tbuckley/cabot-search huggingface dataset:
Improving the microbiological diagnosis of tuberculous meningitis: A prospective, international, multicentre comparison of conventional and modified Ziehl–Neelsen stain, GeneXpert, and culture of cerebrospinal fluid
Authors: A. Dorothee Heemskerk, Joseph Donovan, Do Dang Anh Thu, Suzaan Marais, Lidya Chaidir, Vu Thi Mong Dung, Chad M. Centner, Vu Thi Ngoc Ha, Jessi Annisa, Sofiati Dian, Louise Bovijn, Nguyen Thi Hoang Mai, Nguyen Hoan Phu, Nguyen Van Vinh Chau, Ahmad Rizal Ganiem, Cao Thao Van, Ronald B. Geskus, Nguyen Thuy Thuong Thuong, Rovina Ruslami, Graeme Meintjes, Reinout van Crevel, Robert J. Wilkinson, Guy E. Thwaites
Journal: Journal of Infection (2018)

ObjectivesTuberculous meningitis (TBM) is the severest form of tuberculosis, but current diagnostic tests are insensitive. Recent reports suggest simple modifications to conventional cerebrospinal fluid (CSF) Ziehl–Neelsen (ZN) staining may greatly improve sensitivity. We sought to define the performance of modified and conventional ZN stain for TBM diagnosis.MethodsIn hospitals in Vietnam, South Africa and Indonesia we conducted a prospective study of modified ZN with or without cytospin, conventional ZN smear, GeneXpert, and culture on CSF in adults with suspected TBM.ResultsA total of 618 individuals were enrolled across 3 sites. Compared with the TBM clinical diagnostic gold standard for research (definite probable or possible TBM), sensitivity of conventional ZN and modified ZN with cytospin were 33.9% and 34.5% respectively (p = 1.0 for the difference between tests), compared with culture 31.8% and Xpert 25.1%. Using culture as a reference, sensitivities of conventional ZN, modified ZN with cytospin, and Xpert were 66.4%, 67.5%, and 72.3%, respectively. Higher CSF volume and lactate, and lower CSF:blood glucose ratio were independently associated with microbiologically confirmed TBM.ConclusionsModified ZN stain does not improve diagnosis of TBM. Currently available tests are insensitive, but testing large CSF volumes improves performance. New diagnostic tests for TBM are urgently required.
Association Between Autism Spectrum Disorders With or Without Intellectual Disability and Depression in Young Adulthood
Authors: Dheeraj Rai, Hein Heuvelman, Christina Dalman, Iryna Culpin, Michael Lundberg, Peter Carpenter, Cecilia Magnusson
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Depression is a frequently occurring mental disorder and may be common in adults with autism spectrum disorders (ASD), but there is a lack of longitudinal population-based studies examining this association. Whether any increased risk of depression in ASD has a shared familial basis and whether it differs by co-occurring intellectual disability is not well known. <h3>Objectives</h3> To examine whether individuals with ASD are more likely to be diagnosed as having depression in adulthood than the general population and their nonautistic siblings and to investigate whether these risks differ by the presence or absence of intellectual disability. <h3>Design, Setting, and Participants</h3> Population-based cohort study with a nested sibling comparison. The Stockholm Youth Cohort is a total population record linkage study that includes all children and young people (age range, 0-17 years) who were ever resident in Stockholm County, Sweden, between January 2001 and December 2011 (n = 735 096). Data analysis was conducted between January 5 and November 30, 2017, in Stockholm County, Sweden. <h3>Main Outcomes and Measures</h3> Clinical diagnosis of depressive disorders was identified using the Stockholm County Adult Psychiatric Outpatient Register and the Swedish National Patient Register. <h3>Results</h3> Participants were 223 842 individuals followed up to age 27 years by 2011, of whom 4073 had diagnosed ASD (mean [SD] age, 21.5 [2.7] years; 65.9% male; 2927 without intellectual disability and 1146 with intellectual disability) and 219 769 had no ASD (mean [SD] age, 22.1 [2.8] years; 50.9% male). By age 27 years, 19.8% (n = 808) of individuals diagnosed having ASD had a diagnosis of depression compared with 6.0% (n = 13 114) of the general population (adjusted relative risk [RR], 3.64; 95% CI, 3.41-3.88). The risk of a depression diagnosis was higher in ASD without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability (adjusted RR, 1.81; 95% CI, 1.51-2.17). Nonautistic full-siblings (adjusted RR, 1.37; 95% CI, 1.23-1.53) and half-siblings (adjusted RR, 1.42; 95% CI, 1.23-1.64) of individuals with ASD also had a higher risk of depression than the general population. Compared with their nonautistic full-siblings, individuals with ASD had more than a 2-fold risk of a depression diagnosis (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27) in young adulthood. <h3>Conclusions and Relevance</h3> According to this study's results, ASD, particularly ASD without intellectual disability, is associated with depression by young adulthood compared with the general population. It appears that this association is unlikely to be explained by shared familial liability. Future research to identify modifiable pathways between ASD and depression may assist in the development of preventive interventions.
Prevalence and prognosis of DNA repair deficiency in squamous cell carcinoma (SCC) patients enrolled on the S1400 LungMAP study.
Authors: Taofeek Kunle Owonikoko, Mary Weber Redman, Lauren Averett Byers, Katie Griffin, Fred R. Hirsch, Philip C. Mack, David R. Gandara, Jeffrey D. Bradley, Tom Stinchcombe, Karen Kelly, Suresh S. Ramalingam, Roy S. Herbst, Vassiliki Papadimitrakopoulou
Journal: Journal of Clinical Oncology (2018)

