tbuckley/cabot-search huggingface dataset:
Evaluation of the in vitro activity of isavuconazole and comparator voriconazole against 2635 contemporary clinical Candida and Aspergillus isolates
Authors: K.M.T. Astvad, R.K. Hare, M.C. Arendrup
Journal: Clinical Microbiology and Infection (2017)

The in vitro activity of isavuconazole was determined for 1677 Candida and 958 Aspergillus isolates from 2012 to 2014 with voriconazole as comparator.Aspergillus isolates were screened for resistance using azole-agar. Aspergillus isolates that screened positive and all Candida isolates underwent EUCAST broth microdilution testing. Isolates were categorized as wild-type (wt) or non-wt, adopting EUCAST epidemiological cut-off values (ECOFFs) (where available) or wt upper limits (wtULs; two two-fold dilutions above the MIC50). The CYP51A gene was sequenced for non-wt Aspergillus fumigatus isolates. Itraconazole and posaconazole MICs were determined for selected Aspergillus isolates with isavuconazole MIC ≥2 mg/L.Isavuconazole MIC50 (range) (mg/L) against Candida species were: Candida albicans: ≤0.03 (≤0.03 to >4), Candida dubliniensis: ≤0.03 (≤0.03), Candida glabrata: ≤0.03 (≤0.03-4), Candida krusei: 0.06 (≤0.03-0.5), Candida parapsilosis: ≤0.03 (≤0.03-0.06), Candida tropicalis: ≤0.03 (≤0.03 to >4), Saccharomyces cerevisiae (anamorph: Candida robusta): ≤0.03 (≤0.03-0.5). Non-wt isavuconazole/voriconazole MICs were found for C. albicans: 0.8/1.0%, C. dubliniensis: 0/1.8%, C. glabrata: 14.9/9.5%, C. krusei: 2.7/1.4%, C. parapsilosis: 1.7/1.8%, C. tropicalis: 14.3/19.1% and S. cerevisiae: 10.0/0%. Isavuconazole MIC50 (range) (mg/L) against Aspergillus species were: A. fumigatus: 1 (≤0.125 to >16), Aspergillus niger: 2 (1-8), Aspergillus terreus: 1 (0.25-8), Aspergillus flavus: 1 (0.5-2), Aspergillus nidulans: ≤0.125 (≤0.125-0.25). Non-wt isavuconazole/voriconazole MICs were found for 13.7/15.2% A. fumigatus, 4.9/0% A. niger and 48.2/22.2% A. terreus.Isavuconazole displayed broad in vitro activity, similar to that of voriconazole. Up to 15% of C. glabrata, C. tropicalis and A. fumigatus isolates were non-wt, reflecting increased resistance at a reference centre and technical issues. Significant CYP51A alterations were reliably detected applying the isavuconazole breakpoint.
Prognostic significance of thromboembolic events in chemotherapy-treated germ cell tumors.
Authors: Enrique Gonzalez-Billalabeitia, Josep Guma, Daniel E. Castellano, Maria Isabel Luengo, Jorge Aparicio, Alfonso Sanchez Munoz, Begona Mellado, Alberto Saenz, Claudia María Valverde, Antonio Fernandez, Mireia Margeli, Ignacio Duran, Sara Fernandez Arrojo, Javier Sastre, Silverio Ros, José Pablo Maroto Rey, Alberto Carmona Bayonas, Francisco Ayala, David Hervas, Jose R. Germa-Lluch
Journal: Journal of Clinical Oncology (2015)

