tbuckley/cabot-search huggingface dataset:
Correlation of <i>PIK3CA</i> mutations in cell-free DNA (cfDNA) and efficacy of everolimus (EVE) in metastatic breast cancer: Results from BOLERO-2.
Authors: Mary Ellen Moynahan, Patricia Sung, David Chen, Wei He, Aliaksandra Samoila, Daoqi You, Trusha Bhatt, Parul Patel, Francois Philippe Ringeisen, Gabriel N. Hortobagyi, Jose Baselga, Sarat Chandarlapaty
Journal: Journal of Clinical Oncology (2016)

519 Background: PIK3CA is the most commonly mutated gene in metastatic HR+ breast cancer but its impact on the clinical efficacy of mTOR inhibitor EVE and endocrine therapies is not fully established. We analyzed cfDNA for PIK3CA hotspot mutations to determine their impact on the clinical benefit of exemestane (EXE) or EXE plus EVE from the BOLERO-2 trial that randomized patients (pts) to these two treatment arms (2:1). Methods: Baseline plasma samples were analyzed by ddPCR for H1047R, E545K, and E542K mutations (~85% of activating PIK3CAmutations). Cox-proportional hazards model was used to assess PFS in pt subgroups defined by all or domain specific mutations separately (E545K/E542K for helical and H1047R for kinase domain). Results: 550 of 724 pts (76% trial population) had evaluable genotype results. 238 (43.3%) mutations were identified with frequencies of 25.3%, 11.3% and 7.5% for H1047R, E545K and E542K, respectively. Among 247 pts with PIK3CA genotype derived from sequencing matched archival tumors, the mutation site concordance was 66%. Comparable PFS benefit from adding EVE to EXE was observed in all pts, regardless of their PIK3CA genotypes, consistent with the results from archival tumor analysis (Hortobagyi JCO2015). Furthermore, similar PFS EVE benefits were observed in subgroups defined by mutations in helical and kinase domain separately (Table). In the EXE alone arm, pts with helical domain mutations had decreased PFS, compared to WT [HR 1.56 (CI95% 1.12-2.18)]. Conclusions: Retrospective analysis of cfDNA from BOLERO-2 trial show that PFS benefit from EVE was independent of PIK3CA genotypes at the time of study entry. Analysis of larger populations may identify mutation site differences for disease prognosis and/or predictive for treatment benefit. Clinical trial information: NCT00863655.PFS. PIK3CA genotype Treatment N Events Median PFS mo, (95% CI) HR (95% CI) WT EXE 124 111 2.96 (2.76 - 4.17) 0.43 (0.34 - 0.56) EVE+EXE 188 132 7.36 (6.77 - 9.69) MT EXE 69 60 2.69 (1.51 - 4.11) 0.37 (0.27 - 0.51) EVE+EXE 169 123 6.90 (5.55 - 8.31) H1047R EXE 43 38 4.04 (1.51 - 4.7) 0.37 (0.24 - 0.56) EVE+EXE 95 65 7.59 (5.59 - 9.76) E545K/E542K EXE 26 22 2.22 (1.38 - 2.76) 0.30 (0.18 - 0.51) EVE+EXE 74 58 5.59 (4.14 - 7.82)
Abstract 14971: Revacept (Dimeric GPVI-Fc) Does Not Alter Bleeding Time in Humans, but Effectively Inhibits Collagen-Induced Platelet Aggregation. Results of a Clinical Phase I Trial.
Authors: Gotz Munch, Andreas Bultmann, Kai Rosport, Richard Piechatzek, Kerstin Uhland, Meinrad Gawaz, Martin Ungerer
Journal: Circulation (2010)

Background: GPVI-dependent blocking of vascular collagen sites is an attractive target for an activation-specific treatment of acute atherosclerotic diseases, such as myocardial infarction or strok...
Показники добової рН-метрії та їх взаємозв’язок між клінічними та ендоскопічними проявами ГЕРХ у хворих при поєднанні її з цукровим діабетом 2-го типу
Authors: E.Yu. Frolova-Romanyuk
Journal: GASTROENTEROLOGY (2013)

