tbuckley/cabot-search huggingface dataset:
PHEREXA: A phase III study of trastuzumab (H) + capecitabine (X) ± pertuzumab (P) for patients (pts) who progressed during/after one line of H-based therapy in the HER2-positive metastatic breast cancer (MBC) setting.
Authors: Ander Urruticoechea, Mohammed Rizwanullah, Seock-Ah Im, Antonio Carlos Sánchez-Ruiz, Istvan Lang, Gianluca Tomasello, Hannah Douthwaite, Tanja Badovinac Crnjevic, Sarah Heeson, Jennifer Eng-Wong, Montserrat Munoz
Journal: Journal of Clinical Oncology (2016)

504 Background: P provides a progression-free and overall survival (PFS, OS) benefit in HER2-positive MBC, and is standard of care in the 1st line. Continuing H post-progression on 1st-line H improves response and time to progression. H + X is well tolerated and more effective than X in these pts, and dual P + H anti-HER2 therapy has activity in this population. However, efficacy and safety of P + H + X is unknown. We report the primary analysis of a multicenter, open-label randomized study of H + X vs P + H + X (NCT01026142). Methods: Pts who received a prior taxane and progressed during/after 1st-line H-based therapy for HER2-positive MBC were randomized to intravenous (IV) H 8 mg/kg then 6 mg/kg q3w + oral X 1250 mg/m2 twice daily (2 weeks on, 1 week off q3w; Arm A) or IV P 840 mg then 420 mg q3w + IV H per Arm A + oral X per Arm A but at 1000 mg/m2 (Arm B). The primary endpoint was independent review facility-assessed PFS (IRF PFS). The secondary endpoints of OS and safety are also reported. Hierarchical testing procedures were used to control type I error in the multiple statistical testing of IRF PFS and OS. Results: At clinical cutoff (5/29/15), 224 pts had been randomized to H + X and 228 to P + H + X (ITT populations; median follow-up 28.6 and 25.3 months, respectively). Baseline demographics/characteristics were generally balanced across arms. Median IRF PFS was 9.0 months in Arm A vs 11.1 months in Arm B (HR 0.82, 95% CI 0.65‒1.02; p = .0735). Interim OS was 28.1 months in Arm A vs 36.1 months in Arm B (HR 0.68, 95% CI 0.51‒0.90). Adverse events (AEs) were reported in 214/218 pts (98.2%) in Arm A vs 222/228 (97.4%) in Arm B; grade ≥ 3 AEs in 130 (59.6%) vs 118 (51.8%), and treatment discontinuations due to AEs in 42 (19.3%) vs 48 (21.1%), respectively (safety populations). Conclusions: PHEREXA did not meet its primary endpoint of IRF PFS. An 8-month improvement in median OS with P to 36.1 months was observed. Statistical significance for OS cannot be claimed due to the hierarchical testing; however, the magnitude of benefit is in keeping with prior experience of P in MBC. No new safety signals were identified. Clinical trial information: NCT01026142.
Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin–lysoPA axis in COPD
Authors: Shama Naz, Johan Kolmert, Mingxing Yang, Stacey N. Reinke, Muhammad Anas Kamleh, Stuart Snowden, Tina Heyder, Bettina Levänen, David J. Erle, C. Magnus Sköld, Åsa M. Wheelock, Craig E. Wheelock
Journal: European Respiratory Journal (2017)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and a leading cause of mortality and morbidity worldwide. The aim of this study was to investigate the sex dependency of circulating metabolic profiles in COPD. Serum from healthy never-smokers (healthy), smokers with normal lung function (smokers), and smokers with COPD (COPD; Global Initiative for Chronic Obstructive Lung Disease stages I–II/A–B) from the Karolinska COSMIC cohort (n=116) was analysed using our nontargeted liquid chromatography–high resolution mass spectrometry metabolomics platform. Pathway analyses revealed that several altered metabolites are involved in oxidative stress. Supervised multivariate modelling showed significant classification of smokers from COPD (p=2.8×10 −7 ). Sex stratification indicated that the separation was driven by females (p=2.4×10 −7 ) relative to males (p=4.0×10 −4 ). Significantly altered metabolites were confirmed quantitatively using targeted metabolomics. Multivariate modelling of targeted metabolomics data confirmed enhanced metabolic dysregulation in females with COPD (p=3.0×10 −3 ) relative to males (p=0.10). The autotaxin products lysoPA (16:0) and lysoPA (18:2) correlated with lung function (forced expiratory volume in 1 s) in males with COPD (r=0.86; p&lt;0.0001), but not females (r=0.44; p=0.15), potentially related to observed dysregulation of the miR-29 family in the lung. These findings highlight the role of oxidative stress in COPD, and suggest that sex-enhanced dysregulation in oxidative stress, and potentially the autotaxin–lysoPA axis, are associated with disease mechanisms and/or prevalence.
Global democratic consensus on neuropathological disease criteria
Authors: Cristian Achim, Roland Auer, Catherine Bergeron, Adriana Cardozo, Manuel Deprez, Rob de Vos, Charles Duyckaerts, Rupert Egensperger, Margaret Esiri, Matthew P Frosch, Caterina Giannini, Hans H Goebel, Manuel B Graeber, David I Graham, Francoise Gray, Matti Haltia, Yoshio Hashizume, Kenji Ikeda, James W Ironside, Georg W Kreutzberg, Peter Lantos, James Lowe, Samuel Ludwin, Yoh Matsumoto, Yngve Olsson, Atsushi Sasaki, Bernd W Scheithauer, Hitoshi Takahashi, Markus Tolnay, John Q Trojanowski, Dirk Troost, Henry de F Webster
Journal: The Lancet Neurology (2002)
Plasma cholesterol response to dietary saturated fat
Authors: S. Doepfmer, I. Guggenmoos-Holzmann
Journal: BMJ (1996)

