tbuckley/cabot-search huggingface dataset:
A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem–Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy
Authors: Paolo Luraghi, Viola Bigatto, Elia Cipriano, Gigliola Reato, Francesca Orzan, Francesco Sassi, Francesca De Bacco, Claudio Isella, Sara E. Bellomo, Enzo Medico, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio
Journal: Clinical Cancer Research (2017)

Purpose: Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies.Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition.Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807-20. ©2017 AACRSee related commentary by Napolitano and Ciardiello, p. 727.
Open peroral endoscopic myotomy for achalasia with sigmoid-shaped esophagus
Authors: Wei Liu, Ling Liu, Hong-Lin Chen, Hong-Ze Zeng, Chun-Cheng Wu, Lian-Song Ye, Bing Hu
Journal: Endoscopy (2017)

A 54-year-old woman sought clinical consultation because of a > 27-year history of dysphagia. She had an Eckardt score of 13 and was diagnosed with sigmoid-type achalasia (S2 type, type II) based on esophageal motility testing, upper endoscopy, barium esophagography, and clinical presentations.
Do physical conditioning programmes reduce work absenteeism related to back pain? (PEDro synthesis)
Authors: Vinicius Cunha Oliveira, Guilherme C Jardim, Steve J Kamper
Journal: British Journal of Sports Medicine (2017)

Schaafsma FG, Whelan K, van der Beek AJ, et.al. Physical conditioning as part of a return to work strategy to reduce sickness absence for workers with back pain. Cochrane Database of Systematic Reviews 2013; Issue 8: CD001822.

Back pain is the leading cause of years lived with disability worldwide,1 and related work absenteeism contributes to the substantial economic burden of this health condition.2 Identification of effective treatments is important to reduce this burden. Physical conditioning programmes are an option for improving health-related outcomes including work absenteeism, but the effectiveness of these programmes on work absenteeism related to back pain is unclear.

The aim of this Cochrane review was to investigate the effectiveness of physical conditioning on work absenteeism related to back pain.3 

Searches for randomised controlled trials (RCTs) were conducted on CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and PEDro up to May 2013. RCTs were eligible if they included adults (>16 years) with work disability related to back pain who took part in physical conditioning programmes. …
68Ga–Prostate-Specific Membrane Antigen–Avid Tubercular Lesions Mimicking Prostate Cancer Metastasis on Simultaneous Prostate-Specific Membrane Antigen PET/MRI
Authors: Aashim Ahuja, Sangeeta Taneja, Kiran Thorat, Amarnath Jena
Journal: Clinical Nuclear Medicine (2017)

Abstract 68 Ga–prostate-specific membrane antigen (PSMA) has gained increasing interest as a target molecule in imaging of prostate cancer because of its selective overexpression in local prostate cancer lesions and metastasis. We report a case of a 62-year-old man with raised serum prostate-specific antigen levels who presented for 68 Ga-PSMA HBED-CC simultaneous PET/MRI for prostate cancer evaluation. A PSMA-nonavid PI-RADS 5 (Prostate Imaging—Reporting and Data System) lesion was confirmed as adenocarcinoma on histopathology. The PSMA-avid lesions were noted in the calvarium and lung, with the calvarial lesion confirmed to be of tubercular etiology on biopsy, and both lesions subsequently responded to antitubercular treatment.
The prognostic role of gender and MGMT methylation status in glioblastoma patients: The female power
Authors: A. Tosoni, E. Franceschi, R. Depenni, B. Urbini, M. Faedi, M. Michiara, C. Biasini, E. Giombelli, G. Pavesi, F. Zanelli, M.A. Cavallo, L. Tosatto, A. Fioravanti, E. Zunarelli, G. Lanza, D. Bartolini, E.M. Silini, A.A. Brandes
Journal: Annals of Oncology (2017)
Abstract #5640: Activity of the vascular disrupting agent Oxi4503 against an acute myelogenous leukemia xenograft model.
Authors: Bronwyn Siim, Patricia Walicke, David Chaplin
Journal: Cancer Research (2009)