4536 Background: To evaluate the incremental prognostic value of thromboembolic events (TEE) in combination with the International Germ Cell Cancer Collaborative Group (IGCCCG). Methods: Patients with germ-cell cancer receiving first-line platinum-containing chemotherapy (CT-GCC) between 2000-2014 were pooled from the Spanish Germ-Cell Cancer Group (Grupo Germinal)/Spanish Oncology Genitourinary Group (SOGUG) registry and another 3 tertiary hospitals. We used the Cox-proportional hazard model with bootstrap resampling to identify prognostic factors for both overall survival (OS) and progression-free survival (PFS). Good risk IGCCCG was used as the reference category. Results: We included 683 consecutive patients from 17 centers. With a median follow-up of 50 months TEE were observed in 8% of the patients (n=65), of which 86% were venous and 14% were arterial. Venous TEEs (VTE) occurred before, during and after chemotherapy in 27%, 57% and 16%. All arterial thrombosis (ATE) ensued during or after chemotherapy. On Cox regression analysis, the IGCCCG risk category, as well as pre-chemotherapy venous and arterial events were independent prognostic variables (Table 1). Bootstrap bias-corrected Harrell’s C-index was 0.74 (95% CI, 0.692-0.794) and 0.880 (95%CI, 0.837-0.922) for PFS and OS in the model combining the IGCCCG score and the presence of VTE and ATE. Conclusions: Thromboembolic events are clinically significant in CT-GCC. The classification of germ-cell tumors might be improved by incorporating surrogate variables of hipercoagulable states, such as the presence of early venous thromboembolisms and arterial thrombosis. Explanatory covariates included in the Cox-Proportional Hazard Model for PFS and OS. Variable Progression-Free Survival Overall Survival HR 95%CI p-value HR 95%CI p-value IGCCCG risk score Intermediate 2.41 1.40-4.16 0.002 8.61 3.48-21.3 <0.001 Poor 8.58 5.34-13.80 <0.001 39.27 16.89-91.30 <0.001 Venous thrombosis Pre-CT 3.13 1.42-6.89 0.005 3.61 1.40-9.29 0.008 On-CT 1.13 0.54-2.40 0.744 1.39 0.61-3.19 0.432 Post-CT 3.36 1.50-7.52 0.003 0.98 0.26-3.70 0.972 Arterial thrombosis 5.11 2.05-12.75 <0.001 4.40 1.52-12.74 0.006
Living in an adaptive world: Genomic dissection of the genus <i>Homo</i> and its immune response
Authors: Hélène Quach, Lluis Quintana-Murci
Journal: The Journal of Experimental Medicine (2017)

More than a decade after the sequencing of the human genome, a deluge of genome-wide population data are generating a portrait of human genetic diversity at an unprecedented level of resolution. Genomic studies have provided new insight into the demographic and adaptive history of our species, Homo sapiens, including its interbreeding with other hominins, such as Neanderthals, and the ways in which natural selection, in its various guises, has shaped genome diversity. These studies, combined with functional genomic approaches, such as the mapping of expression quantitative trait loci, have helped to identify genes, functions, and mechanisms of prime importance for host survival and involved in phenotypic variation and differences in disease risk. This review summarizes new findings in this rapidly developing field, focusing on the human immune response. We discuss the importance of defining the genetic and evolutionary determinants driving immune response variation, and highlight the added value of population genomic approaches in settings relevant to immunity and infection.
Skeletal-related events (SRE) and bone-targeted agents for metastatic prostate cancer: Are we changing outcomes?
Authors: Patricia Moretto, Brian Hutton, Iryna Kuchuk, Christina M. Canil, Terry L. Ng, Christina L. Addison, Mark J. Clemons
Journal: Journal of Clinical Oncology (2013)

