutant NSCLC, with a manageable AE profile. This study is the first reported combination trial of a BRAF inhibitor and MEK inhibitor in BRAF V600E–mutant NSCLC. Clinical trial information: NCT01336634.
Image-based collection to allow isolation and analysis of pure intact tumor cell populations from FFPE: Implications for more precise HER2 FISH analysis.
Authors: Amanda Gerber, Trisky C. Clarin, Ambica Bhandari, Gianni Medoro, Nicolò Manaresi, Mathew Moore, Philip D. Cotter, Chiara Bolognesi, Farideh Bischoff
Journal: Journal of Clinical Oncology (2016)

e12094 Background: Guidelines worldwide focus on the importance of precise and accurate Fluorescent In Situ Hybridization (FISH) methods for testing companion diagnostic markers, including Human Epidermal Growth Factor Receptor 2 (HER2) gene amplification in breast cancer. Despite these guidelines, variations in test results are observed due to pre-analytical sampling. In this study, we demonstrate a unique approach to isolating pure and intact tumor cells from breast cancer Formalin-Fixed, Paraffin-Embedded (FFPE) samples for precise FISH analysis. Methods: Fifty-micron thick FFPE curls from both HER2 non-amplified breast cancer tumors (n = 4; each with a reported HER2/CEP17 ratio 1.8) and positive control SKBr3 breast cancer cells were tested. Isolation of ∼250 pure and intact cytokeratin-positive/vimentin-negative/DAPI positive cells from each sample were captured using the DEPArray platform, an automated system enabling image-based cell sorting with single-cell resolution for pure cell population isolation and collection. Standard dual-color HER2/CEP17 FISH (Vysis PathVysion) analysis was performed on recovered cells. Results: Positive HER2 amplification levels for the FFPE derived control SKBr3 cells were observed HER2/CEP17 ratio > 4.4. Among the patient samples, ≥ 75% of the DEPArray isolated tumor cells were recovered onto slides. Through routine FISH scoring, an expected non-amplified result was observed for each patient sample, with HER2/CEP17 ratios ranging from 1.1 to 1.4. Conclusions: We demonstrate feasibility in performing FISH on pure and intact tumor cells isolated from breast cancer derived FFPE using the DEPArray platform. Using a 50-micron section permitted recovery of whole, intact, tumor cells based on immunostaining for cytokeratin, vimentin, and DAPI. Efficient recovery of the DEPArray sorted cells onto slides further permitted routine FISH analysis of only tumor cells. These preliminary results imply the possibility of more precise FISH analysis when standard FISH results are inconclusive or when insufficient tumor content prohibits downstream analysis. Evaluation of larger numbers of patient samples is underway
Analyse des Indications de l'endoscopie oeso-gastro-duodénale: une étude prospective utilisant les critères du Panel Européen sur le caractère approprié de l'EOGD (EPAGE) et ceux de l'Agence Nationale d'Accréditation et d'Evaluation en Santé (ANAES)
Authors: B Kaliszan, J Soulé, T Vallot, M Mignon
Journal: Endoscopy (2005)

L'endoscopie oeso-gastro-duodénale (EOGD) est l'exploration digestive haute la plus efficace. Mais son prix, le risque de complications, la réticence des patients imposent que les indications reposent sur des critères qualitatifs explicites. Un panel d'Experts Européens, l'European Panel on Appropriateness of Gastrointestinal Endoscopy (EPAGE) a élaboré un programme interactif, accessible par internet: www.epage.ch. En France les indications de l'EOGD de l'adulte ont été élaborées sous l'égide de l'ANAES, et sont aussi consultables par internet: www.anaes.fr. L'étude a évalué l'applicabilité en pratique clinique des critères de l'EPAGE et de l'ANAES, a vérifié la pertinence des indications de l'EOGD selon les référentiels de l'EPAGE et de l'ANAES, en a comparé les résultats et les a corrélés avec les informations diagnostiques fournies par l'EOGD.
SAT0164 Two year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosisis
Authors: R Rizzoli, C Roux, S Greenspan, H Bone, T Schnitzer, N Watts, S Adami, B Uebelhart, J Foldes, C Peverly, A Santora, A Kaur, M Wu, J Orloff
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The therapeutic equivalence of alendronate (ALN) 70 mg once weekly (OW) (provided by Merck and Co., Inc., Whitehouse Station, NJ, USA), ALN 35 mg twice weekly (TW), and ALN 10 mg once daily (OD) in the treatment of postmenopausal osteoporosis for 1 year has been reported previously.<sup>1</sup> We will present preliminary two-year BMD results from a one-year extension. <h3>Objectives</h3> <h3>Methods</h3> We compared the efficacy of treatment with OW ALN 70 mg (n = 519), TW ALN 35 mg (n = 369), and OD ALN 10 mg (n = 370) over 2 years in a double-blind, multicenter study of postmenopausal women (age 40 to 90) with osteoporosis (BMD of either the lumbar spine or femoral neck ≥2.5 SDs below peak mean, or prior vertebral or hip fracture). The primary efficacy endpoint was change in lumbar spine BMD. Secondary endpoints included changes in BMD at the hip and total body. <h3>Results</h3> Mean BMD increases at the lumbar spine, total hip, femoral neck, hip trochanter, and total body sites for each treatment regimen after two years were very similar, with no clinically meaningful differences. <h3>Conclusion</h3> These findings confirm that once-weekly ALN 70 mg is therapeutically equivalent to once-daily ALN 10 mg in patients with postmenopausal osteoporosis. In addition, the two-year results demonstrate that once-weekly ALN 70 mg is generally as safe and well tolerated as ALN 10 mg once daily. <h3>Reference</h3> Schnitzer, <i>et al</i>. Aging 2000;12:1–12
L'élastographie guidée par échoendoscopie(Ee) peut-elle faire la différence entre ganglions bénins et malins?
Authors: M Giovannini, CH Pesenti, E Bories, G Monges, F Caillol
Journal: Endoscopy (2006)