The combretastatin analogue OXi4503 has a dual mechanism of action, involving antivascular effects and direct cytotoxicity towards tumor cells via oxidation to a highly reactive orthoquinone. Oxi4503 is currently in clinical trial against solid tumors. As some leukemia cells possess high levels of myeloperoxidase that can oxidize Oxi4503 to the cytotoxic orthoquinone species, we investigated whether an acute myelogenous leukemia (AML) xenograft model would be sensitive to Oxi4503. Subcutaneous injection of HL-60 cells was used to establish a leukemia xenograft-bearing mouse model. Mice were treated with OXi4503 at a dose of 75 mg/kg, administered IP once weekly for 2 weeks, or a dose of 25 mg/kg administered IP three times a week for 2 weeks. OXi4503 treatment produced significant antitumor activity. There was complete regression (no palpable tumor 90 days after initiation of tumor treatment) in 4 out of 8 mice treated with 75 mg/kg OXi4503 given once weekly for 2 weeks. Complete tumor regression was seen in 9 out of 9 mice treated with 25 mg/kg OXi4503 given three times weekly for 2 weeks. The combination of Oxi4503 with araC (cytarabine) was investigated and compared with the antitumor activity of fosbretabulin (combretastatin-A4 phosphate, CA4P) alone or with araC. Treatment with araC alone (20 mg/kg tid on Days 1, 4, 8, and 12) had no activity relative to controls. Treatment with fosbretabulin alone (75 mg/kg on Days 2 and 9) produced a small delay in tumor growth that was not enhanced when given in combination with araC. In contrast, single agent OXi4503 (75 mg/kg on Days 2 and 9) caused a significant tumor growth delay that was further enhanced by the combination with araC treatment. Five out of ten of animals treated with OXi4503 alone had long-term tumor regressions, while 6 out of 10 animals treated with OXi4503 plus araC had long-term tumor regressions. Investigation of the Oxi4503 dose response for treatment of HL-60 xenografts alone (days 3 and 10), or in combination with araC (tid Days 1, 4, 8, and 12) demonstrated that OXi4503 at doses > 2.5 mg/kg inhibited tumor growth in a dose-dependent manner. This effect was enhanced by combination with araC administration. These studies indicate that AML xenografts are highly sensitive to the vascular disrupting agent Oxi4503. Further studies are in progress to evaluate the activity of Oxi4503 against orthotopic leukemia models.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5640.
Abstract 14302: One-Year Survival in Heart Failure Patients With Preserved Ejection Fraction and Isolated Post-Capillary or Combined Post- and Pre-Capillary Pulmonary Hypertension
Authors: Elizabeth L Nichols, Michael E Rezaee, Jeremiah R Brown
Journal: Circulation (2015)

Introduction: Patients with combined post- and pre-capillary pulmonary hypertension (CpcPH) or isolated post-capillary pulmonary hypertension (PH) have been understudied due to limited hemodynamic information from right heart catheterization (RHC), which is not routinely performed in heart failure patients. This study compared the characteristics and outcomes of stable heart failure patients with no PH, isolated PH, and CpcPH determined by diastolic pulmonary gradient. Hypothesis: We hypothesized CpcPH would have lower 1-year survival compared to no PH or isolated PH patients undergoing RHC. Methods: We used the Dartmouth Dynamic Registry to identify patients with heart failure and preserved ejection fraction that underwent RHC at Dartmouth Hitchcock Medical Center between 1994 and 2012. CpcPH was defined by a diastolic pulmonary gradient &gt;7mmHg. We obtained mortality data from the National Death Index. We compared demographic, clinical, laboratory, and hemodynamic characteristics of patients with no PH, isolated PH, and CpcPH. We used Kaplan-Meier statistics and multivariable Cox proportional hazards models to compare hazard for 1-year mortality for patients with no PH, isolated PH, and CpcPH adjusted for age, sex, diabetes, chronic kidney disease, and atrial fibrillation. Results: We identified 724 patients, of which 29% had no PH, 63% had isolated PH, and 7% had CpcPH. Mean follow up time was 341.8 days with a total of 676.1 person-years. There was a significant difference in crude one-year mortality; 4.0 for no PH, 8.4 for isolated PH and 21.0 (per 100 person-years) for CpcPH (log rank p =0.001). Adjusted Cox proportional hazard ratios compared to patients with no PH were 1.6 (95%CI: 0.1, 3.4) for isolated PH and 5.3 (95%CI: 2.1, 13.9) for CpcPH. Conclusions: Patients with CpcPH had worse survival than patients with isolated or no PH. Diastolic pulmonary gradient should be measured as a risk marker for identifying patients at high-risk of 1-year mortality.
Predicting 30-Day Mortality for Patients With Acute Heart Failure in the Emergency Department
Authors: Òscar Miró, Xavier Rossello, Víctor Gil, Francisco Javier Martín-Sánchez, Pere Llorens, Pablo Herrero-Puente, Javier Jacob, Héctor Bueno, Stuart J. Pocock
Journal: Annals of Internal Medicine (2017)