9055 Background: DNA homologous recombination repair deficiency (HRRD) is a vulnerability that has been exploited for PARP inhibitor therapy. This concept is currently being evaluated in S1400G substudy of LungMAP where HRRD(+) SCC patients are treated with a PARP inhibitor, talazoparib. We assessed the prevalence and characteristics of HRRD(+) SCC patients screened on LungMAP. Methods: All patients receive Foundation One NGS screening platform for enrollment on LungMAP sub-studies. HRRD is defined as genetic alteration predicted to have functional consequence in genes involved in HRR (ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1) but also define a key subgroup based on a set of the best clinically validated genes: ATM, ATR, BRCA1, BRCA2, and PALB2 . Survival was measured from the date of sub-study assignment. Results: Biomarker results were available for 1244 eligible patients screened between June 2014 and October 2017. HRRD was detected in 190 (15.3%) patients, higher than the 9% rate assumed for the design of S1400G substudy. HRRD(+) and HRRD(-) patients did not differ in terms of median age (67 vs. 66 years); male gender (68% vs. 67%); race (85% vs. 84% and 11% vs. 9% for White and Black) or tobacco exposure (94% vs. 95%). BRCA2 alteration was the most frequent of the HRRD gene alterations. Survival was not different by HRRD(+) versus HRRD(-) status (HR[95%CI]: 1.11 [0.91-1.37], p = 0.29). Alterations in BRIP1 (0.58 [0.28-1.23]; p = 0.16), CHK2 (0.43[0.16-1.15]; p = 0.09), FANCM (1.48[0.87-2.52]; p = 0.15) and FANC-A/C/D2 (1.70[1.07-2.72]; p = 0.03) showed a trend in prognostic association. Conclusions: HRRD is frequent in SCC and could define a large subset of SCC for targeted therapy if validated in the ongoing S1400G substudy of LungMAP. Overall prevalence Prevalence among HRRD alterations BRCA2 3.9% 23.0% FANCM 2.0% 11.7% BRCA1 1.7% 9.9% BRIP1 1.3% 7.5% ATM 1.1% 6.6% PALB2 1.1% 6.6% ATR 1.0% 6.1% CHEK2 1.0% 5.6% FANCA 0.8% 4.7% FANCC 0.7% 4.2% FANCD2 0.4% 2.3% BARD1 0.3% 1.9% CHEK1 0.3% 1.9% FANCF 0.2% 1.4% RAD51L1 0.2% 1.4% RAD51 0.2% 1.4% NBN 0.2% 0.9% RAD51B 0.2% 0.9% RAD54L 0.2% 0.9% RPA1 0.2% 0.9%
Cost burden of first-line antineoplastic treatment failure in patients with chronic lymphocytic leukemia.
Authors: Mekre Senbetta, Marie-Helene Lafeuille, Patrick Lefebvre, Hela Romdhani, Bruno Emond, Song Wang
Journal: Journal of Clinical Oncology (2017)

e19037 Background: Treatment failure (TF) is associated with significant cost burden in patients with non-Hodgkin’s lymphoma (NHL) in the US. This study assessed treatment patterns and healthcare cost burden of first-line (FL) TF in patients with chronic lymphocytic leukemia (CLL), a subtype of NHL, overall, and for the top 5 FL regimens. Methods: A retrospective study of a large national claims database identified adult patients with CLL who initiated an antineoplastic agent (AA) after their first CLL diagnosis (index date) from 01/2011- 07/2016. Patients included had ≥12 and ≥6 months of observation pre- and post-index, respectively, and were treatment-naïve with no solid or selected blood malignancies in the pre-index period. FL therapy included AA administered within the first 30 days post-index. TF occurred at the earliest of: initiation of a new AA, resumption of initial treatment following a gap of ≥3 months, radiotherapy, stem cell transplant, or hospice care. The total cost difference between patients with and without FL TF was estimated using ordinary least squares regressions adjusted for baseline characteristics. Non-parametric bootstrap was used to estimate confidence intervals (CI) and p-values. Results: Among the 2,226 patients included (mean age: 68 years; female: 41%), 46% experienced FL TF. Overall, the average adjusted total cost difference between patients with and without FL TF was $3,011 per patient per month (PPPM) (95% CI: 2,400, 3,583; P &lt; 0.001). Among the 5 most common FL regimens, fludarabine / cyclophosphamide / rituximab (FCR) regimen was associated with the highest PPPM cost of TF (N = 281; $4,758; 95% CI: 2,652, 7,346), followed by other cyclophosphamide-based regimens (N = 142; $4,579; 95% CI: 2,474, 6,311), chlorambucil-based regimens (N = 223; $3,761; 95% CI: 2,029, 5,602), bendamustine / rituximab (BR) regimen (N = 592; $3,163; 95% CI: 2,206, 4,148), and other rituximab-based regimens (N = 474; $3,030; 95% CI: 2,164, 3,956) (P &lt; 0.001 for all). Conclusions: The most common FL regimens used in patients with CLL were associated with 46% treatment failure. Clinicians should consider the cost of treatment failure when selecting the initial therapy in these patients.
TCT-764 Long-term follow-up of covered stent implantation
Authors: Daisuke Hahcinohe, Azeem Latib, Alessandra Laricchia, Gianmarco Iannopollo, Ozan Demir, Marco Ancona, Antonio Mangieri, Damiano Regazzoli, Francesco Giannini, Lorenzo Azzalini, Satoru Mitomo, Alaide Chieffo, Matteo Montorfano, Antonio Colombo
Journal: Journal of the American College of Cardiology (2018)
Public perception of cancer risk.
Authors: Lisa Burns, Ursula Kenny, Laura Healy, Samantha Cushen, Seamus O'Reilly, Aoife M Ryan, Derek Gerard Power
Journal: Journal of Clinical Oncology (2012)

1559 Background: The public’s knowledge of cancer risk factors has rarely been studied in Ireland. An understanding of this can help inform cancer prevention programs. Methods: An online surveywas used to assess the public’s perception of cancer risk. Results: 525 people completed the survey. Mean age was 40yrs (range:18-74), 82% were female and 36% had college degrees. 81% were concerned about developing cancer, however 20% believed if cancer was in their family there was nothing they could do about personal cancer risk. 20% did not know that cancer risk increased with age, 27% believed that &gt;50% of cancers are inherited, and 54% believed 10-20% of cancers are inherited. The top 5 risk factors listed by respondents were: smoking 85%, diet 74%, alcohol 44%, genetics 38%, and environment 31%. Only 32% were aware that obesity is a risk factor for cancer and 33% did not think the location of fat was important for cancer prevention. When given a list of potential behaviours relevant to cancer risk 33% believed wearing a tight bra and 49% believed a blow to the breast could increase cancer risk. 87% believed genetics ‘strongly’ increased risk, 85% stress, and 86% believed cell phones increased risk. 12% believed ‘luck’ was important in avoiding cancer, 35% thought ‘detox’ diets and 61% believed organic food reduced risk. Only 33% agreed with the statement that ‘frozen vegetables/fruit are as good as fresh’, 40% were unaware of the link between red meat and cancer. The following foods were thought to increase risk: cheese (29%), soy (9%), milk chocolate (30%), red wine (25%), and eggs (11%). Aerosol use (71%), cleaning agents (73%), smoking (99%), cooking methods (68%), processed meat (86%), food irradiation (77%), and genetically modified foods (81%) were believed to increased risk. The majority were aware that berries, green tea, garlic, brassica vegetables and physical activity of 30 minutes a day can reduce cancer risk. Conclusions: There is a sizable portion of the population who are misinformed about cancer risk. Most are aware of classic risk factors (e.g. smoking, poor diet). Many overestimate risk attributable to genetics, environment, stress, and underestimate age, obesity and sunlight. One in 5 believes lifetime risk of cancer is non-modifiable.
E-selectin ligand binding affinity to determine anti-metastatic efficacy of proteasome inhibition.
Authors: Tobias Lange, Ursula Valentiner, Daniel Wicklein, Hanna Maar, Vera Labitzky, Ann-Kristin Brauns, Thomas Streichert, Benjamin Otto, Guido Sauter, Gerrit Wolters-Eisfeld, Kristoffer Riecken, Christian BÃ Â¶rnchen, Rainer Kiefmann, Valsamma Abraham, Horace M DeLisser, Timo Gemoll, Jens K Habermann, Udo Schumacher
Journal: Journal of Clinical Oncology (2016)

