tbuckley/cabot-search huggingface dataset:
Results of the 2016 International Skin Imaging Collaboration International Symposium on Biomedical Imaging challenge: Comparison of the accuracy of computer algorithms to dermatologists for the diagnosis of melanoma from dermoscopic images
Authors: Michael A. Marchetti, Noel C.F. Codella, Stephen W. Dusza, David A. Gutman, Brian Helba, Aadi Kalloo, Nabin Mishra, Cristina Carrera, M. Emre Celebi, Jennifer L. DeFazio, Natalia Jaimes, Ashfaq A. Marghoob, Elizabeth Quigley, Alon Scope, Oriol Yélamos, Allan C. Halpern
Journal: Journal of the American Academy of Dermatology (2017)
Enhanced Radiotherapy using Bismuth Sulfide Nanoagents Combined with Photo-thermal Treatment
Authors: Xiaju Cheng, Yuan Yong, Yiheng Dai, Xin Song, Gang Yang, Yue Pan, Cuicui Ge
Journal: Theranostics (2017)

Nanotechniques that can improve the effectiveness of radiotherapy (RT) by integrating it with multimodal imaging are highly desirable. ResultsIn this study, we fabricated Bi2S3 nanorods that have attractive features such as their ability to function as contrast agents for X-ray computed tomography (CT) and photoacoustic (PA) imaging as well as good biocompatibility.Both in vitro and in vivo studies confirmed that the Bi2S3 nanoagents could potentiate the lethal effects of radiation via amplifying the local radiation dose and enhancing the anti-tumor efficacy of RT by augmenting the photo-thermal effect.Furthermore, the nanoagent-mediated hyperthermia could effectively increase the oxygen concentration in hypoxic regions thereby inhibiting the expression of hypoxia-inducible factor (HIF-1α).This, in turn, interfered with DNA repair via decreasing the expression of DNA repair-related proteins to overcome radio-resistance.Also, RT combined with nanoagent-mediated hyperthermia could substantially suppress tumor metastasis via down-regulating angiogenic factors.Conclusion In summary, we constructed a single-component powerful nanoagent for CT/PA imaging-guided tumor radiotherapy and, most importantly, explored the potential mechanisms of nanoagent-mediated photo-thermal treatment for enhancing the efficacy of RT in a synergistic manner.
A phase 1, open-label, dose escalation, safety, PK and PD study of a first in class Pol1 inhibitor (CX-5461) in patients with advanced hematologic malignancies (HM).
Authors: Simon J Harrison, Amit Khot, Natalie Brajanovski, Don Cameron, Nadine Hein, Grant A. McArthur, John K.C. Lim, Sean O'Brien, David M Ryckman, Grace I Yu, Emma Link, Carrie Donohoe, Alicia Snowden, Narmatha Kuru, Ross Hannan
Journal: Journal of Clinical Oncology (2015)

