tbuckley/cabot-search huggingface dataset:
Erratum to: Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures
Authors: Yasin Şenbabaoğlu, Ron S. Gejman, Andrew G. Winer, Ming Liu, Eliezer M. Van Allen, Guillermo de Velasco, Diana Miao, Irina Ostrovnaya, Esther Drill, Augustin Luna, Nils Weinhold, William Lee, Brandon J. Manley, Danny N. Khalil, Samuel D. Kaffenberger, Yingbei Chen, Ludmila Danilova, Martin H. Voss, Jonathan A. Coleman, Paul Russo, Victor E. Reuter, Timothy A. Chan, Emily H. Cheng, David A. Scheinberg, Ming O. Li, Toni K. Choueiri, James J. Hsieh, Chris Sander, A. Ari Hakimi
Journal: Genome biology (2017)
Phase 1b/2 trial of BI 836845, an insulin-like growth factor (IGF) ligand-neutralizing antibody, combined with exemestane (Ex) and everolimus (Ev) in hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (BC): primary phase 1b results.
Authors: Javier Cortes, Noelia Martinez Janez, Marie-Paule Sablin, Jose Alejandro Perez-Fidalgo, Patrick Neven, Elham Hedayati, Alexandra Ballester, Marie-Paule Ehrhart, Dennis C Huang, Thomas Bogenrieder, Peter Schmid
Journal: Journal of Clinical Oncology (2016)

530 Background: BI 836845, an IGF ligand-neutralizing antibody, binds IGF-1 and IGF-2, inhibits growth-promoting signaling and mitigates AKT activation induced by Ev. This Phase 1b/2 trial evaluates BI 836845 combined with Ex and Ev in HR+/HER2– locally advanced or metastatic BC (Study 1280.4; NCT02123823). Primary Phase 1b results are reported. Methods: The ‘3+3 design’ dose-escalation part enrolled postmenopausal women with HR+/HER2– locally advanced or metastatic BC not amenable to curative therapy, which recurred or progressed and was refractory to non-steroidal aromatase inhibitors. Patients (pts) received escalating doses of BI 836845 (750 or 1000mg/wk, 1-hr IV infusion) combined with oral Ex (25mg/d) and Ev (10mg/d) in 28-day cycles until disease progression, intolerable adverse events (AEs) or other reasons for withdrawal. Primary endpoints: incidence of dose limiting toxicity (DLT) during cycle 1 and determination of the maximum tolerated dose (MTD). Results: Twenty-four pts (median [range] age, 65 [49–80] years) were treated (750mg, n = 3; 1000mg, n = 21); 13 (54%) discontinued due to progressive disease (750mg, n = 3; 1000mg, n = 10) and 11 were still on treatment at the time of analysis. During cycle 1, 0/3 and 1/6 evaluable pts (grade 3 stomatitis) in the 750mg and 1000mg groups had DLT. The MTD was determined as 1000mg/wk BI 836845 combined with 25mg/d Ex and 10mg/d Ev. The most common drug-related AEs were decreased appetite, hyperglycemia and mucosal inflammation (each 12/24 pts; 50%), mostly grade 1/2. No drug-related AEs led to discontinuation. No dose reductions due to AEs were required for BI 836845 or Ex; 14 pts (1000mg group) required Ev dose reduction. In the 1000mg group, 12/21 (57%) pts had disease control, with 4 (19%) of the pts achieving partial response; median PFS was 9.4 months. Conclusions: The MTD and recommended Phase 2 dose of BI 836845 was 1000mg/wk combined with Ex 25mg/d and Ev 10mg/d. This triple combination exhibited a manageable safety profile and encouraging antitumor activity. The randomized Phase 2 part of the study is ongoing. Clinical trial information: NCT02123823.
Greenville health system (GHS) experience with risk reduction endocrine therapy for women diagnosed with breast lobular carcinoma in situ (LCIS).
Authors: Richard O'Neal, Wendy R. Cornett, Yonge R Jones, Morgan Stewart, Regina A. Franco, Leann Perkins, Mark Allen O'Rourke
Journal: Journal of Clinical Oncology (2017)