are) are the only measure available.Moreover, croup scores are useful in hospital clinical practice.As most croup presents outside normal working hours, croup scores are useful to junior paediatricians as a reminder of assessment criteria and as a measure of severity.M Cronin and R Diedericks express concern that I did not refer to nebulised adrenaline.As the title of my editorial made clear, my primary aim was to draw attention to the role of corticosteroids in croup.The one trial comparing nebulised adrenaline with nebulised corticosteroids showed broadly similar effects, although, as it is reported only in abstract form, interpretation must be limited (D Fitzgerald et al, meeting of Australian Thoracic Society, March 1995).Although nebulised adrenaline clearly has a role in the management of croup, I believe that it has no role in mild to moderate croup and (with rare exceptions) should not be used in the community.The role of nebulised adrenaline is to avert or delay the need for intubation, and consequently it should be used only under controlled conditions.Relapse after the use of nebulised adrenaline is well describedindeed, in the study that Cronin and Kiedericks cite, by Kristjansson et al, over a third of the children receiving adrenaline relapsed, and the authors recommended that children receiving adrenaline should be observed for two hours.I believe that children who require nebulised adrenaline should be observed where facilities are available for urgent intubation should the need arise.
Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy
Authors: Fotios Mpekris, Panagiotis Papageorgis, Christiana Polydorou, Chrysovalantis Voutouri, Maria Kalli, Athanassios P. Pirentis, Triantafyllos Stylianopoulos
Journal: Journal of Controlled Release (2017)
Characteristics of recurrence after completing adjuvant tamoxifen therapy for 5 years: Retrospectove analysis.
Authors: Eunshin Lee
Journal: Journal of Clinical Oncology (2014)

e11507 Background: Treatment with tamoxifen (TMX) reduce the recurrence rate and increase overall survival in patients with hormone receptor positive breast cancer. Up to now, 5-year TMX therapy is generally accepted, but it is demonstrated that the rate of late recurrence after 5 years is considerably higher in hormone receptor positive type than in other subtype. Several clinical trials such as ATLAS and aTTom showed the benefit of continuing tamoxifen up to 10 years instead of stopping at 5 years without increasing mortality due to the effect of extended tamoxifen medication. Methods: We collected data of 1,633 hormone receptor positive breast cancer patients who received surgery at Seoul National University Hospital from 1997 to 2007, and had completed 5-year TMX therapy with no recurrence within 5 years after diagnosis. We excluded the cases treated aromatase inhibitor (AI) or switched to AI. Results: Among these patients, recurrence after 5 years of TMX therapy were found in 93 patients(late recurrence group). Local recurrence and distant metastasis were found in 43 and 50 patients, respectively. Electronic medical records were retrospectively reviewed for clinicopathological factors. When comparing between patients with no recurrence and patients with late recurrence, p53 and HER-2 expression were significantly related to late recurrence (p=0.01, p<0.001 respectively). Also when subgroup analysis was done for distant metastasis of late recurrence group, distant metastasis was significantly associated with HER-2 expression and high nuclear grade (p=0.005, p=0.006 respectively). There are no relation between late recurrence and age, stage and ki-67. Conclusions: our data shows that p53 and HER-2 expression is associated to late recurrence and especially HER-2 expression is related to distant metastasis after completing TMX for 5 years. On the basis of the result of large clinical trials, extending TMX therapy significantly reduces recurrence rate and increase survival. Our result support continuing TMX in patients with HER-2 expression and high nuclear grade is considerable after 5 years of TMX medication.
Effect of different regimens of chemotherapy on stem-cell marker expression.
Authors: Vasyl Vasko, Phil Grimley, Michael Wick, David Sidransky
Journal: Clinical Cancer Research (2007)