e23010 Background: E-selectin-mediated adhesion of circulating tumor cells (CTCs) to vascular endothelial cells (ECs) initiates CTC extravasation at a distant site and is hence a critical step of the metastatic cascade. E-selectin expression is induced by a pro-inflammatory milieu caused by the primary tumor, which might depend on disinhibition of NF-kB in the proteasome. Methods: in vivo, ex vivo and in vitro analyses of metastasis formation, dynamic tumor cell adhesion, glycosylation, glycsoyltransferase and glycoprotein expression. Results: We show that the approved proteasome inhibitor bortezomib (BZM) counteracts cytokine-mediated up-regulation of E-selectin on ECs. This can lead to impaired endothelial adhesion of tumor cells in vitro, reducedspontaneous pulmonary metastasis in vivo and decreased adhesion of human CTCs to pulmonary microvessels ex vivo. Surprisingly, efficacy of BZM is crucially determined by the nature of the tumor cell’s E-selectin ligands. BZM-‘sensitive’ tumors (neural crest-derived tumors) are characterized by newly specified, non-canonical, low affinity E-selectin ligands such as poly-N-acetyllactosamine, which require shear stress for E-selectin binding and mediate cell rolling under flow. In contrast, BZM-‘resistant’ tumors (gastrointestinal adenocarcinomas) are characterized by the canonical, high affinity E-selectin ligand sialyl Lewis A (CA 19-9), which does not require shear stress for E-selectin binding and mediates firm adhesion under flow. For both classes of ligands, we exemplarily demonstrate MGAT5B and C2GNT2 as key glycosyltransferases and CD44 and CD24 as glycoprotein carriers on neuroblastoma and colorectal cancer cells, respectively. The identified glycoconjugates are shown to be frequently co-expressed in corresponding clinical samples and experimental metastases. Conclusions: This is the first report proving anti-metastatic efficacy of BZM in a subset of solid human tumors. Clinical studies are needed to investigate whether BZM might be helpful to reduce metastatic spread particularly during transient periods of increased CTC release such as biopsy and surgery and whether serum sLeA (CA 19-9) can be used as a predictor of therapy response.
Efficacy and safety of fulvestrant 500 mg in Chinese HR-positive, HER2-negative metastatic breast cancer patients: A real-world study.
Authors: Xiying Shao, Wang Xiao Jia, Yabing Zheng, Zhan-Hong Chen, Guangliang Li, Lei Shi, Weibin Zou
Journal: Journal of Clinical Oncology (2018)