e16074 Background: Bone-targeted agents (BTA) have been extensively studied in patients (pts) with prostate cancer (PC) and bone metastases (BM). Relatively little is known about the impact of BTAs on skeletal morbidity in the non-trial setting. We evaluated the impact BTAs on SRE and survival at a large Canadian cancer centre. Methods: Electronic heath records were reviewed for PC pts referred for further management from January 2008-June 2012. Demographic, clinical, and treatment data including: date of CRPC, occurrence of SRE, and BTA use were collected and analyzed. Results: A total of 141 pt charts were examined and were included in the analysis. Median age was 74 years (IQR 63-82), and 95% were stage IV at time of referral. Consequences of BMs included:101 pts had at least one SRE (72%), 58 (40%) pts had ≥1 SRE and 39% were hospitalised due to an SRE. Median overall survival from diagnosis of BM was 35.4 months (m) (IQR 16.1-65.9). Overall, 74 pts (52%) developed castration resistant PC (CRPC). In the CRPC group, the use of imaging to assess BM was highly variable, ranging from only once (12%) to every 1-2 m (4%), however the mode was every 3-5 m (43%). Sixty one percent (45/74) received a BTA, primarilyzoledronic acid (ZA). Despite having CRPC and BM, 39% never received a BTA, mainly because it was not offered (64%), or due to patient’s refusal (29%). Median time from diagnosis of CRPC to start of BTA was 1 month. Sixty-nine percent of pts had BTA discontinued, mainly due to progression of disease and pts deterioration. Osteonecrosis of the jaw occurred in 4% (2/45). In 39 pts (53%) the first SRE occurred prior to CRPC diagnosis, and 62 pts (84%) had at least 1 SRE after CRPC diagnosis. Forty seven percent (21/45) had a new SRE after starting BTA. Conclusions: BM have significant consequences for pts with PC irrespective of hormone sensitivity. Even for pts with CRPC the use of BTAs is highly variable. This reflects physician’s belief in the efficacy of BTAs, tailored by the expected benefits to each pt according to performance status and extent of disease. Interestingly in the CRPC group 53% have had an SRE prior to CRPC diagnosis. Strategies to optimise the care of pts with BM are clearly warranted.
QuantiFERON-TB<sup>®</sup> Gold Plus as a potential tuberculosis treatment monitoring tool
Authors: Arisu Kamada, Masaru Amishima
Journal: European Respiratory Journal (2017)

Novel approaches to controlling tuberculosis (TB) are required, especially in light of the growing number of multidrug-resistant pathogens [1]. The results of sputum smears and culture are often insensitive or slow to detect treatment failure and acquired drug resistance. The lack of biomarker assays for treatment monitoring is listed among the main requirements for next generation assays, as identified among the global TB community [2]. The surrogate CD8 response of QuantiFERON-TB Plus is a potential monitoring aid during treatment for active TB <http://ow.ly/2eNb308prn6>
An 18-gene blood-based IVD test for colorectal cancer early detection with high sensitivity and specificity.
Authors: Ye Xu, Qinghua Xu, Xun Ye, Fei Wu, Fang Liu, Li Yang, Guoxiang Cai, Cong Tan, Xia Meng, SanJun Cai, Xiang Du
Journal: Journal of Clinical Oncology (2012)

3551 Background: Colorectal cancer (CRC) is often curable particularly diagnosed at early stages. Different screening strategies are in place in various counties. However, the compliance rate with current CRC screening recommendations remains poor. A simple blood-based IVD test would represent an interesting alternative. We previously reported a 100-gene signature for early detection of CRC using microarray technology. Based on this result, we have developed a new blood test with real-time PCR technology. Methods: 144 CRC cases and 153 Controls were enrolled. A total of 52 genes were selected as candidate markers to be transferred from microarray to real-time PCR. The gene expression profiles from 100 CRC cases and 100 Controls were used as a training set for signature discovery. Signature identification process was conducted by Minimum Redundancy Maximum Relevance (mRMR) feature selection method and Support Vector Machine (SVM) classification algorithm under the Leave-One-Out Cross Validation (LOOCV) framework. The optimal size of signature was determined by a stepwise inclusion selection procedure which started with one gene and repeatedly added genes one by one until all genes were included. The performance of each N-gene signature by the LOOCV was estimated and used to determine the best size of signature. Results: The gene expression profiles measured by microarray and real-time PCR technology were highly comparable and resulted in a significant correlation in term of fold change ratio between CRC cases and Controls (Pearson’s Correlation Coefficient = 0.95). An 18-gene signature was identified and validated in an independent validation set with 44 CRC cases and 53 Controls. The performance of 18-gene signature in the validation set reached 88.7% accuracy (95%CI: 0.80-0.94), 88.6% sensitivity (95%CI: 0.75-0.96), and 88.7% specificity (95%CI: 0.76-0.95). Conclusions: Our new results demonstrated the feasibility of technology transfer from microarray to real-time PCR. The blood test could be offered to individuals who are unwilling or unable to undergo colonoscopy to increase the CRC screening compliance rate. Meanwhile, its high specificity could also help to avoid unnecessary colonoscopies.
Rituximab-Induced CD20-Mediated Signals and Suppression of PI3K-AKT Pathway Cooperates to Inhibit B-Cell Lymphoma Growth By Down-Regulation of Myc.
Authors: Tsuyoshi Nakamaki, Yuta Baba, Maasa Abe, Sou Murai, Megumi Watanuki, Nobuyuki Kabasawa, Kouji Yanagisawa, Norimichi Hattori, Yukiko Kawaguchi, Nana Arai, Shun Fujiwara, Bungo Saito
Journal: Blood (2016)
A matched case control study in veteran patients with high cardiovascular risk (CVR) examining cardiac medication (CMed) prescribing differences between prostate cancer (PC) patients on androgen deprivation therapy (ADT) and men without PC.
Authors: Yash R. Patel, Angela D. Reed, Marietta L. Moore, Angela C. Canfield, James A Kruer, Noah M. Hahn
Journal: Journal of Clinical Oncology (2012)