B32  Background:  Nanog is a critical factor underlying pluripotency in embryonic stem cells. The genetic program induced by Nanog is maintained by BMI1 and other epigenetic regulators that belong to the family of polycomb group proteins (PcG). The expression of stem cells markers has been associated with poor therapeutic outcome for patients with various types of cancer. However, the effects of chemotherapy on stem cells have not been fully elucidated.   Methods:  A transplantable mesenchymal chondrosarcoma (MCS) xenograft model was used to evaluate the effects of chemotherapy on tumor growth. Drug combinations were selected based on the cell signaling activation profile detected in MCS and included the alkylating agent Ifosfamide, VEGF inhibitors (Avastin and Sorafenib), an inhibitor of telomerase activity (Irinotecan), a regulator of microtubule assembly (Docetaxel) and a proteosome inhibitor (Velcade). After treatment, paraffin embedded MCS tissue samples were evaluated for changes in morphological features, cell signaling activation and stem cell markers (Nanog, Oct4, BMI1) expression. MCS cells lines were used for in vitro functional studies.   Results:  Morphological patterns in MSC xenograft model were similar to the primary human MCS and included two distinct tumor components: small round mesenchymal cells and cells differentiated towards cartilage. A high level of proliferation (Ki67), activations of VEGF signaling pathway (VEGF, VFGFR1, VEGFR2, EphA4 and phospho-VEGFF), RAS ERK signaling (phospho-ERK) and activation of anti apoptotic pathway (phospho-Akt) were found in both primary human MCS and in the MSC xenograft model. The MCS cells lines similarly demonstrated activation of VEGF and PI3K-Akt signaling, and were characterized by PI3K dependant type of cell migration in Boyden Chamber assays. Nanog and BMI1 expressions both were increased in metastases as compared to primary MCS; they were also detectable in MCS xenograft model and in MSC cell lines by PCR and immunostaining.  All chemotherapeutical regimens resulted in inhibition of MCS growth; however, different regimens induced specific post treatment morphological changes in xenografts. The combination of Ifosfamide and Avastin induced necrosis and inhibited growth of differentiated cartilaginous cells. Avastin treatment also inhibited Nanog and BMI1 expression. Treatment with Irinotecan, Docetaxel or Velcade resulted in formation of highly cellular tumors without necrosis. MCS cells which survived chemotherapy were characterized by increased expression of Nanog and BMI1. Docetaxel and Velcade induced Nanog, Oct4, BMI1, EZH2 expression in the MCS cell lines.   Conclusions:  Targeted chemotherapy altered cancer stem cell marker expression. Some chemotherapeutic agents resulted in a gain of stem cell marker expression. Therapeutic combination of such agents with compounds targeting developmental signals (e.i. Notch, HH) therefore might improve the outcome of sarcoma treatment.
THU0594 Developing the korean leeds satisfaction questionnaire (KOREAN-LSQ) in rheumatoid arthritis: a cross-cultural validation using rasch analysis
Authors: S-K Cho, D Kim, SJ Cha, D Yoo, S-H Kim, J Hill, M Ndosi, Y-K Sung
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The Leeds Satisfaction Questionnaire (LSQ)<sup>1</sup> is a patient-completed questionnaire designed to measure satisfaction among patients attending a rheumatology outpatient clinic. It was originally developed in the UK and it comprises 45 items grouped into 6 subscales: general satisfaction, information, empathy, technical competence, attitude, access and continuity. <h3>Objectives</h3> To undertake cross-cultural adaptation and validation of the LSQ in RA for use in Korea. <h3>Methods</h3> The adaptation of the LSQ from English into Korean was established according to guideline of cross-cultural adaptation of self-report measures.<sup>2</sup> Patients with RA were then recruited from an outpatient clinic of a university hospital in South Korea and Cross-cultural validation of the Korean-LSQ was carried out by Rasch analysis using the WINSTEPS program. Model data fit was determined by Infit and Outfit statistics (≥0.50 and ≤1.50). If the values of the Infit and Outfit are 1.00, the observed score perfectly fit the expected model. The unidimensionality of the scale was determined by separation index (SI ≥2.00) and reliability (RI ≥0.80). <h3>Results</h3> An adequate conceptual equivalence was achieved following the adaptation process. The dataset for validation comprised 125 patients, 103 (82.4%) of whom were female, mean (SD) age =47.2 (12.5) and disease duration =52.8 (69.4) months. Forty-item of the 45 items had acceptable fit statistics (individual item data not shown). The individual items overall had good separation index and reliability (SI =5.98 and RI =0.97). Analysis of the 6 subscales of the Korean-LSQ resulted in good fit to the Rasch model (Table 1), high internal consistency and unidimensionality (Person SI =2.31 and RI =0.84; item SI =5.44 and RI =0.97). <h3>Conclusions</h3> Fit to the Rasch model confirmed that the construct validity, reliability, and unidimensionality of the Korean-LSQ were preserved after the adaptation process. The Korean LSQ is a valid and reliable tool for measuring satisfaction with care among patients with RA in South Korea. <h3>References</h3> Hill J, et al. Survey of satisfaction with care in a rheumatology outpatient clinic. Ann Rheum Dis. 1992; 51(2): 195–7. Beaton DE, et al. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine. 2000; 25(24): 3186–91. <h3>Acknowledgements</h3> This research was supported by a grant from the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (grant number: HI16C0061). <h3>Disclosure of Interest</h3> None declared
Can the Spot Sign Identify Who Benefits From Aggressive Blood Pressure Reduction in Intracerebral Hemorrhage?
Authors: Jimmy V. Berthaud, Bradford B. Worrall
Journal: JAMA Neurology (2017)