Background: Physicians in the emergency department (ED) need additional tools to stratify patients with acute heart failure (AHF) according to risk. Objective: To predict mortality using data that are readily available at ED admission. Design: Prospective cohort study. Setting: 34 Spanish EDs. Participants: The derivation cohort included 4867 consecutive ED patients admitted during 2009 to 2011. The validation cohort comprised 3229 patients admitted in 2014. Measurements: 88 candidate risk factors and 30-day mortality. Results: Thirteen independent risk factors were identified in the derivation cohort and were combined into an overall score, the MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score. This score predicted 30-day mortality with excellent discrimination (c-statistic, 0.836) and calibration (Hosmer–Lemeshow P = 0.99) and provided a steep gradient in 30-day mortality across risk groups (<2% for patients in the 2 lowest risk quintiles and 45% in the highest risk decile). These characteristics were confirmed in the validation cohort (c-statistic, 0.828). Multiple sensitivity analyses did not find important amounts of confounding or bias. Limitations: The study was confined to a single country. Participating EDs were not selected randomly. Many patients had missing data. Measurement of some risk factors was subjective. Conclusion: This tool has excellent discrimination and calibration and was validated in a different cohort from the one that was used to develop it. Physicians can consider using this tool to inform clinical decisions as further studies are done to determine whether the tool enhances physician decision making and improves patient outcomes. Primary Funding Source: Instituto de Salud Carlos III, Spanish Ministry of Health; Fundació La Marató de TV3; and Catalonia Govern.
Coronary Computed Tomography Angiography vs Functional Stress Testing for Patients With Suspected Coronary Artery Disease
Authors: Andrew J. Foy, Sanket S. Dhruva, Brandon Peterson, John M. Mandrola, Daniel J. Morgan, Rita F. Redberg
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Coronary computed tomography angiography (CCTA) is a new approach for the diagnosis of anatomical coronary artery disease (CAD), but it is unclear how CCTA performs compared with the standard approach of functional stress testing. <h3>Objective</h3> To compare the clinical effectiveness of CCTA with that of functional stress testing for patients with suspected CAD. <h3>Data Sources</h3> A systematic literature search was conducted in PubMed and MEDLINE for English-language randomized clinical trials of CCTA published from January 1, 2000, to July 10, 2016. <h3>Study Selection</h3> Researchers selected randomized clinical trials that compared a primary strategy of CCTA with that of functional stress testing for patients with suspected CAD and reported data on patient clinical events and changes in therapy. <h3>Data Extraction and Synthesis</h3> Two reviewers independently extracted data from and assessed the quality of the trials. This analysis followed the PRISMA statement for reporting systematic reviews and meta-analyses and used the Cochrane Collaboration's tool for assessing risk of bias in randomized trials. The Mantel-Haenszel method was used to conduct the primary analysis. Summary relative risks were calculated with a random-effects model. <h3>Main Outcomes and Measures</h3> The outcomes of interest were all-cause mortality, cardiac hospitalization, myocardial infarction, invasive coronary angiography, coronary revascularization, new CAD diagnoses, and change in prescription for aspirin and statins. <h3>Results</h3> Thirteen trials were included, with 10 315 patients in the CCTA arm and 9777 patients in the functional stress testing arm who were followed up for a mean duration of 18 months. There were no statistically significant differences between CCTA and functional stress testing in death (1.0% vs 1.1%; risk ratio [RR], 0.93; 95% CI, 0.71-1.21) or cardiac hospitalization (2.7% vs 2.7%; RR, 0.98; 95% CI, 0.79-1.21), but CCTA was associated with a reduction in the incidence of myocardial infarction (0.7% vs 1.1%; RR, 0.71; 95% CI, 0.53-0.96). Patients undergoing CCTA were significantly more likely to undergo invasive coronary angiography (11.7% vs 9.1%; RR, 1.33; 95% CI, 1.12-1.59) and revascularization (7.2% vs 4.5%; RR, 1.86; 95% CI, 1.43-2.43). They were also more likely to receive a diagnosis of new CAD and to have initiated aspirin or statin therapy. <h3>Conclusions and Relevance</h3> Compared with functional stress testing, CCTA is associated with a reduced incidence of myocardial infarction but an increased incidence of invasive coronary angiography, revascularization, CAD diagnoses, and new prescriptions for aspirin and statins. Despite these differences, CCTA is not associated with a reduction in mortality or cardiac hospitalizations.
Breast cancer and racial disparity between Caucasian and African American women, part 1 (BRCA-1).
Authors: Khurram Bilal Tariq
Journal: Journal of Clinical Oncology (2014)