У статті наведені власні дані з вивчення клінічних особливостей, показників добової рН-метрії стравоходу, ендоскопічної картини у хворих при поєднанні ГЕРХ і цукрового діабету 2-го типу.
Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples
Authors: Manuel Valero, Robert G. Averkin, Ivan Fernandez-Lamo, Juan Aguilar, Diego Lopez-Pigozzi, Jorge R. Brotons-Mas, Elena Cid, Gabor Tamas, Liset Menendez de la Prida
Journal: Neuron (2017)
Implementing decision support for breast cancer chemoprevention in primary care.
Authors: Jersen Telfort, Meghna S. Trivedi, Hae Seung Yi, Hilary Colbeth, Alejandro Vanegas, Jennifer Vargas, Rossy Sandoval, Jeffrey Wood, Jill Dimond, Joseph Finkelstein, Rita Kukafka, Katherine D Crew
Journal: Journal of Clinical Oncology (2017)

e13038 Background: Breast cancer risk assessment and chemoprevention with anti-estrogens among high-risk women are underutilized. We developed web-based decision support tools for high-risk women, RealRisks, and their primary care providers (PCPs), BNAV, which are integrated into clinic workflow. Methods: We conducted a pilot study in 50 women who were found to have a 5-year risk of invasive breast cancer ≥1.67% according to the Gail model during screening mammography. RealRisks includes modules on breast cancer risk and chemoprevention, as well as interactive games to communicate risk and preference elicitation for chemoprevention. A tailored patient and provider action plan is generated summarizing their breast cancer risk profile. Before and after interacting with RealRisks, participants completed validated questionnaires on breast cancer and chemoprevention knowledge and chemoprevention intention. Prior to their next clinic visit, their PCPs were given access to the BNAV reference toolbox. High-risk referrals and chemoprevention uptake were assessed by medical chart review. Paired t-tests and chi-square tests were used to analyze continuous and categorical variables pre/post-intervention, respectively. Results: From Mar to Aug 2016, 50 high-risk women were enrolled and 40 were evaluable. Median age 64.5 years (range, 49-72); white/black/Hispanic (%): 37.5/25/37.5; 35% had adequate health literacy; median 5-year breast cancer risk was 2.2% (range, 1.7-3.9). Before and after interacting with RealRisks, we observed an increase in adequate breast cancer knowledge (60% vs. 84%, p = .01) and chemoprevention knowledge (5% vs. 25%, p &lt; .01). After viewing RealRisks, 30% of women were interested in taking an anti-estrogen for chemoprevention, 33% not interested, and 37% unsure. Thus far, only 2 were referred for high-risk consultations and no high-risk women initiated chemoprevention. Conclusions: Despite increased interest in chemoprevention after exposure to RealRisks, additional barriers to chemoprevention uptake exist, including competing comorbidities and time constraints during the clinical encounter. Targeting younger women with higher breast cancer risk may increase chemoprevention uptake. Clinical trial information: NCT02954900.
Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis
Authors: James W.B. Bainbridge, Manjit S. Mehat, Venki Sundaram, Scott J. Robbie, Susie E. Barker, Caterina Ripamonti, Anastasios Georgiadis, Freya M. Mowat, Stuart G. Beattie, Peter J. Gardner, Kecia L. Feathers, Vy A. Luong, Suzanne Yzer, Kamaljit Balaggan, Ananth Viswanathan, Thomy J.L. de Ravel, Ingele Casteels, Graham E. Holder, Nick Tyler, Fred W. Fitzke, Richard G. Weleber, Marko Nardini, Anthony T. Moore, Debra A. Thompson, Simon M. Petersen-Jones, Michel Michaelides, L. Ingeborgh van den Born, Andrew Stockman, Alexander J. Smith, Gary Rubin, Robin R. Ali
Journal: New England Journal of Medicine (2015)

Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited.
ETNA (Evaluating Treatment with Neoadjuvant Abraxane) randomized phase III study comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by anthracycline regimens in women with HER2-negative high-risk breast cancer: A MICHELANGO study.
Authors: Luca Gianni, Mauro Mansutti, Antonio Anton, Lourdes Calvo, Giancarlo Bisagni, Begoña Bermejo, Vladimir Semiglazov, Marc Thill, Jose Ignacio Chacon, Arlene Chan, Serafin Morales, Isabel Alvarez, Arrate Plazaola, Milvia Zambetti, Andrew D. Redfern, Christian Dittrich, Rebecca Alexandra Dent, Domenico Magazzu', Pinuccia Valagussa, Ignacio Tusquets
Journal: Journal of Clinical Oncology (2016)

502 Background: Neoadjuvant chemotherapy regimens employing anthracyclines and taxanes have reported essentially doubled pCR rates with the addition of a taxane after anthracycline combinations. A reverse sequence did not reduce activity. nab-Paclitaxel (nab-P) is an albumin-bound nanoparticle of paclitaxel (P) that allows for safe infusion without premedication, and led to a significantly higher rate of pCR in the GeparSepto trial (Untch et al, Lancet Oncol 2016). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to P 90 mg/m2 (349 patients) or nab-P 125 mg/m2(346 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. Results: The ITT analysis of the primary endpoint pCR (absence of invasive cells in breast and nodes) along with the overall objective clinical response after systemic therapy is reported below. Conclusions: The improved rate of pCR after nab-P failed to reach statistical significance. The multivariate analysis revealed that tumor subtype was the most significant factor (OR 5.11) influencing treatment outcome. Extensive collection and banking of tumor ( > 90%) and blood was performed and translational studies might provide clues for more informative correlations with available results. Supported in part by an unrestricted grant from Celgene. Clinical trial information: NCT01822314. # patients P % (95% CI) nab-P % (95% CI) OR (95% CI) P value pCR overall 695 18.1 (14.2-22.5) 22.5 (18.2-27.3) 0.74 (0.50-1.09)* 0.127* pCR Luminal B 476 10.0 (6.5-14.6) 13.9 (9.8-19.0) 0.69 (0.39-1.21) 0.193 pCR Triple negative 219 35.5 (26.6-45.1) 41.3 (31.9-51.1) 0.78 (0.45-1.35) 0.376 Objective clinical response 695 74.5 (69.6-79.0) 77.2 (72.4-81.5) 0.87 (0.61-1.23)* 0.427* *Cochran-Mantel-Haenszel test Overall, 11% of patients had at least one serious adverse event with P, and 16% with nab-P. Peripheral neuropathy of grade > 2 was 2% and 4.5%, respectively.
Impact of routine subspecialty pathology review on the care of women age ≤ 65 years with lymph node negative breast cancer: A practice review.
Authors: Gloria Beatriz Roldan Urgoiti, Fahad Ibnshamsah, Hua Yang, Sasha M. Lupichuk
Journal: Journal of Clinical Oncology (2016)

e12006 Background: Changes in classic pathological features of lymph node negative breast cancer (LNBC) can have a profound impact on local-regional and systemic therapy recommendations. The impact of routine subspecialty pathology review on the care of these patients has not been well described. Methods: Women diagnosed with LNBC from January 1 to December 21, 2012 referred to our cancer centre were identified. As per routine institutional practice, patients ≤ 65 years whose pathology had originally been reported by a general pathologist, had their pathology automatically sent for subspecialty review by a breast pathologist. Medical records were examined to determine if original pathology was changed and if treatment recommendations were altered. Results: Of 468 patients diagnosed with LNBC, 187 patients had their pathology initially reported by a general. Eighty-two (82/187) had at least one change on subspecialty pathology review including increase in tumour grade (35), increase in tumour size (18), and documentation of lymphovascular invasion (14). Lymph node involvement was identified in 3 cases. There was at least one change in treatment recommendation for 21 patients (11.2%). The most common change was inclusion of adjuvant chemotherapy (10). Had Oncotype DX funding been in place during the study period, 14 cases would have become eligible and 8 would have become ineligible according to our current institutional testing guidelines (Estrogen receptor-positive, Human epidermal growth factor receptor 2-negative, grade 2 or 3, and node negative). Nine of 26 treatment recommendation changes occurred in Oncotype DX eligible patients. Conclusions: Routine subspecialty pathology review of LNBC yielded substantial changes in classic pathological features and subsequent alterations in treatment recommendations. Optimal practice with the availability of gene signature testing requires further investigation.
Response Assessment in Neuro-Oncology Clinical Trials
Authors: Patrick Y. Wen, Susan M. Chang, Martin J. Van den Bent, Michael A. Vogelbaum, David R. Macdonald, Eudocia Q. Lee
Journal: Journal of Clinical Oncology (2017)

Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro-Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed.
Efficacy of multikinase inhibitors (MKIs) in successive treatment lines of refractory advanced thyroid cancer patients (pts).
Authors: Ignacio Matos, Juan J. Grau, Enrique Grande, Javier Martinez Trufero, Jose Manuel Trigo, Carlos Lopez, Jose Luis Manzano, Òscar Reig, Cristina Alvarez, Miguel Beltran, Manuel Duran, Javier Aller, Lara Iglesias, Sara Arevalo, Aránzazu Manzano, Ricard Mesia, Juan J Reina, Juan Manuel Sepúlveda, JA Virizuela, Jaume Capdevila
Journal: Journal of Clinical Oncology (2016)

e17553 Background: Sequential therapy with MKIs in the management of refractory thyroid cancer cannot be standardized with data coming form randomized clinical trials. Methods: We retrospectively analyzed pts with advanced radioactive-iodine refractory differentiated thyroid cancer (DTC) or unresectable medullary thyroid cancer (MTC) treated with MKIs, from January 2010 to November 2015 included in the Spanish group of rare cancers (GETHI) database. Most used MKIs included sorafenib, lenvatinib, vandetanib, cabozantinib, sunitinib and pazopanib. Primary endpoint was to evaluate the progression-free survival in first-line (PFS1) compared to PFS in second-line (PFS2) independently of the MKIs used in both setting. Secondary objectives were overall survival (OS), overall response rate (RR) and overall safety profile. Results: 74 pts were analyzed (43 DTC, 31 MTC). All pts received MKIs in first-line (1st) and 43 (58.1%) in second-line (2nd). Median PFS1 was 11.53 months (CI 95% 11.53-14.5) and median PFS2 was 14.07 months (CI 95% 8.07-20.06) in pts with MTC (p = 0.698). In patients with DTC median PFS1 was 8.66 months (CI 95% 6.74-10.59) and median PFS2 was 5.53 months (CI 95% 3.99-7.06) (p = 0.036). Dose reductions were needed in 66.7% and 40% for 1st and 2nd respectively in MTC. In the case DTC, fewer reductions were necessary 41,9% and 21.7%. 64 patients were assessable for efficacy. Overall RR in 1st of DTC was 47%, stable disease (SD) was 38,2% and 14.7% had progressive disease (PD); in the 2nd RR was 25%, SD was 35% and PD was 40%. In MTC, RR were 39,2% and 27.8%, SD were 50% and 50%, PD were 10.5% and 22.2; for 1st and 2ndrespectively. Median OS in MTC (27 months [CI95% 18.8-35.1]) was significantly longer compared with DTC (15.43 months [CI95% 6.64-24.22] p = 0.05). Conclusions: The use of MKIs in different treatment lines in DTC and MTC is a common approach in routine clinical practice even the lack of randomized clinical trials that support this strategy. However, signals of activity could be observed with sequential therapies in retrospective series in these orphan tumors that warrants further prospective trials to demonstrate improvements in survival.
Clinical actionability of germline testing in patients with limited colorectal polyps.
Authors: Mersedeh Rohanizadegan, Saud H Aldubayan, Marios Giannakis, Xinmeng Jasmine Mu, Reiko Nishihara, Zhi Rong Qian, Jonathan Nowak, Yin Cao, Li Liu, Mingyang Song, Andrew T. Chan, Levi A. Garraway, Shuji Ogino, Charles S. Fuchs, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2017)

