tbuckley/cabot-search huggingface dataset:
Do the efficacy of BP-C1 correlate to receptor status in patients suffering from metastatic breast cancer stage IV?
Authors: Stig Einride Larsen, Kritiya Butthongkomvong, Sirikul Sorraritchingchai, Isaraporn Sangsaikae, Alexey Manikas, Ekaterina Trishkina, Marina Matrosova, Elena Poddubuskaya
Journal: Journal of Clinical Oncology (2017)

e12581 Background: Cis-coordinated complexes of platinum(II) with polymer of benzene polycarboxylic is currently evaluated in clinical trials for treatment of metastatic breast cancer (MBC) patients. The RECIST was used for evaluation of the target lesions and the sum diameter of the five largest target lesions was measured. BP-C1 inhibits tumor growth, improves quality of life with only few mild to moderate adverse events. The aim was to investigate the correlation between the efficacy of BP-C1 and the receptor status of Estrogen (ER), Progesterone (PR) and Human epidermal growth factor (HER-2) Methods: The material consists of prospectively collected results from 30 Thai and 30 Russian MBC patients included in two randomized and double-blinded controlled clinical trial with stratified semi-cross-over design. The patients received daily IM injections of 0.035mg/ml bw BP-C1 for 32 days. The results from Russia available by March 2017, and will be included in the final presentation Results: Negative ER recorded in 13 patients and positive in 15. During 32 days of BP-C1 treatment, the sum lesion diameters reduces with 1.9 % in the negative receptor group, but increases with 8.0 % among the positive. Similar pattern also detected regarding the PR. Negative PR detected in 17 patients and positive in 12. No changes (0.1%) in the sum lesion diameter found in the group with negative PR, but an increase of 8.8% in the positive group. Negative HER-2 receptor recorded in 13 patients and positive in 13. The sum lesion diameter increases with 7% in the negative group and 6.0% in the positive. In five patients, all the three receptors were positive, 10 patients had one negative receptor, 12 had two negative and three were triple negative. During the 32 days of BP-C1 treatment, the sum lesions increases by 20.7% in the triple positive group and by 7.6% in the group with one negative receptor. In the patients with two or three negative receptors, the sum lesion diameter was unchanged; -0.6% and 0.5%, respectively. The reduction sum lesion diameter seem to increase with increasing number of negative receptors. Conclusions: These findings indicate that BP-C1 may be an important treatment of stage IV MBC with negative ER, PR or HER-2 receptor.
Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding
Authors: Sarah K. Westbury, Matthias Canault, Daniel Greene, Emilse Bermejo, Katharine Hanlon, Michele P. Lambert, Carolyn M. Millar, Paquita Nurden, Samya G. Obaji, Shoshana Revel-Vilk, Chris Van Geet, Kate Downes, Sofia Papadia, Salih Tuna, Christopher Watt, Kathleen Freson, Michael A. Laffan, Willem H. Ouwehand, Marie-Christine Alessi, Ernest Turro, Andrew D. Mumford
Journal: Blood (2017)
Complexity of the response evaluation during primary systemic therapy of breast cancer.
Authors: Timea Tökes, Gyöngyver Szentmartoni, Laszlo Torgyik, Janina Kulka, Zsolt Lengyel, Tamas Gyorke, Magdolna Dank
Journal: Journal of Clinical Oncology (2014)