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Low grade glioma patients with IDH mutation and 1p19q codeletion: To treat or not to treat?
Authors: Enrico Franceschi, Dario De Biase, Alexandro Paccapelo, Antonella Mura, Alicia Tosoni, Stefania Bartolini, Giovanni Tallini, Annalisa Pession, Daniela Danieli, Sabrina Rossi, Daniela Bartolini, Marina Paola Gardiman, Lorenzo Volpin, Vania Ramponi, Antonio Fioravanti, Maria Pia Foschini, Enrico Di Oto, Santino Minichillo, Stefano Pizzolitto, Alba Ariela Brandes
Journal: Journal of Clinical Oncology (2017)

2017 Background: Molecular characterization of low grade gliomas (LGG) is essential for diagnosis and treatment of these diseases. LGG patients (pts) with IDH mutation and 1p19q codeletion (codel) are characterized by a median OS (mOS) longer than 10 years. Thus, the role of treatments and side effects should be carefully evaluated. Methods: We evaluated LGG pts from our data warehouse (n=679 pts) who received surgery and had sufficient tissue to assess biomarkers characterization. Pts with gliomatosis were excluded. IDH1/2 assessment was performed on formalin-fixed paraffin-embedded samples by qPCR. In wild type cases we performed NGS. 1p/19 codel analysis was performed by FISH. Results: 93 consecutive LGG with IDH mutation and codel were included. The median follow up (FU) was 96.1 months. Mean age was 40 yrs (range: 25-66); 8 pts (8.6%) underwent biopsy, 61 pts (65.6%) partial resection, 24 pts (25.8%) complete resection. 84 pts (90.3%) were considered high risk using RTOG criteria (&gt;40 years and/or incomplete resection). Fifty pts (53.7%) received only FU, 17 pts (18.3%) received chemotherapy (CT), 18 pts (19.4%) received radiotherapy (RT), 8 pts (8.6%) received RT + CT. Median PFS (mPFS) was 59.6 months (95%CI: 41.8-77.4) and was significantly longer in pts who received postsurgical treatments (79.5 months, 95%CI: 66.4-92.7) than pts who received FU (46.3 months, 95%CI: 36.0-56.5; P=0.001). mPFS was 50.8 months (95%CI: 17.4-84.3), 103.6 months (95%CI: 11.7-195.6) and 120.2 months (95%CI: 40.5-199.8) in pts treated with CT alone, RT alone and RT + CT, respectively. Multivariate analysis showed that receiving a post-surgical treatment (P&lt;0.001), and the extent of resection (P=0.043) were significantly correlated with PFS. Conclusions: Our study evaluated the role of treatments in LGG pts assessed with NGS and FISH. Post-surgical treatments are crucial to extend PFS in pts with IDH mutation and codel. The choice of post-surgical treatments seems to have a role, being CT alone less effective than RT and RT+CT. Longer FU is needed to provide information about OS.
Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma.
Authors: Donna Molaie, Albert Lai, Benjamin M. Ellingson, Thien Nguyen, Hye Hyun Bahng, Emese Filka, Stacey Green, Whitney B. Pope, Mei Leng, William H. Yong, Richard M. Green, Jonathan Polikoff, Liz Spier, Fabio Massaiti Iwamoto, Andrew B. Lassman, Timothy Francis Cloughesy, Phioanh Leia Nghiemphu
Journal: Journal of Clinical Oncology (2020)

2540 Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m 2 /day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .