tbuckley/cabot-search huggingface dataset:
First-line phase Ib and II studies of picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI) as a potential neuropathy-sparing therapy for colorectal cancer (CRC)
Authors: D. A. Karlin, S. V. Cheporov, O. A. Gladkov, M. Y. Biakhov, G. S. Baker, H. B. Breitz
Journal: Journal of Clinical Oncology (2008)

4100 Background: Picoplatin (Pico) is a therapy designed to overcome platinum resistance with improved safety and efficacy compared with other platinum agents. FOLFOX (FU, LV, oxaliplatin) treatment for advanced CRC has significant neurotoxicity due to oxaliplatin. The incidence of grade 3–4 neurotoxicity with Pico in previous studies was <2% suggesting that Pico may provide a neuropathy-sparing alternative to oxaliplatin. The present studies were designed to determine the maximum tolerated dose (MTD) of Pico when administered q2w or q4w with FU and LV (FOLPI) and to evaluate the efficacy and safety of FOLPI at the MTD. Methods: Each patient (pt) received LV and infusional FU per FOLFOX6 q2w. Pts received Pico either every 2 or every 4 wks. Starting dose of Pico q2w was 45 mg/m2 and increased by 15 mg/m2 in subsequent cohorts. Starting dose of Pico q4w schedule was 60 mg/m2 and increased by 30 mg/m2 in subsequent cohorts. The 100 pt Phase II study is a randomized study comparing 50 pts treated with FOLPI using the q4w schedule at the MTD dose of 150 mg/m2 with 50 pts treated with q2w modified FOLFOX6 (85 mg/m2 oxaliplatin). Tumor response is assessed by RECIST using CT scans. Neuropathy is assessed using the FACT- Neurotoxicity questionnaire and by a blinded neurologist. Results: 59 pts have been treated in phase I FOLPI CRC studies to date. In the q4w schedule, 18 pts were studied and DLT, febrile neutropenia and thrombocytopenia, was observed at 180 mg/m2 in 2 of 6 pts. In the q2w schedule, 41 pts have been treated up to 120 mg/m2 and DLT has not been observed to date. Pts have received up to 24 cycles of Pico. 15 pts received a total Pico exposure of >600 mg/m2 and 7 have received >800 mg/m2. Mild neuropathy occurred in 9 pts, but no grade 3 or higher neuropathy was observed. Adverse events were primarily neutropenia, thrombocytopenia, nausea, asthenia and anorexia. The randomized Phase II study has enrolled 16/100 pts to date. Conclusions: The Phase I FOLPI study identified the MTD at 150 mg/m2 when Pico was infused every 4 wks with FU and LV. The DLT of Pico was hematological with no Grade 3 or 4 neuropathy. The Phase I FOLPI q2w study is ongoing with doses up to 120 mg/m2. Additional data is expected from the Phase I and ongoing Phase II studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Poniard Pharmaceuticals Poniard Pharmaceuticals
Profiling of Caspase Signaling Pathways Predicts Clinical Response to Chemotherapy in Diffuse Large B-Cell Lymphomas.
Authors: Joost J. Oudejans, Jettie J.F. Muris, Gert J. Ossenkoppele, Saskia A.G.M. Cillessen, Inge van Houdt, Alain J. Kummer, Han van Krieken, Hanneke C. Kluin-Nelemans, Chris J.L.M. Meijer
Journal: Blood (2004)
P2.44: An Update of a Pooled Analysis of Nivolumab for the Treatment of Advanced NSCLC and the Role of PD-L1 as a BIOMARKER
Authors: Pedro Aguiar, Ramon De Mello, Ilka Santoro, Hakaru Tadokoro, Carmelia Barreto, Pedro Oliveira, Gilberto Lopes
Journal: Journal of Thoracic Oncology (2016)
Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors
Authors: Tiago C Luis, Sidinh Luc, Takuo Mizukami, Hanane Boukarabila, Supat Thongjuea, Petter S Woll, Emanuele Azzoni, Alice Giustacchini, Michael Lutteropp, Tiphaine Bouriez-Jones, Harsh Vaidya, Adam J Mead, Deborah Atkinson, Charlotta Böiers, Joana Carrelha, Iain C Macaulay, Roger Patient, Frederic Geissmann, Claus Nerlov, Rickard Sandberg, Marella F T R de Bruijn, C Clare Blackburn, Isabelle Godin, Sten Eirik W Jacobsen
Journal: Nature Immunology (2016)
Functional Correction of Lymphocytes and Dendritic Cells of Patients with WAS or XLT, Using Lentiviral Vectors Targeting the Expression of WAS Protein to Hematopoietic Cells.
Authors: Sabine Charrier, Loic Dupre, Mike Blundell, Samantha Scaramuzza, Laurence Jeanson, William Vainchenker, Olivier Danos, Maria-Grazia Roncarolo, Adrian Thrasher, Anne Galy
Journal: Blood (2005)
Anticipating gemcitabine-related severe/lethal toxicities: A feasibility study
Authors: L. Padovani, L. Dahan, A. Blesius, C. Mercier, M. Duluc, S. Giacometti, F. Duffaud, R. Favre, J. Seitz, J. Ciccolini
Journal: Journal of Clinical Oncology (2008)