e12010 Background: We analyzed the accuracy of different response evaluation score systems in a group of breast cancer patients treated with primary systemic therapy (PST). The score systems tested were based on the metabolical, morphological and proliferation markers of tumor response. Methods: We report on 42 patients in whom staging FDG-PET/CTs were carried out before and after the PST. Maximal SUVs (Standardized Uptake Values) and morphological changes were evaluated in the primary tumor (PT) and axillary lymph node (AL) region. Ki-67 labeling indexes (LI) were measured in the core-biopsies and surgical specimens. Response scoring was performed with the Chevallier and Sataloff (pathological), WHO and RECIST (morphological), EORTC and PERCIST (metabolical) systems and a Ki-67 LI score. Results: The SUVmax and size decreased significantly in the PTs (p<0.001;<0.001) and in the ALs (p<0.001;=0.027). Ki-67 LI decrease was significant (p=0.001). Significant differences were detected between the complete responder (pCR) and non-responder patients by the post-treatment Ki-67 LI (p<0.001), SUVmax (p=0.004) and size (p=0.045) as well as by the pre-treatment Ki-67 LI (p=0.001) and SUVmax (p=0.042). The best predictor of the pCR was the ΔKi-67 (AUC=0.84) before ΔSUV (AUC=0.82). Significant correlation (r;p) was found between ΔKi-67 and ΔSUV (0.51;<.000), ΔKi-67 and size reduction (0.49;<.000), and - although modestly - between ΔSUV and size (0.45;0.008). Chevallier and Sataloff scores showed the best correlation with the RECIST (0.5;<.000/0.4;0.009) and WHO (0.54;<,000/0.46;0.002) scores. The Ki-67 score correlated well with the PERCIST (0.46;0.002) and EORTC (0.48;0.001), but slightly better with the RECIST (0.52;<.000) and WHO (0.48;0.001) classification results. PERCIST and RECIST score values showed modest correlation (0.45;0.003). Conclusions: The direct measurement of the metabolical, morphological and proliferation response of the tumors indicated different correlation patterns than those detected with the response evaluation scoring methods. During PST, PET/CT is a robust method to assess the efficacy of the treatment, but for more precise evaluation, more reliable scoring systems are still needed.
Progression of hepatic fibrosis in irish females with HCV infection (genotype 1) – the impact of menopause
Authors: R Mac Nicholas, G Mc Donald, S Norris
Journal: Endoscopy (2006)

Introduction: Liver fibrosis is known to be highly variable within HCV infected cohorts. Co-factors for fibrosis progression include alcohol excess, steatosis and viral co-infection. Recent data suggest that low oestrogen and menopause are associated with accelerated fibrosis. This has not been validated in patients with paired biopsies.
Evaluation of pro-apoptotic BIM gene loss of function on lapatinib efficacy in patients with metastatic breast cancer (MBC) and in HER2-amplified cell lines.
Authors: Colin F. Spraggs, Linda P Briley, Karen S King, Felix Zhou, Sherry Qin, Crystal Ying Qin, Mark W. Russo, Laura Rae Parham
Journal: Journal of Clinical Oncology (2014)

e11590 Background: BIM is a pro-apoptotic Bcl-2 protein. Cellular BIM levels are upregulated by tyrosine kinase inhibitors (TKI) and BIM expression is correlated with TKI-induced cancer cell apoptosis. Limited studies suggest lapatinib response is correlated with BIM expression in HER2-amplified cell lines and in tumor samples from a small cohort of MBC patients. A common germline deletion polymorphism in BIM confers loss of function and has been reported to mediate resistance to TKI therapy in patients with NSCLC or CML. Methods: Using blood sample germline DNA collected from patients with HER2 positive MBC during the clinical study EGF104535 (NCT00281658), we investigated the effect of the BIM deletion polymorphism on response to lapatinib, when administered in combination with paclitaxel. In addition, the effect of BIM siRNA knockdown on lapatinib anti-proliferative activity was evaluated in three HER2-amplified breast cancer cell lines (BT474, SrBr3, and HCC1954). Results: DNA was collected from 279 of the 444 randomized patients. Consistent with published data, BIM deletion was only observed among the 238 Asian patients. The deletion polymorphism was identified in 13 patients (11 heterozygous, 2 homozygous) randomized to lapatinib plus paclitaxel (n=120) and in 20 patients (19 heterozygous, 1 homozygous) receiving paclitaxel alone (n=118), providing 80% power to identify moderate genetic effects (hazard ratio>2, one-sided test; p<0.05). There was a clear PFS response distinction between treatments (lapatinib plus paclitaxel being favorable), however, there was no PFS distinction between BIM deletion carriers versus non-carriers in either treatment arm. No differences were observed in lapatinib IC50 values when cell lines were exposed to BIM-specific or scrambled siRNA. Conclusions: In these limited studies, reductions in BIM function, conferred by the BIM deletion polymorphism in HER2 positive, lapatinib plus paclitaxel-treated MBC patients, or by BIM-specific siRNA treatment of HER2-amplified cell lines did not influence lapatinib efficacy. Further evaluation of the genetics and expression of BIM and other Bcl-2 proteins is warranted. Clinical trial information: NCT00281658.
Whole Genome Sequencing Of Chronic Myeloid Leukemia (CML)-Derived Induced Pluripotent Stem Cells (iPSC) Reveals Faithful Genocopying Of Highly Mutated Primary Leukemic Cells
Authors: Ivan Sloma, Maria Teresa Mitjavila-Garcia, Olivier Feraud, Noufissa Oudrhiri, Lucie Tosca, Sanaa El Marsafy, Emilie Gobbo, Dominique Divers, Alexis Proust, Frank Griscelli, Gerard Tachdjian, Marco A. Marra, Connie J Eaves, Annelise Bennaceur-Griscelli, Ali G Turhan
Journal: Blood (2013)
FDA analysis of MRD data in hematologic malignancy applications.
Authors: Nicole Gormley, Vishal Bhatnagar, Lori A. Ehrlich, Bindu Kanapuru, Hyon-Zu Lee, Amy E. McKee, Ann Farrell, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