e13041 Background: LCIS is associated with a 1% annual risk of developing invasive breast cancer, twice that of the general population. Endocrine therapy for chemoprevention has been shown to decrease this risk by 56% in women with LCIS. Barriers include failure to offer endocrine therapy and failure to tolerate it. This study examined a population of women with LCIS and their experience with endocrine therapy for breast cancer risk reduction. Methods: 337 patients with LCIS from 2010-2015 at the GHS were retrospectively identified through electronic health record review. Median age was 55.5 years; 303 underwent breast-conserving surgery and 34 mastectomy. Chart review assessed the documented recommendations for endocrine therapy, duration of adherence, and presence of side effects. Results: Endocrine therapy was prescribed in 155 (46%), refused in 33 (10%), and not recommended in 120 (36%). Of the 146 women who were started on endocrine therapy for risk reduction and followed for six months, 75% adhered to the endocrine therapy. Of the 94 followed for 2 years, 71% adhered. The rate of documented side effects was 14% and was the most commonly cited reason for discontinuation (78%). Conclusions: The number of women with LCIS that were not prescribed endocrine therapy in the absence of absolute contraindications was substantial (36%). Under documentation in the medical record may account for a portion of this. The rate of side effects of those started on endocrine therapy (14%) is lower than expected, although this may represent underreporting. With a low refusal rate (10%) and a high adherence rates (75% at 6 months and 71% at 2 years) in the treated population, improving the number of women with LCIS that are offered endocrine therapy has considerable potential for reducing breast cancer risk. Controlling side effects can increase the benefit further.
A network meta-analysis of fulvestrant vs alternative first-line endocrine therapies for endocrine therapy-naive postmenopausal hormone receptor-positive advanced or metastatic breast cancer.
Authors: Claire Telford, Shweta Takyar, Parth Joshi, Mattias Ekman, Nick Jones
Journal: Journal of Clinical Oncology (2017)

e12545 Background: Fulvestrant (F) is a selective estrogen degrader for hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). This network meta-analysis examined the efficacy of F (500 mg) vs alternative endocrine therapies (ETs) for first-line treatment of ET-naïve HR+ LA/MBC. Methods: Randomized controlled trials of first-line F, tamoxifen (Tam), anastrozole (A), exemestane (E), letrozole (L), and toremifene (T) for women (≥18 years) with HR+ LA/MBC and no prior ET were identified in a systematic review of MEDLINE, EMBASE, and Cochrane databases from inception to October 2016. Conference proceedings of the American Society of Clinical Oncology, European Society of Medical Oncology, and San Antonio Breast Cancer Symposium from 2013-2016 were hand searched. Trials of targeted combination therapies were excluded. Studies were checked for heterogeneity. A standard fixed-effect Bayesian network meta-analysis was conducted based on hazard ratios (HRs) and assuming proportional hazards for progression-free and overall survival (PFS/OS). Results: Seven eligible studies (1 Phase [Ph] 2, 5 Ph 3, 1 Ph 2/3) were identified. All had PFS data; five had OS data. Two trials compared F vs A; PFS data were available for both trials; sufficiently mature OS data for F were available from Ph 2 only. The proportional hazards assumption was met for PFS only.F had significantly improved PFS vs Tam (HR 0.57, 95% credibility interval [Crl] 0.44-0.73), A (HR 0.75, 95% Crl 0.62-0.91), E (HR 0.65, 95% Crl 0.47-0.91), and T (HR 0.53, 95% Crl 0.37-0.78). Numerically improved PFS was observed for F vs L (HR 0.81, 95% Crl 0.59-1.11). F had significantly improved OS vs Tam (HR 0.63, 95% Crl 0.40-0.98), A (HR 0.63, 95% Crl 0.42-0.94), and E (HR 0.56, 95% Crl 0.33-0.95). OS was numerically improved with F vs L (HR 0.66, 95% Crl 0.41-1.04). Conclusions: This analysis suggests improved PFS and OS for fulvestrant vs tamoxifen, anastrozole, exemestane, and letrozole, and PFS for fulvestrant vs toremifene. Further analysis should be conducted, using non-proportional hazard methods and more mature OS data, to confirm the OS results.
Abstract 18719: Relationship Between Proximal Aorta Morphology and Progression Rate of Aortic Stenosis
Authors: Romain Capoulade, Philipp Bartko, Jonathan G Teoh, Elisa Teo, Yong H Park, Eric M Isselbacher, Thoralf Sundt, Thomas E Macgillivray, Judy Hung
Journal: Circulation (2015)