14652 Background: Gemcitabine is an antimetabolite drug extensively used for treating solid tumors in adults. Gemcitabine pharmacokinetics is altered by Cytidine Deaminase (CDA) gene polymorphism, resulting in impaired detoxification, systemic overexposure and potentially severe toxicities in deficient patients. To ensure a better safety in the handling of gemcitabine, we have developed a simple and rapid phenotypic test to determine the CDA status in patients with cancer. The aim of this work was to evaluate the feasibility and relevance of screening CDA status in patients undergoing gemcitabine-based therapy. Methods: CDA status was evaluated by measuring spectrophotometrically the residual CDA activity in serum. This retrospective study was performed in 100 adult patients (56M/44F, 64± 16 years) with either lung, pancreatic or vesical cancers. Early toxicities were monitored following standard NCI grading. Results: Four patients (2M/2F, mean age 68± 9 years, mean gemcitabine dose: 1200± 240 mg/m2) displayed early severe toxicities (e.g., > grade 3), including one toxic-death. Mean recorded CDA activities in non-toxic patients were 3.5± 2 U/mg protein. Conversely, mean CDA activities in patients with severe/lethal toxicities upon gemcitabine intake were as low as 0.8± 0.14 U/mg (i.e., -77% vs non-toxic patients), thus suggesting that CDA deficiency could be at the origin of the side-effects reported. Conclusions: In this study, 4% of the patients administred with gemcitabine displayed severe or lethal (1%) toxicities. All of them showed marked impairment in CDA function, as measured with the phenotypic test we used. These preliminary data strongly suggests, therefore, that our simple test could be of interest in a routine setting to detect CDA-deficient patients at risk with gemcitabine, a major drug extensively used in clinical oncology. No significant financial relationships to disclose.
Transmission of methicillin-resistant Staphylococcus aureus in long-term care facilities and their related healthcare networks
Authors: Ewan M. Harrison, Catherine Ludden, Hayley J. Brodrick, Beth Blane, Gráinne Brennan, Dearbháile Morris, Francesc Coll, Sandra Reuter, Nicholas M. Brown, Mark A. Holmes, Brian O’Connell, Julian Parkhill, M. Estee Török, Martin Cormican, Sharon J. Peacock
Journal: Genome Medicine (2016)

Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant Staphylococcus aureus (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF. Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland. MRSA isolates were whole-genome sequenced and analyzed using established methods. Genomic data were available for MRSA isolated in the local healthcare systems (isolates submitted by hospitals and general practitioners). We sequenced a total of 181 MRSA isolates from the two study sites. The majority of MRSA were multilocus sequence type (ST)22. WGS identified one likely transmission event between residents in the English LTCF and three putative transmission events in the Irish LTCF. WGS also identified closely related isolates present in colonized Irish residents and their immediate environment. Based on phylogenetic reconstruction, closely related MRSA clades were identified between the LTCF and their healthcare referral network, together with putative MRSA acquisition by LTCF residents during hospital admission. These data confirm that MRSA is transmitted between residents of LTCF and is both acquired and transmitted to others in referral hospitals and beyond. Our data present compelling evidence for the importance of environmental contamination in MRSA transmission, reinforcing the importance of environmental cleaning. The use of WGS in this study highlights the need to consider infection control in hospitals and community healthcare facilities as a continuum.
Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective
Authors: Neil Lineberry, Jesse A Berlin, Bernadette Mansi, Susan Glasser, Michael Berkwits, Christian Klem, Ananya Bhattacharya, Leslie Citrome, Robert Enck, John Fletcher, Daniel Haller, Tai-Tsang Chen, Christine Laine
Journal: BMJ (2016)