2541 Background: There is considerable interest in the use of minimal residual disease (MRD) in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval. Although surrogacy has not yet been established in most hematologic malignancies (except CML), MRD data has been submitted in applications to the agency to allow for further characterization of the product’s activity. Here we describe the new drug applications (NDA) or biologics licensing applications (BLA) that included MRD data and provide an analysis of the MRD data and the Agency’s decisions. Methods: The authors reviewed internal databases for all original and supplemental NDA and BLA applications submitted to the Division of Hematology Products (DHP) between 2014 and 2016 that pertained to malignant hematologic conditions. The applications were reviewed for inclusion of MRD data. The clinical reviews and prescribing information (PI) of the identified applications were reviewed for assessment of MRD data and FDA’s findings. Results: There were 34 NDAs or BLAs submitted between 2014-2016. Of these, 13 (38%) included MRD data, in the following diseases: CML, CLL, ALL, and MM. MRD data was added to the PI in 6 cases (46%), not included in 4 (31%), and was not proposed for inclusion in 3 (23%). Among the 6 cases in which MRD data was included in the PI, 5 used PCR testing and 1 used flow cytometry. Among the 4 in which MRD data was not included in the PI, the identified issues included: missing data among those in CR, incomplete test performance characteristics data (e.g.-limit of detection), disparate sample sources (blood, bone marrow), high amount of test failure rates (i.e.-inability to identify a clonal rearrangement), lack of test validation in the proposed disease setting, and inappropriate planned statistical analyses. Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.
The Burden of Specific Symptoms Reported by Survivors after Critical Illness
Authors: David M. Griffith, Lisa G. Salisbury, Robert J. Lee, Nazir Lone, Judith L. Merriweather, Timothy S. Walsh, T. S. Walsh, L. G. Salisbury, J. L. Merriweather, J. A. Boyd, D. M. Griffith, G. Huby, S. Kean, S. J. Mackenzie, A. Krishan, S. C. Lewis, G. D. Murray, J. F. Forbes, J. Smith, J. E. Rattray, A. M. Hull, P. Ramsay, C. Wallis, J. Stewart, A. Bateman, E. Wilson, M. Gillies, D. Hope, H. Dawson, C. McCulloch, J. Antonelli, L. Boardman, L. Dow, W. Williams, A. McCann, S. Alexander, J. Norrie, M. Dennis, C. Waldmann, S. Brett
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Germline mutational spectrum of Brazilian HBOC patients tested with hereditary cancer multigene panels.
Authors: Barbara Alemar, Cristina Netto, Camila Bittar, Osvaldo Artigalas, Cleandra Gregorio, Marina Roberta Scheid, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2016)

e13113 Background: Hereditary breast and ovarian cancer syndrome (HBOC) is a condition with significant phenotypic heterogeneity caused by mutations in BRCA1 and BRCA2. In addition, several other genes have been implicated in an increased risk of breast (BC) and ovarian cancer (OC). In the past years, multigene panels performed through next generation sequencing (NGS) were consolidated as a cost-effective method to access the germline mutational status of patients with HBOC-like phenotypes. We aimed to evaluate the mutational spectrum of patients fulfilling HBOC clinical criteria (according to the NCCN guidelines). Methods: NGS (including deletion/duplication analyses) were performed at a commercial laboratory in the USA using Illumina technology (minimum coverage 50x depth). For all 89 patients included in this study, at least seven genes were analysed (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11 and TP53). In a few patients, expanded panels (up to 48 genes) were used. Results: Most patients had BC (68%, mean age at diagnosis 44 years) or OC (3%, mean age at diagnosis 54 years), and 22 patients had only a family history of the disease. Overall, thirteen pathogenic variants were identified in four genes (2 in ATM, 5 in BRCA1, 4 in BRCA2 and 2 in MUTYH) and 40 variants of uncertain significance (VUS) were detected in 19 genes (APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, MEN1, MLH1, MSH2, MUTYH, NF1, PALLD, PMS2, PTCH1, RAD50, RAD51 and RET). Excluding patients negative for pathogenic mutations or VUS in BRCA1 or BRCA2 genes, multigene panel identified 29 VUS and 3 pathogenic mutations among 15 genes. Conclusions: These results shows that multigene panels contribute in the diagnosis of hereditary cancer predisposition, allowing the identification of patients who can benefit of surveillance strategies, and genetic counseling for additional at-risk relatives. Nevertheless, is important that a significant proportion of HBOC families remain without a molecular diagnosis and another significant number of patients are diagnosed with novel and/or variants of uncertain significance, mainly in in moderate/low penetrance genes, for which there are no management guidelines available.
Outcomes of extraskeletal osteosarcoma patients and role of perioperative chemotherapy.
Authors: Jonas Paludo, Karen Fritchie, Candace L Haddox, Peter S. Rose, Carola A. S. Arndt, Scott H. Okuno, Steven Ian Robinson
Journal: Journal of Clinical Oncology (2016)