e22212 Background: Ribosome biogenesis driven by RNA polymerase 1 (Pol1) is a fundamental cellular process increased in malignancy. We have shown that CX-5461, a small molecule inhibitor of Pol1, selectively targets AML, lymphoma and myeloma cells in preclinical in-vivomodels with minimal effects on normal hematopoietic cells (Cancer Cell 2012). Methods: Key Eligibility Criteria; Relapsed HM, >1 prior therapy, no standard of care therapeutic options; ECOG PS: 0-2; Adequate organ function. CX-5461 is administered by 3 weekly IV infusion over 1 hour. Based on preclinical animal testing, dosing commenced at 25mg/m2, with planned escalations up to 450mg/m2. Biomarkers of Pol1 transcription inhibition (Pol1ti) include 47S ribosome subunit pre-rRNA FISH in PBMC and tumor tissue. Results: Since July 2014, 13 patients have been treated in 4 dose cohorts (table1).To date there have been no dose-limiting toxicities (n=12). The most common drug associated toxicity was skin rash (photosensitive grade 1-2 n=4 easily managed by sun avoidance and erythroderma grade 3 in one CTCL patient). Other adverse events (AEs) have been mild cytopenias related to underlying disease. 3 patients, 2 (MM) and 1 (DLBCL), have shown prolonged disease stabilisation receiving 6, 3 and 15 cycles of drug. The latter remains on drug after 10 months. PK analyses showed favorable and linear exposure with dose. Treatment with CX-5461 causes robust and significant Pol1ti 1hr post-infusion. Median Pol1ti 49.0% (Range:22.9- 69.9%, n=3), 51.1% (34.4 - 64.4%, n=4), 19.6% (-72.0 – 69.7%, n=4) and 46.5% (n=1) for cohorts 1-4 respectively. At 24hrs, Pol1 transcription levels rebound and return to baseline levels. Conclusions: CX-5461 is well tolerated with low grade manageable AEs to date. Inhibition of Pol1 transcription in PBMC indicated on-target drug activity in these initial dose cohorts. The trial continues in dose escalation. Clinical trial information: ACTRN12613001061729. Pt ID Age Sex Diagnosis Dose level mg/m2 No. of doses Best Response 1 73 M MM 25 6 SD 2 47 F MM 25 3 SD 3 54 F DLBCL 25 1 PD 4 79 F CTCL 50 2 mixed 5 26 F HD 50 1 PD 6 74 M CLL 50 1 Early PD 7 70 F DLBCL 50 15 SD 8 47 M MM 100 1 PD 9 78 M TPLL 100 1 Early PD 10 21 F DLBCL 100 2 PD 11 34 M HD 100 2 PD 12 74 F MM 170 1 NA 13 56 M MM 170 1 NA
Accuracy of dermatoscopy for the diagnosis of nonpigmented cancers of the skin
Authors: Christoph Sinz, Philipp Tschandl, Cliff Rosendahl, Bengu Nisa Akay, Giuseppe Argenziano, Andreas Blum, Ralph P. Braun, Horacio Cabo, Jean-Yves Gourhant, Juergen Kreusch, Aimilios Lallas, Jan Lapins, Ashfaq A. Marghoob, Scott W. Menzies, John Paoli, Harold S. Rabinovitz, Christoph Rinner, Alon Scope, H. Peter Soyer, Luc Thomas, Iris Zalaudek, Harald Kittler
Journal: Journal of the American Academy of Dermatology (2017)
Characterization of the immune microenvironment of synchronous primary tumor and liver colorectal metastases.
Authors: Marc Van Den Eynde, Bernhard Mlecnik, Jean-Pascal H. Machiels, Daphne Debetancourt, Gabriela Bindea, Anne Jouret-Mourin, Christine Sempoux, Javier Carrasco, Jean Francois Gigot, Catherine Hubert, Yves Humblet, Nacilla Haicheur, Florence Marliot, Franck Pages, Jerome Galon
Journal: Journal of Clinical Oncology (2015)

3610 Background: The adaptive Th1 immune response (CD3, CD8, CD45RO T cells) observed in resected primary colorectal tumor (PCT) and liver colorectal metastases (LCM) is an important prognostic factor. Preoperative treatment modifies the LCM immune microenvironment with a significant association between pathological response and increase of T (CD3, CD8) and B cells (CD20) and downregulated T regulatory cells (FoxP3). We investigated the impact of different preoperative treatments on the quality and density of the immune infiltrates in synchronous resected PCT and LCM. Methods: Metastatic colorectal patients (n = 107) undergoing curative liver surgery for all resected LCM (n = 338) were investigated. 28 patients have been operated concomitantly for synchronous LCM (n = 102) and PCT (n = 23 available) after surgery alone (S), chemotherapy (Cht) alone, Cht + anti-VEGF and Cht + anti-EGFR. The density of CD3 (T cells), CD8 (cytotoxic), CD45RO (memory), CD20 (B cells) and FoxP3 (regulatory) in the core (CT) and invasive margin (IM) of all synchronous LCM and PCT was quantified on immunostained slides. The mean density value (CT, IM) was calculated for each marker with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Results: Global analysis of immune cell density in LCM and corresponding PCT showed no significant correlation even when further subcategorizing by treatment (preoperative or S), metastasic burden or subdividing by the least, the mean or the highest infiltrated LCM for patients with multiple LCM.Compared to PCT, LCM were more frequently associated with a high immune infiltrate for CD3 and CD45RO in the IM (p < 0.001) and CD8 in CT and IM (p < 0.001). Conversely, high CD20 and FoxP3 density were higher in the CT of PCT (p < 0.005). When comparing preoperative treatment to S, only Cht+anti-EGFR significantly increases CD3 and CD8 in CT of LCM but not PCT (p < 0.001). Conclusions: Cytotoxic/memory T cells and B/regulatory T cell densities were significantly higher in LCM and PCT, respectively. Only anti-EGFR treatment increases T cells densities in the CT of the LCM but not in the PCT, suggesting a specific treatment effect in this tumor region.
Sentences for serious manslaughter in healthcare should start at 12 years, report recommends
Authors: Clare Dyer
Journal: BMJ (2017)

Sentences for gross negligence manslaughter could increase after the Sentencing Council for England and Wales concluded that prison terms imposed by judges were too short in some cases.