Medical Publishing Insights &amp; Practices (MPIP)—a partnership among pharmaceutical companies and the International Society for Medical Publication Professionals—aims to identify ways to improve transparency and credibility in publishing the results of industry sponsored research. This article provides guidance from MPIP on clinically relevant and more informative adverse event reporting, previously identified by journal editors as a significant unmet need to improve patient care and increase the credibility of industry sponsored publications. Our recommendations include highlighting adverse events of most relevance to practitioners and their patients, avoiding broad summary statements such as "generally safe" or "well tolerated," and including more detailed adverse event data (where appropriate) to offer additional clinically important insight. These recommendations complement the earlier recommendations in the Consolidated Standards of Reporting Trials (CONSORT) Harms Extension. Although developed for industry sponsored trials, the adoption of our recommendations would enhance adverse event reporting in clinical research publications regardless of the funding source and thereby facilitate clinical decision making.
Comparison of Approaches for Heart Failure Case Identification From Electronic Health Record Data
Authors: Saul Blecker, Stuart D. Katz, Leora I. Horwitz, Gilad Kuperman, Hannah Park, Alex Gold, David Sontag
Journal: JAMA Cardiology (2016)

Accurate, real-time case identification is needed to target interventions to improve quality and outcomes for hospitalized patients with heart failure. Problem lists may be useful for case identification but are often inaccurate or incomplete. Machine-learning approaches may improve accuracy of identification but can be limited by complexity of implementation.To develop algorithms that use readily available clinical data to identify patients with heart failure while in the hospital.We performed a retrospective study of hospitalizations at an academic medical center. Hospitalizations for patients 18 years or older who were admitted after January 1, 2013, and discharged before February 28, 2015, were included. From a random 75% sample of hospitalizations, we developed 5 algorithms for heart failure identification using electronic health record data: (1) heart failure on problem list; (2) presence of at least 1 of 3 characteristics: heart failure on problem list, inpatient loop diuretic, or brain natriuretic peptide level of 500 pg/mL or higher; (3) logistic regression of 30 clinically relevant structured data elements; (4) machine-learning approach using unstructured notes; and (5) machine-learning approach using structured and unstructured data.Heart failure diagnosis based on discharge diagnosis and physician review of sampled medical records.A total of 47 119 hospitalizations were included in this study (mean [SD] age, 60.9 [18.15] years; 23 952 female [50.8%], 5258 black/African American [11.2%], and 3667 Hispanic/Latino [7.8%] patients). Of these hospitalizations, 6549 (13.9%) had a discharge diagnosis of heart failure. Inclusion of heart failure on the problem list (algorithm 1) had a sensitivity of 0.40 and a positive predictive value (PPV) of 0.96 for heart failure identification. Algorithm 2 improved sensitivity to 0.77 at the expense of a PPV of 0.64. Algorithms 3, 4, and 5 had areas under the receiver operating characteristic curves of 0.953, 0.969, and 0.974, respectively. With a PPV of 0.9, these algorithms had associated sensitivities of 0.68, 0.77, and 0.83, respectively.The problem list is insufficient for real-time identification of hospitalized patients with heart failure. The high predictive accuracy of machine learning using free text demonstrates that support of such analytics in future electronic health record systems can improve cohort identification.
Should We Abandon Routine Visits?
Authors: David U. Himmelstein, Russell S. Phillips
Journal: Annals of Internal Medicine (2016)