L'élastographie est une nouvelle technologie dans laquelle les modifications de contrainte des tissus sont employées pour détecter des tumeurs. Une tumeur cancéreuse est normalement 5–10 fois plus «rigide» que le tissu normal. Quand une compression mécanique est appliquée, la tumeur se déforme moins que le tissu environnant c.-à-d. La contrainte dans la tumeur est moindre que dans le tissu environnant. Cette propriété produit des images remarquablement claires. Le but de cette étude a été d'appliquer cette technologie à l'échoendoscopie pour différencier les ganglions néoplasiques des adénopathies inflammatoires.
Use of the 21 gene recurrence score (RS) assay results in patients (pts) treated with intraoperative radiation therapy (IORT) for early stage (ES) breast cancer.
Authors: Barbara Stewart Schwartzberg, Daniel Chin, Kathryn T. Howell, Tyler James Kemmis, Stephanie Miller, Joyce Moore, Devchand Paul
Journal: Journal of Clinical Oncology (2016)

e12537 Background: IORT patient criteria have not been defined. Suitability criteria have been established for pts receiving accelerated partial breast irradiation (APBI) by the American Society of Therapeutic Radiation Oncology (ASTRO). Certain pts (women aged ≥ 70 with ES estrogen receptor (ER) positive (+) cancers) may not benefit from any radiation therapy (XRT) and could be treated with endocrine therapy alone. Conversely, pts with high RS (HRS) have been shown to have higher local recurrence (LR) rates which are not improved by the addition of tamoxifen when compared to placebo. Pts undergoing IORT were evaluated by ASTRO APBI guidelines and RS with a comparison of the results. Methods: Outcomes of consented pts completing IORT (11/ 2011 – 5/ 2013) per protocol in a single institution IRB approved clinical trial were reviewed. Data collection included demographics, histopathology, prognostic factors, RS, adjuvant therapy, LR, and survival. Results: 100 pts (aged 43-96, mean 63) completed IORT per protocol. 16 (16%) pts had DCIS (mean size 0.7 cm). 84 (84%) pts had invasive carcinoma (IC) (mean size 1.0 cm): ductal - 82 pts, lobular - 2 pts, which was ER positive (+) in 76 (90%) pts. RS was obtained in 65 (86%) IC patients with ER+ cancers. The remaining IC pts declined (4 pts) or had cancers <5mm (7 pts). Low (L) RS was found in 44 (67%) pts, intermediate (I) RS in 16 (25%) pts, and HRS in 5 (8%) pts. These 65 patients were classified using ASTRO APBI guidelines with 40 (62%) ranked as “Suitable”, 18 (27%) “Cautionary”, and 7 (11%) “Unsuitable”. IORT pts received adjuvant therapy per current standards. At median follow up of 36 months, there has been one LR (age 98, HRS at recurrence; pt declined RS testing and endocrine therapy at age 96 with initial diagnosis), and one breast cancer related death (age 50, ER negative, Her2neu +). Conclusions: The 21 gene RS assay may be an independent additional prognostic factor which will be useful in making appropriate therapeutic recommendations for IORT patients. Longer follow up is necessary. RS CATEGORIES ASTRO APBI CATEGORIES
Decreased copy number aberrations in genomes of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (dCR) to trastuzumab (T).
Authors: Alanna Maguire, Giuseppe Gullo, Cecily Quinn, Smriti Malasi, Elizabeth Lenkiewicz, Michael T. Barrett, Norma O'Donovan, Naomi Walsh, John Crown
Journal: Journal of Clinical Oncology (2016)