11025 Background: Extraskeletal osteosarcoma (EO) is a rare malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. The mainstay of treatment is surgical resection. We present our experience with EO, evaluating the role of chemotherapy. Methods: Records of all patients (pts) with EO seen between Jan, 1990 and Dec, 2014 were reviewed. All archived pathology slides were reviewed to confirm the diagnosis. Time-to-event analyses were performed from date of diagnosis and date of surgical resection using the Kaplan-Meier method. Results: Forty five pts with EO were included. Median age at diagnosis was 55 (range 8-81) years (y), and 58% were males. Frontline therapy was multimodal (90%) and included surgical resection in 41 (98%), chemotherapy in 28 (74%) and radiation therapy in 28 (68%) pts. Chemotherapy was predominantly anthracycline based, and included platinum in 22 (79%) pts. Eighteen pts received neoadjuvant chemotherapy. In those that received platinum, median necrosis rate was 50%, with 41% of the pts achieving > 90% necrosis. At the time of analysis, 29 (64%) pts were deceased, with 76% of those due to disease progression. Median follow up was 12 y (95% CI 10-14). Median overall survival (OS) and progression free survival (PFS) were 3.1 y (95% CI 2-7.5), and 1.5 y (95% CI 1-NR) respectively. 5-y OS and 5-y PFS were 43%. There was a trend towards longer OS and PFS in pts who received pre or post-op chemotherapy, and of those, platinum-based therapy was associated with a remarkably prolonged OS (median 15.1 vs. 1.7 y; 5-y 60% vs. 0%; p0.009) and PFS (median NR vs 0.9 y; 5-y 56% vs. 0%; p = 0.005). Baseline characteristics were similar in the platinum and non-platinum group. For 21 (47%) pts who relapsed, the median post relapse survival was 1 y (95% CI 0.8-1.5). In pts who received chemotherapy, the rate of relapse was greater in the non-platinum-based group (5 of 5 pts) as opposed to those who received platinum-based therapy, (9 of 22 pts, p = 0.04). Conclusions: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of pts with EO. We plan to explore this further with a multi-center retrospective study.
Comparison of clinical outcomes in patents with early stage ER-/PR+, HER2- breast cancer patients with triple negatives.
Authors: Ozan Yazici, Gokmen Umut Erdem, Sercan Aksoy, Mehmet Ali Nahit Sendur, Nuriye Özdemir, Mutlu Dogan, Nurullah Zengin, Kadri Altundag
Journal: Journal of Clinical Oncology (2016)