e12033 Background: Despite the lower incidence of breast cancer among African American women they are more likely to die from the disease each year compared to their Caucasian counterparts. Socioeconomics has historically played a significant role in this racial disparity, however, part one of our two part study predates universal health care measures under the Patient Protection and Affordable Care Act and aims to assess for breast cancer and racial disparity between white and black females.Methods: We present a retrospect cohort study of the tumor registry data from electronic medical records of patients diagnosed with breast cancer at University of Florida Health Jacksonville from the year 2000 to 2005. Results: A total of 907 patients were diagnosed with breast cancer. 445 patients with invasive breast cancer had complete medical records and were selected for this review. Advanced stage breast cancer was defined as stage IIB or higher and was present in 43% of African American females and in about 28% of Caucasian females ( p-value= 0.0007). Aggressive breast cancer was defined as triple negative breast cancer and was present in 12% of African American and 7% of Caucasian patients ( p-value= 0.074). Estrogen/Progesterone receptor positive breast cancer was present in 60% of African American women and 72% of Caucasian patients ( p-value of 0.006). Her2/neu was over-expressed in 30% of African American and 21% of Caucasian women ( p-value= 0.075). At the time of diagnosis about 30% of Caucasian and 31% of African American women were pre-menopausal, while 76% of Caucasian compared to 65% of African American females had health insurance at the time of diagnosis.Conclusions: Our data suggests that African Americans present with a more advanced stage and aggressive subtype of breast cancer than Caucasian females, and are less likely to have health insurance. However, we are yet to establish if universal health care insurance can lead to an earlier diagnosis and better outcomes. We aim to revisit this study with a follow up research study, BRCA-2, a few years after the implementation of universal healthcare reforms.
A genetic roadmap of pancreatic cancer: still evolving
Authors: Faiyaz Notta, Stephan A Hahn, Francisco X Real
Journal: Gut (2017)

A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the ‘incurable cancers’ because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.
A phase Ib trial of JX-594 (Pexa-Vec), a targeted multimechanistic oncolytic vaccinia virus, in combination with low-dose cyclophosphamide in patients with advanced solid tumors
Authors: M. Toulmonde, S. Cousin, A. Bessede, M. Homerin, N. Stojkowitz, M. Lusky, M. Pulido, A. Italiano
Journal: Annals of Oncology (2017)
Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): Update from a phase Ib study.
Authors: Stephen V. Liu, D. Ross Camidge, Scott N. Gettinger, Giuseppe Giaccone, Rebecca Suk Heist, F. Stephen Hodi, Neal E. Ready, Wei Zhang, Jeffrey Wallin, Roel Funke, Daniel Waterkamp, Paul Foster, Koho Iizuka, John D. Powderly
Journal: Journal of Clinical Oncology (2017)