610 Background: Although, 40-60 % of HER2+ MBC pts obtain a clinical response to T, most develop de novo or acquired resistance after a median response duration of < 1 year. However, long-term durable complete response (dCR) MBC cases have been documented. We previously reported that 9 % of HER2+ MBC pts achieved dCR (median follow-up 7 years) following T and chemotherapy in Irish and Italian institutions. Understanding the mechanisms of exceptional responses to T may improve patient selection and treatment rationale to identify HER2+ MBC pts who are more likely to achieve dCR following T treatment. Methods: HER2+ MBC pts treated with T and chemotherapy in the metastatic setting were retrospectively identified. Cases (n = 3) with extraordinary responses to T dCR > 60 mo and controls (n = 2) NR (non-responder) or PR < 6 mo had sufficient FFPE material available for analysis. Flow cytometry was used to sort diploid and aneuploidy populations from the archived tissue. DNA from sorted tumour nuclei was extracted using QIAamp DNA Micro Kit and amplified using Ovation WGA FFPE System and aCGH were performed. Results: aCGH analysis of pure tumour DNA from dCR and NR identified distinct patterns of copy number alterations. HER2 amplicon was confirmed in all samples. Decreased copy number alterations were observed in the dCR group compared to the NR group (11±5.2 vs 19.5±3.5). Interestingly, no deletions were observed in the dCR group. Conclusions: Our preliminary data highlights distinct copy number alterations between dCR and NR suggesting that exceptional responder genomes are potentially more stable with overall less genomic aberrations. A larger study is ongoing to further validate genomic determinants of dCR following T therapy which could serve as the basis for a predictive assay for the risk stratification of pts.
Patterns and predictors of BRCA 1/2 testing in young breast cancer survivors.
Authors: Shoshana M. Rosenberg, Kathryn Jean Ruddy, William Thomas Barry, Kim Sprunck, Jennifer A. Ligibel, Susan M. Domchek, Ann H. Partridge
Journal: Journal of Clinical Oncology (2016)

1514 Background: Current NCCN guidelines recommend that young women diagnosed with breast cancer (BC) undergo BRCA 1/2 (BRCA) testing. We sought to describe experiences surrounding testing among women diagnosed with BC at age ≤45. Methods: The Young and Strong Study is a 54 site cluster randomized trial that evaluated an education and support intervention for women, aged 18-45, diagnosed in 2012-2013, with early stage BC. Socio-demographic information was collected at baseline; women were surveyed again 3 months after enrollment about BRCA testing, family history, how genetic concerns affected treatment decisions, and reasons for not undergoing testing. We used logistic regression to identify predictors of not undergoing testing. Results: 338/403 (84%) women reported having undergone BRCA testing. Among those tested, 6% reported a BRCA1 or 2 mutation; 3% an indeterminate variant; 85% no abnormality; results were unknown for 6%. Among untested women (N=65), 20% said they could not afford it; 15% perceived they were not at high risk for having a mutation; 43% were planning future testing. Among women who were tested and indicated genetic concerns affected treatment decisions (N=133), 78% of BRCA+ and 52% of BRCA- women chose bilateral mastectomy. In the multivariable analysis (Table), older age (≥40 vs. <35) at diagnosis was an independent predictor of not undergoing testing. Conclusions: While most young women with BC enrolled in an intervention study through US community and academic practices underwent genetic testing, women age ≥40 were less likely to have been tested. The finding that a majority of women citing genetic risk concerns factored into treatment decisions were BRCA- yet chose bilateral mastectomy suggests a need to understand further and potentially improve decision making surrounding surgery in young women. Multivariable analysis: factors associated with not undergoing testing. OR (95% CI) Age 35-39 vs <35 2.16 (0.74-6.34) ≥40 vs < 35 4.11 (1.54-10.97) 4 year college graduate vs less educated 0.84 (0.47-1.50) White non-Hispanic vs non-WNH 0.97 (0.51-1.85) Stage 2 vs 1 1.64 (0.86-3.12) 3 vs 1 1.53 (0.65-3.60) Academic practice vs. community 0.85 (0.48-1.51) 1° family history of breast/ovarian ca vs none 0.43 (0.17-1.05)
A retrospective audit to compare length of history, severity and clinical course of disease, of patients diagnosed with ulcerative colitis via acorn (Aintree colorectal neoplasia service) and conventional referral pathways
Authors: J Gasem, E Brown, P O'Toole
Journal: Endoscopy (2005)

Aim: To compare the length of history prior to diagnosis, the severity of the condition at diagnosis and the subsequent clinical course of patients diagnosed with ulcerative colitis via ACORN and conventional referral pathways.
Abstract P094: Anesthetic Preconditioning in Human Cardiomyocytes Derived from Type II Diabetic Patient-Induced Pluripotent Stem Cells in a Varying Glucose Environment
Authors: Scott Canfield, Ana Sepac, Filip Sedlic, Maria Muravyeva, Xiaowen Bai, Zeljko Bosnjak
Journal: Circulation Research (2011)