The council, an independent, non-departmental public body of the Ministry of Justice, is consulting on plans to issue comprehensive sentencing guidelines on manslaughter, in a consultation that closes on 10 October.1

Of the four types of manslaughter, the council has specified …
Abstract 319: Duration of Resuscitation Efforts and Functional Outcome After Out-of-Hospital Cardiac Arrest: When Should We Change to Novel Therapies?
Authors: Joshua C Reynolds, Adam Frisch, Jon C Rittenberger, Clifton W Callaway
Journal: Circulation (2013)

Objectives: Strategies such as extracorporeal life support yield favorable outcomes in select OHCA patients who fail traditional CPR. However, it is unclear how long to attempt CPR before switching to more intensive strategies. We hypothesized that most patients with good outcome after traditional CPR achieve return of spontaneous circulation (ROSC) quickly, and determined the maximal CPR duration (DUR) required to restore pulses in the majority (75%, 95% or 99%) of patients with good outcome. Methods: Retrospective cohort study of subjects with atraumatic OHCA and attempted resuscitation from 2005-2011. Good outcome was defined as a modified Rankin scale (mRS) 0-3. We determined DUR until ROSC for subjects with mRS 0-3 (good outcome), mRS 4-5 (poor outcome), or mRS 6 (in-hospital death) with Kaplan-Meier curves, and the association between DUR and good outcome with logistic regression. Results: Of 1,014 patients, 47% had ROSC, 11% survived, and 6% had mRS 0-3. DUR for each outcome are in Table 1. Cumulative proportions of good outcomes versus DUR are in Figure 1. Adjusting for prehospital and inpatient covariates, DUR (min) is associated with mRS 0-3 (OR 0.84; 95%CI 0.72, 0.98;p=0.02). Conclusions: Novel strategies should be considered early, because 75% and 90% of patients with good outcome have ROSC within 10 and 16 minutes of traditional resuscitation, respectively.
A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers.
Authors: Christian S. Hinrichs, Stacey L. Doran, Sanja Stevanovic, Sabina Adhikary, Michelle Mojadidi, Mei Li Kwong, William C Faquin, Steven Feldman, Robert Somerville, Richard Mark Sherry, James C. Yang, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2017)

3009 Background: Engineered T-cell therapy has shown promise in B-cell malignancies and melanoma, but clinical investigation in epithelial cancers has been limited. Methods: We conducted a phase I/II clinical trial of T cells genetically engineered to express a T-cell receptor that targets an HLA-A*02:01-restricted epitope of E6 (E6 TCR T Cells) for patients with metastatic HPV-16+ carcinoma. The cell dose was escalated in cohorts of single patients (1 x 10 9 , 1 x 10 10 , and 1-2 x 10 11 cells). Patients received a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of E6 TCR T Cells, and systemic high-dose aldesleukin. Results: Twelve patients were treated, 9 at the highest cell dose, plus one retreatment. The cancer types were 6 cervical, 4 anal, 1 oropharyngeal, and 1 vaginal. No dose-limiting toxicity, autoimmune adverse events, or cytokine storm were observed. Two patients with anal cancer treated at the highest cell dose experienced partial tumor responses lasting 6 and 3 months after treatment. The patient with a 6-month response had complete regression of one tumor and partial regression of two tumors that were resected upon progression; she has no evidence of disease 22 months after treatment. T-cell receptor gene transfer efficiency was 45 and 51% in the responding patients, and 47-76% (median 61%) in the non-responding patients. Responding patients showed robust levels of E6 TCR T cell memory (30 and 46% of circulating T cells 1-month after treatment). Non-responding patients showed wide-ranging levels of E6 TCR T cell memory (range 4-53%, median 29%). Expression of programmed cell death protein 1 (PD-1) by circulating E6 TCR T Cells 1-month after treatment was low in all patients ( &lt; 5%). The patient with a 6-month response had 7% E6 TCR T Cells in a resected tumor 10 months after treatment, 25% of which expressed PD-1. A patient with no response had no detectable E6 TCR T Cells in a resected tumor 3 months after treatment. Conclusions: E6 TCR T-cell therapy was safe at doses up to 2 x 10 11 cells. Regression of metastatic HPV+ carcinoma occurred in two patients following treatment, suggesting that TCR T-cell therapy can mediate epithelial cancer regression. Clinical trial information: NCT02280811.
Final results of neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker in advanced pancreatic cancer patients treated with Nab-paclitaxel plus Gemcitabine.
Authors: Jole Ventriglia, Marisol Huerta Alvaro, Maria Maddalena Laterza, Beatrice Savastano, Angelica Petrillo, Valentina Gambardella, Giuseppe Tirino, Anna Diana, Antonio Febbraro, Michele Orditura, Andres Cervantes, Fortunato Ciardiello, Fernando De Vita
Journal: Journal of Clinical Oncology (2016)