9092 Background: Platinum-based chemo is a standard first-line (1L) therapy for NSCLC lacking actionable gene alterations. Preclinical evidence suggests that chemo can play an immunomodulatory role and induce tumor antigen release, supporting combining chemo with immunotherapy. Atezo is a humanized and Fc-region-modified monoclonal anti-programmed death-ligand-1 (PD-L1) antibody that blocks interaction with PD1 or B7.1. The GP28328 study (NCT01633970) assessed safety and efficacy of atezo plus 1L chemo regimens in multiple tumor types. Methods: In this multicenter, multi-arm study, patients (pts) with locally advanced or metastatic NSCLC with no prior chemo for advanced disease received 15 mg/kg atezo IV q3w with standard doses of chemo (Arm C: carboplatin [carbo]+paclitaxel q3w; Arm D: carbo+pemetrexed q3w; Arm E: carbo+nab-paclitaxel qw) all for ≤6 cycles followed by atezo maintenance until loss of clinical benefit (+ pemetrexed maintenance until progression, Arm D). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), PFS, and OS. Results: By the 30 Aug 2016 cut-off, 76 NSCLC pts were evaluable (n = 25, 25, 26 for Arms C, D, E, respectively). At this cut-off, the most common treatment-related grade 3–4 adverse events (AEs) were neutropenia (36% C, 36% D, 42% E) and anemia (16% C, 16% D, 31% E). Three potentially related grade 5 AEs were seen (arm C: pneumonia; arm D: systemic candida; arm E: autoimmune hepatitis). Confirmed ORRs were 36%, 64%, 46% for Arms C, D (1 CR), and E (4 CR). Median PFS (95% CI) was 7.1 months (4.2–8.3) for C, 8.4 months (4.7–11) for D, and 5.7 months (4.4–14.8) for E. Median OS (95% CI) was 12.9 months (8.8–not evaluable) for C, 19.3 months (14.7–27.4) for D, and 14.8 months (12.7–not evaluable) for E. Conclusions: Atezo was well tolerated when combined with various chemo regimens for advanced NSCLC. Clinical activity in terms of ORR was favorable supporting potential synergy between atezo and chemo. PFS and OS data show promising benefits, but are limited by small numbers and wide confidence intervals. Phase III studies that include chemotherapy and atezolizumab are currently ongoing. Clinical trial information: NCT01633970.
Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy
Authors: Tian Tian, Hui-Xin Zhang, Chun-Peng He, Song Fan, Yan-Liang Zhu, Cui Qi, Ning-Ping Huang, Zhong-Dang Xiao, Zu-Hong Lu, Bakhos A. Tannous, Jun Gao
Journal: Biomaterials (2017)
Le nouveau programme de vaccination italien réduit la couverture vaccinale de la poliomyélite à Naples
Authors: M. G. Panico, N M Trinchese, B Serpieri, F Attena
Journal: Eurosurveillance (2000)

Le 7 avril 1999, le ministere de la sante italien introduisait des changements dans le calendrier vaccinal des enfants, notamment dans la vaccination contre la poliomyelite. Le vaccin attenue oral (VPO) utilise jusqu’alors pour les deux premieres doses etait remplace par le vaccin inactive injectable (VPI). Cette mesure a suivi les resultats de la comparaison du risque de contracter la poliomyelite sauvage a celui de developper la poliomyelite paralytique associee au vaccin (risque relatif 0/10). Rappelons qu’en Italie, le dernier cas de poliomyelite autochtone remonte a 1983 et le dernier cas importe a 1988 (1). Cet article montre comment la nouvelle politique a affecte le taux de vaccination contre la poliomyelite dans une region de Naples correspondant a l’Antenne Sanitaire Locale (ASL NA4) comprenant 11 districts sanitaires avec 7500 naissances en 1998.