Background: Morphological changes of the proximal aorta, such as effacement of the sinotubular junction (STJ), may result in increased mechanical stress on the aortic valve leaflets and contribute to calcification and progression of aortic stenosis (AS). The aim of this study was to examine the association between abnormal morphology of proximal aorta and AS progression rate. Methods: Between 2010 and 2012, 426 patients with mild to moderate AS (peak aortic jet velocity &gt;2.5 and &lt;4 m/s) and LVEF≥50% with at least two years of follow up were included in this study. Aortic dimensions were measured at 3 different levels: sinus of Valsalva (SVal), STJ and ascending aorta (Aa). The ratios of SVal by STJ (SVal/STJ) and Aa by STJ (Aa/STJ) were used to determine degree of aortic deformity with smaller ratios consistent with greater perturbation of normal geometry. SVal/STJ&lt;1.13 and Aa/STJ&lt;1.09 were defined as significant low ratios per normal range reported in Guidelines. AS progression rate was assessed by annualized increase in mean gradient (MG; follow-up time = 3.2±0.8 yrs). Results: Mean age was 71±13 yrs and 64% were male. 16% had bicuspid aortic valve and MG was 21±8 mmHg. SVal, STJ and Aa dimensions were respectively 33±4 mm, 27±4 mm and 36±5 mm. Mean SVal/STJ ratio was 1.21±0.15 and Aa/STJ ratio was 1.29±0.19. Patients with significant low ratios had faster AS progression (p≤0.05; figure). After adjustment for age, gender, hypertension, diabetes, renal disease, bicuspid aortic valve, baseline MG, LVEF, aortic regurgitation and indexed STJ, SVal/STJ (p=0.025) or Aa/STJ (p=0.027) were independently associated with faster AS progression. Conclusion: Abnormal aortic root geometry such as effacement of the sinotubular junction is a strong and independent predictor of faster AS progression, regardless of arterial hemodynamics, aortic valve phenotype and baseline AS severity. This finding suggests an interrelation between proximal aorta morphology and stenosis progression.
Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31
Authors: Stephen K. Horrigan, Zarema H. Arbieva, Hong Yan Xie, Jelena Kravarusic, Noreen C. Fulton, Haley Naik, Tiffany T. Le, Carol A. Westbrook
Journal: Blood (2000)
Internal mammary node biopsy for breast cancer patients: Issues for discussion and our practice.
Authors: Qingqing He
Journal: Journal of Clinical Oncology (2013)

e22089 Background: The aims of this study was to determine the clinical implications of internal mammary node biopsy as staging, treatment with radiotherapy and systemic treatment and a prognostic factor in patients with breast cancer. Methods: Internal mammary node biopsy via intercostal space was performed in 344 cases of breast cancer. Anatomical location of internal mammary nodes were recorded. Pathological status of internal mammary node were detected by H and E stains. Results: Internal mammary node biopsy was successfully finished in 344 patients.There were 162 cases (48.26%) with positive axillary nodes, while the internal mammary nodes were involved in 72 cases (20.93%).53 patients (32.72%) had regional metastases in both the axillary and internal mammary lymph nodes.19 (5.52%) patients had internal mammary node metastasis but no axillary node metastases. PN stage migration was seen in 72 patients with a positive internal mammary node. There was no statistic relation between internal mammary nodes metastases and tumor location (X 2 =0.48, P&gt;0.05). There was no complication such as pneumothorax or haemorrhagia. Conclusions: The approach used is a reliable surgical technique for removing lymph node from intercostal space. Without exploring internal mammary nodes status, pN stage was incomplete. Internal mammary node biopsy enables treatment to be better adjusted to the needs of the individual patient. Using internal mammary node biopsy, patients with a negative internal mammary node can be prevented from radiation to internal mammary nodal areas. This leads to optimization of treatment.
Gastric electrical stimulation – Our experience in Cork University Hospital
Authors: V Sibartie, E Quigley, A O'Donnell
Journal: Endoscopy (2005)

Aims: Gastroparesis refractory to prokinetics poses a major challenge to the gastroenterologist. Gastric electrical stimulation (GES) is being increasingly used worldwide in this situation, but despite encouraging clinical trials, had never been tried in Ireland. We describe our experience with gastric neurostimulators.
Caractéristiques cliniques, endoscopiques et immunohistochimiques des adénomes festonnés ou Serrated Adenomas
Authors: R Coriat, M Mozer-Bernardeau, B Terris, S Chaussade
Journal: Endoscopy (2006)