e15737 Background: Pancreatic cancer is the ninth most common cancer and the forth cause of cancer-related mortality worldwide. New regimens have increased overall survival, but it still remains extremely poor. Therefore, it is important to clarify the biological mechanisms that contribute to tumour progression and identify prognostic factors in order to stratify individual risk. There are several evidences suggesting that an elevated NLR is related to an adverse outcome in various types of cancer. In this analysis we investigated the prognostic role of pretreatment NLR in a multicentre cohort of patients with metastatic pancreatic cancer (MPC) treated with Nab-paclitaxel and Gemcitabine.Methods: From January 2012 to November 2015, a homogeneous group of 70 patients (pts) with MPC who received Nab- paclitaxel and gemcitabine as first-line treatment, was included in our retrospective analysis. NLR was performed before chemotherapy on routine blood tests. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by Cox proportional hazard model. Results: Median age of pts was 61 (range 32-78), 18 pts had an age ≥ 70; ECOG PS was 0-1 in 60 pts and 2 in 10 pts. Primary tumor was located to pancreatic head or body-tail in 25 (36%) and 45 (64%) pts respectively. According with NLR values, these pts were divided into two groups: high ( ≥ 5.0) and low ( < 5.0) considering a NLR cut-off of 5 as described in previous trials. A low NLR pre-treatment was observed in 52 patients while high level of NLR was observed in 18 pts. Median Progression free survival of pts with low NLR was 7 months compared with 5 months of pts with a high NLR (HR 1.9; 95%CI 1.0-3.4) p: 0.04. Median Overall survival was 13 months among pts with low NLR compared with 7 months for pts with high NLR (HR 2.4; 95%CI 1.3-4.5) (p: 0.003). On multivariate analysis, after adjusting for other clinic-pathologic factors, high NLR turned out to be an independent risk factor for poor survival (p = 0.01). Conclusions: Our results suggest a potential role of pre-treatment NLR in predicting survival and could thus be used for treatment decision making for stratify patients.
Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8+ T cell response
Authors: Abigail Culshaw, Kristin Ladell, Stephanie Gras, James E McLaren, Kelly L Miners, Carine Farenc, Heleen van den Heuvel, Emma Gostick, Wanwisa Dejnirattisai, Apirath Wangteeraprasert, Thaneeya Duangchinda, Pojchong Chotiyarnwong, Wannee Limpitikul, Sirijitt Vasanawathana, Prida Malasit, Tao Dong, Jamie Rossjohn, Juthathip Mongkolsapaya, David A Price, Gavin R Screaton
Journal: Nature Immunology (2017)
A phase I/II study of lymphodepletion plus adoptive cell transfer (ACT) with T cells transduced with CXCR2 and NGFR followed by high dose interleukin-2 (IL-2) in patients with metastatic melanoma (MM).
Authors: Rodabe Navroze Amaria, Cara L. Haymaker, Chantale Bernatchez, Marie-Andree Forget, Vruti Patel, Wen-Jen Hwu, Michael A. Davies, Sapna Pradyuman Patel, Adi Diab, Isabella Claudia Glitza, Hussein Abdul-Hassan Tawbi, Scott Eric Woodman, Jennifer Ann Wargo, Merrick I. Ross, Jeffrey Edwin Lee, Jeffrey E. Gershenwald, Janice N. Cormier, Richard Eldon Royal, Anthony Lucci, Patrick Hwu
Journal: Journal of Clinical Oncology (2016)