Letters4 October 2016Should We Abandon Routine Visits?David U. Himmelstein, MD and Russell S. Phillips, MDDavid U. Himmelstein, MDFrom City University of New York at Hunter College, New York, New York, and Center for Primary Care, Harvard Medical School, Boston, Massachusetts.Search for more papers by this author and Russell S. Phillips, MDFrom City University of New York at Hunter College, New York, New York, and Center for Primary Care, Harvard Medical School, Boston, Massachusetts.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0321 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Like us, 3 of the correspondents perceive potential value in routine visits. We endorse Dr. Phillips' call for research to optimize the value of each clinical encounter and share his concern about threats to the physician–patient relationship, including the possibility that payers may eventually proscribe payments for routine office visits.Drs. Pomerantz and Gluckman aptly emphasize the importance of trusting relationships and physicians' role in making patients' lives better, not just longer.Dr. Poulton asserts that routine visits to primary care physicians lead to unnecessary and even harmful interventions. As noted in our article, such assertions rely on ...References1. Boulware LE, Marinopoulos S, Phillips KA, Hwang CW, Maynor K, Merenstein D, et al. Systematic review: the value of the periodic health evaluation. Ann Intern Med. 2007;146:289-300. [PMID: 17310053] LinkGoogle Scholar2. Starfield B, Shi L, Macinko J. Contribution of primary care to health systems and health. Milbank Q. 2005;83:457-502. [PMID: 16202000] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From City University of New York at Hunter College, New York, New York, and Center for Primary Care, Harvard Medical School, Boston, Massachusetts.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2097. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoShould We Abandon Routine Visits? There Is Little Evidence for or Against David U. Himmelstein and Russell S. Phillips Should We Abandon Routine Visits? William R. Phillips Should We Abandon Routine Visits? Daniel Pomerantz Should We Abandon Routine Visits? Stephen J. Gluckman Should We Abandon Routine Visits? Thomas J. Poulton Metrics 4 October 2016Volume 165, Issue 7Page: 529-530KeywordsDisclosureEmotionsFearHealth careHealth care qualityPatientsPrimary carePrimary care physiciansRisk assessmentsSystematic reviews ePublished: 4 October 2016 Issue Published: 4 October 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Lessons from PETACC 2: No prognostic impact of KRAS-/BRAF-status in stage III colon cancer treated with adjuvant 5-FU monotherapy.
Authors: D. E. Aust, M. P. Lutz, M. Mauer, I. Popov, G. B. Baretton, L. Bedenne, A. Carrato, C. Kohne
Journal: Journal of Clinical Oncology (2010)

3591 Background: KRAS and possibly BRAF mutations are negative predictors for anti-EGFR therapy in colorectal cancer. The prognostic impact of these mutations is less clear. This study aimed to assess the correlation of KRAS/BRAF status with morphological characteristics and its prognostic impact for long-term outcome in UICC stage III colon cancer (CC). Methods: FFPE material from 493 patients treated with adjuvant 5-FU/FA in the PETACC2 trial (ClinicalTrials.gov NCT00004150) was collected retrospectively. KRAS mutations were detected by direct sequencing (ABI Prism 310), BRAF mutations by pyrosequencing (Pyromark Q24). Statistical analysis was done using Fisher exact test and Kaplan Meier survival analyses (level of significance:0.05). Results: Neither KRAS nor BRAF mutations were associated with patient age or patient sex. KRAS mutations did also not correlate with any pathological parameters. BRAF mutations, however, were significantly more frequent in mucinous (n = 12/45; 26.7%) than in nonmucinous carcinomas (n = 36/408; 8.8%, p = 0.001). BRAF mutations were also associated with higher pT stage (p = 0.016): while pT1 and pT2 tumors showed BRAF mutations in 0 (n = 0/13) and 5.1% (n = 2/39), pT3 and pT4 tumors showed them in 9.2% (n = 32/347) and 20.2% (n = 17/84). BRAF-mutation frequency increased with decreasing histologic differentiation (p = 0.002): only 1.9% of grade 1 (n = 1/35) and 8.2% of grade 2 (n = 26/316) whereas 18.8% of the grade 3 tumors (n = 24/128) had a BRAF mutation. Location in the right-sided colon was correlated with BRAF mutation (p = 0.034): 15.4% of the right-sided tumors (n = 23/149) showed a mutation as opposed to 8.4% of the left sided tumors (n = 25/298). Neither KRAS nor BRAF status showed any impact on disease-free and overall survival in univariate analyses. After 3 years, 63% of the patients with KRAS mutation, 68% with KRAS/BRAF wildtype (HR 0.89) and 65% with BRAF mutation (HR 1.08) were still alive. Conclusions: KRAS/BRAF status has no prognostic impact in stage III CC treated with adjuvant 5-FU/FA therapy. While BRAF mutations are associated with tumor location, histological type, differentiation and pT stage, KRAS mutations are not. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Targeting myeloid-derived suppressor cells and the PD-1/PD-L1 axis to enhance immunotherapy with anti-CEA designer T cells for the treatment of colorectal liver metastases.
Authors: Rachel A. Burga, Mitchell Thorn, Cang T. Nguyen, Lauren Licata, N. Joseph Espat, Richard Paul Junghans, Steven C. Katz
Journal: Journal of Clinical Oncology (2013)