e12556 Background: Although ER-/PR+, HER2- breast cancer patients are treated as hormone receptor positive patients, clinically they behave more aggressive than classic hormone receptor+ tumors.We aimed to retrospectively compare the clinical features and survival rates of the early stage ER-/PR+/HER2 - breast cancer patients with triple negatives. Methods: In between 2002 - 2015, the clinical data of triple negative early breast cancer patients retrospectively compared to ER-/PR+, HER2-. Patients having ER+ or HER2+, metastatic stage at time of diagnosis were excluded. Results: Total 518 patients were included in study [triple negative (n = 348) , ER-/PR+, HER2:- (n = 170)]. Median follow up time was 51 (min:4.4-max: 346.3) months.Mean age, the rate of patients with most common histological subtype (ductal), pre and postmenopausal status, TNM Tumor stage [(Triple(-) vs ER-/PR+, HER2:-, T1 (28.9% vs 25.1%), T2 (54% vs 52.1%), T3 (15.3% vs 17.4%), T4 (1.8% vs 5.4%)] and rate of patients having adjuvant radiotherapy (70.3% vs 71.2) and chemotherapy (93.4% vs 92.4%) was similar in between triple(-) and ER-/PR+,HER2:- patient group.The ratio of patients having grade 3 (75% vs 56.9%) disease, lmyphovascular invasion, negative pathological lymph node (50.6% vs 36.5%) was higher in triple (-) compared to ER-/PR+, HER2:- (p < 0.001).Overall survival(OS) rate at 1.st, 3.th, 5.th and 10.th year in triple(-) and ER-/PR+, HER2:- group were %97 vs %100, %88 vs %87, %82 vs %80, %69 vs %61, respectively (p = 0.17). However, following the 6.th year survival difference was prominently increased in favor of triple(-). Median disease free survival (DFS) rate in triple(-) and ER-/PR+, HER2:- was 166 (95% CI, 132.3-200.5), 115 (95% CI, 66.6-165.2) months (p = 0.49). Following 6. th year DFS rate was markedly increased in favor of triple group (10th year DFS rate; triple(-) vs ER-/PR+/HER2:- 62% vs 47%). Conclusions: In our preliminary results we hypothesized that early stage triple(-) breast cancer patients have similar clinical outcomes with ER-/PR+, HER2- patients. The reasons of the increased DFS and OS rate in favor of triple(-) group following the 6th year of diagnosis might be evaluated in future randomized trials.
Abstract 266: Screening and Validation of Small Molecule Inhibitors of Serum and Glucocorticoid Regulated Kinase-1 as Novel Therapy for Cardiac Arrhythmia Disorders
Authors: Vassilios J Bezzerides, Bridget Simonson, Kumaran Shanmugasundaram, Ottaviano Phyllis, Stacey Lynch, Katherine Hessler, David Milan, Alan Rigby, Saumya Das, Anthony Rosenzweig
Journal: Circulation Research (2015)

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. Recent data demonstrates a critical role for the serum and glucocorticoid regulated kinase-1 (SGK1) by modulation of INa in the heart, by regulating the voltage-gated sodium channel NaV1.5. To better understand and pharmacologically probe the significance of SGK1 in cardiac dysrhythmias, we have used computer aided drug discovery (CADD) to identify small molecule inhibitors of SGK1. Expression of a constitutively active form of SGK1 (SGK1-CA) increased INa (1.7 fold, p &lt;0.005) in a stable line of HEK cells expressing NaV1.5. Conversely, expression of a dominant negative form (SGK-DN) decreased NaV1.5 channel activity (2.8 fold, p &lt;0.005). We examined the effects of SGK1 inhibition in a LQT model, by quantifying the ability of SGK1 inhibition to rescue the 2:1 AV block phenotype of the potassium channel zebrafish mutant, breakdance (bkd). Morpholino injection or expression of SGK1-DN significantly rescued the 2:1 AV block phenotype as compared to controls (p &lt; 0.05). Using CADD partnered with iterative empirical screens we identified several hit chemical scaffolds. Our lead compound inhibits the phosphorylation of the SGK1 target gene, GSK3-β in a dose dependent manner in cardiomyocytes (CMs) expressing SGK1-CA at the lowest effective concentration of 0.5μM. There was no significant inhibition of AKT dependent phosphorylation of GSK3-β up to a concentration of 50μM, demonstrating specificity of the inhibitor for SGK1. Incubation of bkd zebrafish mutants with the inhibitor rescued the 2:1 AV block in a dose dependent manner (60% rescue with 45μM, p &lt; 0.05). Acute application of the inhibitor dramatically inhibited INa with either expression of SGK1-CA (90.8% reduction, p &lt;0.05 ) or with RFP only (77.5% reduction p &lt; 0.005). The half-time of inhibition was 200s with resulting current densities that were not statistically different than those observed with genetic inhibition by expression of SGK1-DN. We conclude SGK1 activity regulates INa and speculate that structure activity relationship (SAR) derivatives of our lead compound might have a role in treatment of human cardiac arrhythmias.
Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models
Authors: Michelle L. Cook Sangar, Laura A. Genovesi, Madison W. Nakamoto, Melissa J. Davis, Sue E. Knobluagh, Pengxiang Ji, Amanda Millar, Brandon J. Wainwright, James M. Olson
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 MYC-amplified tumors that have the worst clinical prognosis. Experimental Design: A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice. Results: Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel “druggable” pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G1 arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors. Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802–13. ©2017 AACR.