TPS9594 Background: Improving T cell trafficking to tumors may help augment anti-tumor responses in ACT using tumor infiltrating lymphocytes (TILs). mm produces the chemokines CXCL1 and CXCL8, which are thought to promote autocrine growth and angiogenesis. However, tumor antigen-specific T cells frequently fail to express the chemokine receptors specific for these ligands, including CXCR2. We have generated modified T cells using retroviral vectors encoding CXCR2 [Kershaw et al. Hum Gene Ther. 2002; 3: 1971-80]. These transduced cells exhibit enhanced trafficking to CXCL1 expressing tumors, leading to improved anti-tumor responses and survival in preclinical models [Peng et al. Cancer Res. 2010; 16: 5458-68]. Methods: Pts with mm who have previously had T cells harvested and cryopreserved at MDACC with disease amenable to serial biopsy with excellent PS and organ function are eligible to enroll. All pts receive a standard conditioning regimen consisting of 7 days of cyclophosphamide and fludarabine for lymphodepletion, followed by infusion of pooled ex-vivo expanded TIL transduced with CXCR2, Nerve Growth Factor Receptor (NGFR) and non-virally transduced TIL followed by high dose IL-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) (NCT 01740557). The NGFR is truncated to render it incapable of eliciting intracellular signaling and will serve as a control for T cell trafficking since human T cells do not express NGFR. Patients have mandatory biopsy prior to lymphodepletion and then at day 21 to allow for assessment of chemokine levels and quantification of CXCR2 and NGFR transduced T cells. There are 5 dose levels of infused CXCR2 transduced cells to be studied including 15, 30, 45, 60, 75 x 109 T cells. Currently 3 patients out of a planned 36 have been enrolled and treated. The primary objective is to determine the safety and toxicity of CXCR2 transduced TIL. Secondary objectives include assessing if CXCR2 transduction enhances TIL ability to migrate to tumors. Levels of CXCL1 and CXCL8 in tumor tissue will be assessed and correlated with tumor localization of CXCR2 transduced TIL and clinical outcomes. Clinical trial information: NCT 01740557.
Acceptability of two colorectal cancer screening tests: pain as a key determinant in sigmoidoscopy
Authors: Benedicte Kirkøen, Paula Berstad, Edoardo Botteri, Eirin Dalén, Jens Nilsen, Geir Hoff, Thomas de Lange, Tomm Bernklev
Journal: Endoscopy (2017)

Abstract Background Participants’ experience with a screening test can influence adherence, and therefore the efficacy of screening programs. We compared screening with unsedated flexible sigmoidoscopy and fecal immunochemical testing (FIT) for participants’ satisfaction with the decision and for willingness to repeat colorectal cancer screening. Methods In a prospective, randomized trial 3257 individuals (50 – 74 years) were invited to either flexible sigmoidoscopy or FIT (1:1), of whom 1650 took up the offer (52.6 %). In total, 1497 screening participants completed at least one questionnaire, either before screening, and/or at three time points in the following year, that measured willingness to repeat screening, willingness to recommend screening, and satisfaction with decision to attend. There were 769 and 728 responders in the flexible sigmoidoscopy and FIT group, respectively. Additionally, 581 flexible sigmoidoscopy participants also completed a pain questionnaire. Results 1 year later, 10 % of the flexible sigmoidoscopy participants were not willing to repeat screening, compared to 5 % of FIT participants. A higher percentage of women compared to men would not repeat flexible sigmoidoscopy screening (adjusted odds ratio [OR] 2.52, 95 % confidence interval [95 %CI] 1.48 to 4.28). Notably, 22 % of women reported pain during flexible sigmoidoscopy compared to 5 % of men. When we added pain to the statistical model, pain was significantly associated with unwillingness to repeat flexible sigmoidoscopy (OR 3.15, 95 %CI 1.68 to 5.87), while gender was no longer associated (OR 1.53, 95 %CI 0.82 to 2.88). Conclusion Acceptability for flexible sigmoidoscopy and for FIT was high among Norwegian screening participants, though FIT participants were more willing to repeat screening. Women were less willing to repeat screening with flexible sigmoidoscopy compared to men. This gender difference seemed partly due to pain, and therefore preventable. This study is registered at ClinicalTrials.gov: NCT01538550.
Downregulation of SETD2-H3K36me3 Tumor Suppression Axis Promotes MLL Leukemia through Activation of DOT1L-H3K79me2 Axis
Authors: Jiachen Bu, Aili Chen, Yunzhu Dong, Fuhong He, Xiaomei Yan, Yile Zhou, Di Zhan, Yoshihiro Hayashi, Qianfei Wang, Gang Huang
Journal: Blood (2016)
CQC rates 90% of general practices as good or better
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Ninety per cent of general practices in England have been rated as “good” or “outstanding” by the Care Quality Commission, making it the highest performing sector that the organisation regulates.

In a report the CQC describes as the most detailed analysis to date of the quality and safety of general practice in England, the regulator found that at the end of its first full inspection programme—in which many general practices had been re-inspected—4% were rated “outstanding,” 86% as “good,” 8% as “requires improvement,” and 2% as “inadequate.”1

This was an improvement from the first set of ratings awarded to general practices before any re-inspections took place, when 4% …