Volatile anesthetic-induced preconditioning (APC) has been shown to pharmacologically precondition the myocardium, providing protection from an ischemia-reperfusion injury. However, APC is attenuated or even eliminated in diabetic individuals and in the presence of acute hyperglycemia with the underlying mechanism(s) being unknown. In this study, we used ventricular cardiomyocytes (CMs) differentiated from non-diabetic and type II diabetic-induced pluripotent stem cells (N-iPSCs and DM-iPSCs, respectively) to investigate the influence of a high glucose environment and genetic background on APC. Differentiated CMs were identified using cardiac-specific immunostaining and expression of green fluorescent protein under the transcriptional control of cardiac promoter myosin light chain-2v, a genetic construct delivered by lentiviral vector. N-iPSC- and DM-iPSC-derived CMs were exposed to varying glucose environments (11 mM and 25 mM). Confocal microscopy was utilized to measure mitochondrial membrane potential and mitochondrial permeability transition pore opening (mPTP) in CMs. The volatile anesthetic isoflurane depolarized mitochondria in N-iPSC-derived CMs via opening of the mitochondrial adenosine triphosphate-sensitive potassium channel; however, isoflurane depolarized mitochondria to a significantly lower level in diabetic-derived cardiomyocytes and in the presence of 25 mM glucose. APC delayed mPTP opening in both N-iPSC- and DM-iPSC-derived CMs in 11 mM glucose environment only. We have established an in vitro model based on directed differentiation of ventricular CMs from N-iPSCs and DM-iPSCs that allows us the unique opportunity to conduct comparative studies to address the inability of diabetic individuals to be preconditioned with anesthetics. Our preliminary results indicate for the first time that both a high glucose environment and a diabetic background have detrimental effects on the efficiency of APC to protect CMs from an ischemia-reperfusion injury.
Neutrophil/lymphocyte ratio as a predictive value for overall survival in locally advanced breast cancer patients receiving neoadjuvant chemotherapy at the National Cancer Institute of Mexico.
Authors: Paula Cabrera-Galeana, Jaime Hidalgo, Fernando Lara, Wendy Rossemary Munoz Montano, Alberto Alvarado Miranda, Juan Antonio Matus, Diana Fabiola Flores Diaz, Claudia Arce-Salinas, Cynthia Villarreal-Garza, Jose Luis Aguilar, Enrique Bargallo Rocha, Alejandro Mohar
Journal: Journal of Clinical Oncology (2016)

e12023 Background: The neutrophil-to-lymphocyte ratio (NLR) is a strong predictor of mortality in patients with pancreatic, colorectal, lung, gastric cancer and renal cell carcinoma. The aim of this study was to determine the relationship between pathological complete response (pCR) and pretreatment NLR values with overall survival in locally advanced breast cancer (LABC) patients receiving neoadjuvant chemotherapy (NACT) at the National Cancer Institute (NCI) of Mexico. Methods: Data were retrospectively collected from the Database of the NCI for LABC patients treated with NACT (including trastuzumab for HER2+ tumors) between January 2007- December 2010. We evaluated data of 690 patients (pts). Patients without complete pathology reports, laboratory test results, inflammatory (T4d) or pregnancy related BC were excluded. Pts who were diagnosed with chronic liver disease, end stage renal disease or any inflammatory disease such as SLE were also excluded. The pretreatment blood count data was retrieved from the electronic medical record. Results: A total of 464 patients were analyzed. 143 (31.8%) achieved a pCR and 321 (69.2%) did not. The median NLR values were similar in both arms. The NLR cut-off point was 1.41 (AUC:0.45, 95% CI [0.393- 0.507], p = 0.087) with sensitivity and specificity of 81% and 83% respectively. For all patients that achieved a pCR and a NLR < 1.41, overall survival (OS) reached was 109.5 months (CI; 104.9-114.0) vs 91.9 months (CI 95%; 84.1-99.6, p < 0.0001) with a NLR > 1.41 and pCR. Conclusions: This study showed a relationship between pCR and pretreatment NLR < 1.41 values with OS in patients with LABC receiving NACT. These results need prospective confirmation, and if so, can be used by clinicians as a predictive tool that can be easily measurable.
Adherence to novel oral anticancer therapies in the phase I setting: The Royal Marsden experience.
Authors: Maxime Chenard-Poirier, Joo Ern Ang, Samuel John Harris, Alvaro Henrique Ingles Garces, Satyanarayana Seeramreddi, Raghav Sundar, Dearbhaile Catherine Collins, Malaka Ameratunga, Juanita Suzanne Lopez, Johann S. De Bono, Udai Banerji
Journal: Journal of Clinical Oncology (2017)

2542 Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.