Les adénomes festonnés (AF) ou serrated adenomas sont des polypes coliques caractérisés par l'intrication d'une architecture hyperplasique et de stigmates cytologiques de dysplasie. Le diagnostic histologique peut être difficile et ils sont à ce titre fréquemment confondus avec des polypes hyperplasiques. La séquence AF – Adénocarcinome est démontrée, aussi, la reconnaissance de ces polypes est indispensable. L'objectif de cette étude était de préciser les caractéristiques cliniques, endoscopiques et immunohistochimiques des AF.
Vemurafenib in patients with <i>BRAF</i><sup>V600</sup> mutant glioma: A cohort of the histology-independent VE-basket study.
Authors: David Michael Hyman, Thomas Joseph Kaley, Antoine Hollebecque, Vivek Subbiah, Jordi Rodon Ahnert, A. Craig Lockhart, Vicki Leigh Keedy, Ralf Hofheinz, Florence Joly Lobbedez, Jean-Yves Blay, Ian Chau, Igor Puzanov, Noopur Raje, Juergen Wolf, Martina Makrutzki, Todd Riehl, Bethany Pitcher, Jose Baselga
Journal: Journal of Clinical Oncology (2017)

2004 Background: Recurrent malignant gliomas (MG) are a universally fatal disease in desperate need of better therapies. Pleiomorphic xanthoastrocytomas (PXA) and juvenile pilocytic astrocytomas (JPA) typically have better outcomes, although when recurrent, also represent an aggressive disease with no proven effective chemotherapy. BRAF V600 alterations have been identified in a substantial proportion of gliomas, including glioblastoma (GBM), astrocytoma, PXA, and JPA. The phase 2, open-label, histology-independent VE-BASKET study of vemurafenib, a selective BRAF V600 kinase inhibitor, in patients with BRAF mutation-positive non-melanoma tumors, included those with gliomas in the ‘all-others’ cohort. We now report final data for patients with recurrent gliomas. Methods: Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints included clinical benefit rate (confirmed complete or partial response or stable disease lasting ≥6 months), progression-free survival (PFS), overall survival (OS), and toxicity. ClinicalTrials.gov NCT01524978. Results: 24 patients (median age 32 years; 18 female, 6 male) with glioma were treated, including mg (n = 11; 6 GBM and 5 anaplastic astrocytoma [AA]), PXA (n = 7), anaplastic ganglioglioma (AG, n = 3), JPA (n = 2), and unknown (n = 1). In patients with mg (n = 11), best response included PR (n = 1; AA), SD (n = 5), PD (n = 3), and unknown (n = 2). Two patients with mg had durable SD lasting 12.9 months (GBM) and 14.9 months (AA). In patients with PXA (n = 7), best response included CR (n = 1), PR (n = 2), SD (n = 3), and PD (n = 1). Additionally, 1 patient with JPA and 1 with AG achieved a PR. The most frequent AEs included arthralgia (67%), melanocytic nevus (38%), palmar-plantar erythrodysesthesia (38%), photosensitivity reaction (38%) and alopecia (33%). Conclusions: Vemurafenib demonstrated activity in patients with BRAF V600 mutant glioma. The safety profile was similar to that seen in previous melanoma studies. Survival data will be presented. Clinical trial information: NCT01524978.
VHVT: An ultra-sensitive somatic mutation detection and performance assessment program.
Authors: Jilong Liu, Zu Liu, Shaomin Cheng, Fengming Guo, Meihua Tan, Jingjing Wang, Di Shao, Pan Zhang, Zhilong Li, Han Liu, Shiyong Li, Zhenfei Hu, Yumei Hou, Mao Mao, Mingzhi Ye
Journal: Journal of Clinical Oncology (2017)