3079 Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed death ligand-1 (PD-L1, CD274) on MDSC binding to programmed death-1 (PD-1, CD279) on T cells. We hypothesize blocking PD-L1 will improve adoptive cellular therapy efficacy for CRCLM through inhibition of MDSC-mediated T cell suppression. Methods: “Designer” T cells (dTc) were produced from activated murine splenocytes transduced with chimeric antigen receptor (CAR) specific for CEA. C57BL/6 mice were injected with CEA + MC38 tumor cells via spleen, and liver MDSC (CD11b + Gr1 + ) were purified with immunomagnetic beads after two weeks. MDSC were co-cultured with stimulated dTc with or without in vitro PD-L1 blockade. Results: MDSC expanded 2.4-fold in response to CRCLM, and expressed high levels of PD-L1 (63.8% PD-L1 + ). PD-L1 was equally expressed on both monocytic (CD11b + Ly6G - Ly6C + ) and granulocytic (CD11b + Ly6G + ) MDSC subsets (43.6% PD-L1 + and 27.9% PD-L1 + , respectively). Expression of related ligand, PD-L2 was found to be negligible in both subsets. The cognate inhibitory receptor, PD-1, was expressed on dTc (23.8% PD-1 + ) and native T cells (37.3% PD-1 + ). Increasing endogenous T cell expression of PD-1 significantly correlated with MDSC expansion (r=0.9774, p&lt;0.0001) in response to CRCLM. Co-culture of dTc with MDSC demonstrated the suppressive effect of MDSC on dTc proliferation which was abrogated with in vitro targeting of PD-L1. The percentage of dTc proliferating in the presence of CEA + tumor decreased from 72.2% to 29.3% (p&lt;0.001) with the addition of MDSC, and immunosuppression was reversed with blockade of PD-L1, which resulted in a 1.6-fold increase in dTc proliferation (p=0.01 ). Conclusions: Liver MDSC expand in the presence of CRCLM and mediate suppression of anti-CEA dTc via PD-L1. Our results indicate that blockade of PD-L1:PD-1 engagement is a viable strategy for enhancing the efficacy of adoptive cell therapy for liver metastases.
Whole Genome Sequence Analysis of a Large Isoniazid-Resistant Tuberculosis Outbreak in London: A Retrospective Observational Study
Authors: Nicola Casali, Agnieszka Broda, Simon R. Harris, Julian Parkhill, Timothy Brown, Francis Drobniewski
Journal: PLoS Medicine (2016)

Background A large isoniazid-resistant tuberculosis outbreak centred on London, United Kingdom, has been ongoing since 1995. The aim of this study was to investigate the power and value of whole genome sequencing (WGS) to resolve the transmission network compared to current molecular strain typing approaches, including analysis of intra-host diversity within a specimen, across body sites, and over time, with identification of genetic factors underlying the epidemiological success of this cluster. Methods and Findings We sequenced 344 outbreak isolates from individual patients collected over 14 y (2 February 1998–22 June 2012). This demonstrated that 96 (27.9%) were indistinguishable, and only one differed from this major clone by more than five single nucleotide polymorphisms (SNPs). The maximum number of SNPs between any pair of isolates was nine SNPs, and the modal distance between isolates was two SNPs. WGS was able to reveal the direction of transmission of tuberculosis in 16 cases within the outbreak (4.7%), including within a multidrug-resistant cluster that carried a rare rpoB mutation associated with rifampicin resistance. Eleven longitudinal pairs of patient pulmonary isolates collected up to 48 mo apart differed from each other by between zero and four SNPs. Extrapulmonary dissemination resulted in acquisition of a SNP in two of five cases. WGS analysis of 27 individual colonies cultured from a single patient specimen revealed ten loci differed amongst them, with a maximum distance between any pair of six SNPs. A limitation of this study, as in previous studies, is that indels and SNPs in repetitive regions were not assessed due to the difficulty in reliably determining this variation. Conclusions Our study suggests that (1) certain paradigms need to be revised, such as the 12 SNP distance as the gold standard upper threshold to identify plausible transmissions; (2) WGS technology is helpful to rule out the possibility of direct transmission when isolates are separated by a substantial number of SNPs; (3) the concept of a transmission chain or network may not be useful in institutional or household settings; (4) the practice of isolating single colonies prior to sequencing is likely to lead to an overestimation of the number of SNPs between cases resulting from direct transmission; and (5) despite appreciable genomic diversity within a host, transmission of tuberculosis rarely results in minority variants becoming dominant. Thus, whilst WGS provided some increased resolution over variable number tandem repeat (VNTR)-based clustering, it was insufficient for inferring transmission in the majority of cases.