e13046 Background: The clinical effectiveness of fulvestrant in postmenopausal HR+/HER2- MBC has been previously confirmed in previous trials. Up to 50% of breast cancers were premenopausal in China. Ovarian suppression was recommended in hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) premenopausal metastatic breast cancer (MBC). This real-world study aimed to evaluate the efficacy and safety profile of fulvestrant 500mg in Chinese HR+/HER2- MBC patients irrespective of menstruation status. Methods: 147 HR+/HER2- MBC patients receiving fulvestrant 500mg were included in Zhejiang Cancer Hospital between September 2014 and June 2017. Progression free survival(PFS) and overall survival(OS) were estimated by Kaplan-Meier method. Objective response rate(ORR), clinical benefit rate(CBR) and safety profile were also evaluated. Results: 118 (80.3%) postmenopausal women received fulvestrant 500 mg, 29 (19.7%) premenopausal patients had fulvestrant 500mg combination with ovarian suppression. With a median follow up of 20months, PFS was 7.2months (95%CI 6.0-8.3), while OS was immature. 45(30.6%) were administered at first-line, 102(69.4%) were at second-line or later. PFS for the first-line was significantly longer than that for the second-line or later (15.9months vs. 6.1months, P= 0.000, HR = 0.448, 95% CI = 0.287-0.700).And it's important to note that PFS in premenopausal women was 9.5months (95%CI 3.3-15.8) which was similar to that for postmenopausal women of 7.0months (95%CI 5.7-8.2) (P= 0.757, HR = 1.076, 95% CI = 0.678-1.707).Additionally, 12(8.2%) achieved partial response(PR), 107(72.8%) had stable disease(SD), and 28(19.0%) reported progressive disease(PD). The ORR and CBR were 8.2%, 51.4%, respectively. The most frequently adverse events were injection site pain (8.0%). Conclusions: Fulvestrant 500 mg administered was shown to be highly effective and well tolerated. And in note, fulvestrant 500mg combination with ovarian suppression was also a reasonable option for HR+/HER2-premenopausal metastatic breast cancer patients which merits further study.
Nivolumab (nivo) + <i>nab</i>-paclitaxel (<i>nab</i>-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study.
Authors: David Michael Waterhouse, Jonathan Wade Goldman, Ben George, Peter J. O'Dwyer, Moncy Ye, Tianlei Chen, Nataliya Trunova, Karen Kelly
Journal: Journal of Clinical Oncology (2017)

9095 Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m 2 d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.
Anti-tumor efficacy of the Runx2-dendritic cell vaccine in triple-negative breast cancer in vitro.
Authors: Yu Liu, Mi Tang, Qiao-Chu Zhang, Peng Zhang, Yong Huang
Journal: Journal of Clinical Oncology (2018)

e24000 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and limited effective treatment. The rise in immunotherapeutic strategies prompted us to establish a genetic vaccine against TNBC in vitro using a possible biological marker of TNBC. Methods: Different detection methods were used to evaluate the distribution and expression of Runx2 in various breast cancer cells. After the Runx2-DC vaccine was developed using a lentivirus, transfection efficacy was recorded. The T lymphocytes co-cultured with the vaccine were collected to assess the anti-tumor potency. Results: Increased levels of Runx2 were expressed in breast cancer cells. However, different breast cancer cells expressed various levels of Runx2. Runx2 showed particularly high expression in TNBC cells compared with non-TNBC cells. A Runx2- lentivirus transfection system was successfully engineered, and Runx2 was transduced into dendritic cells while maintaining stable expression. The sustained and stable cytotoxic T cells induced in the transfected group had higher and more specific anti-tumor efficacy against TNBC than other cell lines. Conclusions: Runx2 may be a new target for TNBC treatment. The Runx2-DC vaccine can induce specific and efficient anti-tumor effects in TNBC in vitro.
Assessment of baroreflex sensitivity has no prognostic value in contemporary, optimally managed patients with mild‐to‐moderate heart failure with reduced ejection fraction: a retrospective analysis of 5‐year survival
Authors: Bartłomiej Paleczny, Martyna Olesińska‐Mader, Agnieszka Siennicka, Piotr Niewiński, Krzysztof Nowak, Agnieszka Buldańczyk, Ewa A. Jankowska, Waldemar Banasiak, Stephan von Haehling, Beata Ponikowska, Stefan D. Anker, Piotr Ponikowski
Journal: European Journal of Heart Failure (2018)
VEGFC Antibody Therapy Drives Differentiation of AML
Authors: Kim R. Kampen, Frank J.G. Scherpen, Hasan Mahmud, Arja ter Elst, André B. Mulder, Victor Guryev, Han J.M.P. Verhagen, Kim De Keersmaecker, Linda Smit, Steven M. Kornblau, Eveline S.J.M. De Bont
Journal: Cancer Research (2018)

Abstract High expression of VEGFC predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC-targeting efficacy as an AML therapy using a VEGFC mAb. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30% to 50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for patients with AML. Significance: These findings reveal VEGFC targeting as a promising new differentiation therapy in AML. Cancer Res; 78(20); 5940–8. ©2018 AACR.