1588 Background: NGS as a high throughput technique is particular valuable for cancer given its ability to detect multiple driver mutations. While reads contain SNVs and short InDels can be mapped to the right position using gatk-like programs, a program designed for germline mutation detection, reads contain long InDels such as EGFR EX19 deletions often wrongly mapped especially when deletions near the ends of the reads. Thus, gatk would not recognize these reads, consequently underestimate the mutation allelic frequency, and even missed out InDels when supporting reads were rare. Methods: Here we present a variation hotspot validation toolkit (VHVT), a validation based method to precisely detect the ultra-low frequency somatic mutations. As far as we know, it is the first specialized somatic mutation detection software. First, reference sequences aimed at the hotspot mutations were assembled, then reads were be mapped to the new assembled reference to precisely distinguish the supporting reads. Moreover, log odds (LOD) and Poisson mathematical model were integrated to control sequencing error, as a result, VHVT can achieve a limitation of detection at 0.01% with sensitivity and specificity above 95% and 99% respectively. In addition, we developed a method to quantitatively assess the performance of variation detection program using standard reference data. By mapping to the reconstructed reference, all supporting reads will be detected in sequencing data, and comparing theses with the number of supporting reads delivered by a program we can define recognition ratio of supporting reads. Results: Our reference standard data showed that VHVT can recognize average 30% more support reads than gatk for EGFR EX19 deletions. In a total 498 NSCLC clinical samples test, VHVT detected actionable mutations in 289 samples. 243 positive mutations were verified (168 by SANGER sequencing, 75 by ddPCR) with concordance rate at 100%. Conclusions: Taken all together, our results demonstrated the robust performance of VHVT for somatic mutation detection and program assessment and thus facilitate the development of personalized cancer therapy.
Novel Inhibitors Of CRM1/XPO1 Nuclear Exporter Exhibit Striking Activity Against AML “primagrafts,” Including AML Leukemia Initiating Cells, While Sparing Normal Hematopoietic Cells
Authors: Julia Etchin, Bonnie Thi Le, Alex Kentsis, Richard M. Stone, Dilara McCauley, Michael Kauffman, Sharon Shacham, Jean C.Y. Wang, Andrew L Kung, A. Thomas Look
Journal: Blood (2013)
MLH1 promoter hypermethylation patterns in sporadic colorectal tumours and paired non-neoplastic mucosa
Authors: EJ Fox, DT Leahy, R Geraghty, AM Lennon, D Keegan, A White, HE Mulcahy, JM Hyland, D Fennelly, DP O'Donoghue, K Sheahan
Journal: Endoscopy (2005)

Aim: Promoter-hypermethylation of the DNA mismatch repair gene MLH1 has been implicated in a subset of colorectal cancers (CRC). We investigated the relationship between MLH1 promoter-hypermethylation in tumour and paired non-neoplastic mucosa, and MLH1 expression in a series of CRCs.
Incidence of germline mutations in risk genes including <i>BRCA1/2</i> in consecutive ovarian cancer (OC) patients (AGO TR-1).
Authors: Philipp Harter, Jan Hauke, Florian Heitz, Alexander Reuss, Stefan Kommoss, Frederik Marme, Andre Heimbach, Katharina Prieske, Lisa Katharina Richters, Alexander Burges, Guido Neidhardt, Nikolaus de Gregorio, Ahmed El-Balat, Felix Hilpert, Werner Meier, Martin Leonhard Heubner, Karin Kast, Ioana Braicu, Eric Hahnen, Rita K. Schmutzler
Journal: Journal of Clinical Oncology (2016)

5538 Background: Identification of families at risk for OC including recommendation for prophylactic surgery is the only effective method to reduce OC mortality. In addition, BRCA1/2 mutations are known as prognostic factor and target for treatment. Methods: Prospective counseling and testing of consecutive patients with first diagnosis or platinum sensitive relapse of invasive epithelial OC in Germany. Testing included 25 risk genes related to ovarian cancer (incl. BRCA1, BRCA2, ATM, PALB2, RAD51C, RAD51D, TP53, MLH1, MSH2, MSH6, PMS2). A positive mutation was defined as class 4/5 mutation and a positive family history (FH) was defined as at least one relative with breast cancer (BC) or OC or BC in personal history. Results: In total, 529 pts entered the study, of which 507 were analyzed so far: 270 (53%) patients with first diagnosis of OC and 237 (47%) patients with platinum sensitive relapse. Median age at registration was 61 years (range 18-93). In total, 21% were BRCA1/2 positive (BRCA positive) and 27% for a mutation in at least one risk gene. The incidence of mutations in BRCA1 was 15%, BRCA2: 6%, RAD51C: 1.8%, PALB2: 1.2%. Mutations in all others were found less frequently ( < 1%). Mutations in Lynch syndrome associated genes were found in 0.6%. The incidences did not differ significantly between patients at first diagnosis (BRCA1/2 positive: 19% / risk gene positive: 25%) and relapse (BRCA1/2 positive: 22% / risk gene positive: 30%). Histological subtype and grading were available for 439 patients (87%). The incidence of BRCA / risk gene in high grade serous OC (364/439; 83%) was 23% / 30% and 9% / 19% in all other histological subtypes (75/439; 17%) (p = ns). In elderly patients ( > 70 years at diagnosis), 13% carried a mutation in a risk gene compared to 31% of patients ≤ 70 years (p < 0.001). For 434 pts (86%) FH was evaluable. Of these, 42% had a positive FH. FH identified 69% of the BRCA1/2 positive patients, but missed 31%. Conclusions: 27% of all OC pts harbor a positive mutation in the genes analyzed. Age and FH are insufficient for identifying these patients. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer; limiting testing to BRCA1/2 analysis seems insufficient. Clinical trial information: NCT02222883.