e13027 Background: As classic adenoma-carcinoma sequence is the main process underlying most colorectal cancer (CRC), early detection and removal of colorectal adenomas is crucial in preventing CRC. Although adenomatous polyps are usually sporadic, several inherited CRC syndromes such as Familial adenomatous polyposis, MUTYH-associated polyposis and Lynch syndrome can present initially with colon polyps. The identification of germline defects in patients with colon polyps is thus critical for proper cancer risk counseling and CRC prevention. Current guidelines recommend germline testing for patients with more than 20 polyps or those with more than 10 polyps and a family history of CRC. However, the diagnostic yield of germline testing on otherwise healthy individuals with 10 or fewer colon polyps has not been well studied. Here, we performed a pilot study to evaluate the clinical actionability of germline genetic testing on these patients. Methods: A total of 13 cancer-free adults, who presented with colon polyps (n &lt; 10) and who otherwise were not selected based on age of onset or family history underwent germline Exome Sequencing. Variants in 13 well-established CRC risk genes ( APC, CHEK2, MYH, MLH1, MSH2, MSH6, PMS2, NTHL1, BMPR1A, SMAD4, PTEN, STK11, TP53) were evaluated for pathogenicity. Results: A total of 13 patients (12 male, 1 female) were evaluated. The median age of presentation was 69 (range 49 to 88). The median number of adenomatous colon polyps was 1 (range 1 to 8). Two (15.4%, 95% CI = 1.9 - 45.4, Binomial Exact) patients had at least one disruptive mutation in the examined genes. One of these patients had a truncating mutation in APC (p.Arg216*) and presented with two tubulovillous adenomas at age 49. The second patient had 8 adenomas in distal colon and rectum at age 64, and harbored a known pathogenic mutation in MSH6(p.Arg1035*). Conclusions: This pilot study provides evidence that a relatively high percentage of patients presenting with a few colon polyps may have inherited defects in highly actionable genes. If validated in larger cohorts with appropriate population controls, these findings may influence the clinical care of such patients and their families and suggest germline molecular testing in those patients.
Impact of aspirin use on the incidence of head and neck cancers: A systematic review and meta-analysis.
Authors: Prakash C. Neupane, Sashidhar Manthravadi
Journal: Journal of Clinical Oncology (2016)

1546 Background: In addition to its widely accepted role in cardiovascular disease, aspirin use has been associated with decreased risk of several malignancies, especially colorectal cancer. The United States Preventive Task Force has recently updated their guidelines and added colorectal cancer prevention as an added benefit to aspirin use. However, the impact of aspirin use on the risk of cancers of the head and neck (HNC) has not been reviewed previously. Methods: A systematic search of PubMed and Embase was performed to identify studies which evaluated the relationship between aspirin use and risk of cancers of the head and neck. Case-control studies and cohort studies were both included in the review. Random effects model was use to estimate a pooled effect size and the inconsistency index (I2) was used to estimate heterogeneity between included studies. We hypothesized that tobacco users are more likely to be prescribed aspirin and also had an increased risk for HNC and thus planned a sensitivity analysis to exclude studies which did not adjust for tobacco usage. Results: After reviewing 879 reports, 8 studies which described the association between aspirin use and HNC risk were selected, all of which were reported from Europe or North America. A total of 206, 865 patients were included in 6 case-control studies and 2 cohort studies of whom 8,395 patients had HNC. Controls were matched for age and sex in all case-control studies and for tobacco use in 2 studies. In a meta-analysis, aspirin use reduced the risk of head and neck cancers; however, this association was of borderline statistical significance (OR 0.87, 95% CI 0.75- 1.02). Moderate heterogeneity (I2= 50%, P = 0.05) was seen in this meta-analysis which was lost in our sensitivity analysis. On restricting meta-analysis to studies which adjusted for tobacco use (N = 7), aspirin use was found to be associated with a significantly reduced risk of HNCs (OR 0.84; 95% CI 0.73- 0.96) with low heterogeneity (I2= 35%, P = 0.16) Conclusions: Aspirin users appear to be at lower risk for cancers of the head and neck after adjustment for tobacco use. Additional cohort studies are required to evaluate the optimal dose or duration of use of aspirin that may be confer this protective effect.