e15179 Background: Conflicting reports exist on associations between ADT and CVR in PC patients (pts). The current study tests the hypothesis that underutilization of CMeds in PC pts with known CVR contributes to their increased cardiac event rates. Methods: Veteran men without malignancy (no-PC, controls) and men with PC on ADT (cases) were consented through the IUSCC IRB-approved biorepository protocol. All pts had high CVR defined as the presence of &gt; 2 of the following: age &gt; 45, Body mass index (BMI) &gt; 30 kg/m 2 , hypertension (HTN), hyperlipidemia (HL), diabetes (DM), and smoking history (SmHx). Prior coronary artery disease (CAD) qualified pts as severe CVR. Each case was matched with 2 controls in the following order of priority: prior CAD, HTN, DM, HL, SmHx, age, BMI, and race. CMeds prescriptions included in the table below were verified via VAMC pharmacy records. CMeds prescription differences between cases and controls were tested by one-sided chi-Squared testing for each medication and by logistic regression for different classes of medications. Results: Between 1/2007 and 6/2011, 53 cases and 254 controls were enrolled in the IUSCC VAMC clinics. After 2:1 matching, the final cohort included 53 cases and 106 controls. Demographics included: prior CAD – 27%, HTN – 60%, DM – 31%, HL – 40%, SmHx – 63%, BMI – median 29.7 kg/m 2 , Age – median 66 yrs. Controls were younger than cases (71.4 yrs cases – 63.1 yrs controls, p&lt;0.0001). No statistically significant differences in CMed prescribing frequency were observed between the two groups. Conclusions: Differences in CMed prescribing practices between PC pts and no-PC men with high CVR is not a factor contributing to increased cardiac events in PC pts on ADT in our Veteran population. The study size warrants confirmation in a larger dataset. [Table: see text]
Observational study of ifosfamide (Ifos) neurotoxicity (N): The prospective use of a nursing assessment tool.
Authors: Jeanne Held-Warmkessel, Monica Davey, Samuel Litwin, John Lee, Mitchell Reed Smith, Michael M Millenson, Adam D. Cohen, Neeta Somaiah, Gary R. Hudes, Elizabeth R. Plimack, Yu-Ning Wong, Sharon Kim, Margaret vonMehren
Journal: Journal of Clinical Oncology (2012)

e19580 Background: Ifos chemotherapy is known to cause central nervous system toxicity. Risk factors have not been well identified in the literature, with limited information on the onset, duration, and severity of this toxicity. No clinical tools are available to assess and document N. Methods: We developed a clinical nursing assessment tool based upon review of the literature. Patients initiating inpatient Ifos chemotherapy, after informed consent was obtained under an IRB approved protocol, were prospectively monitored for signs and symptoms of N during 1 cycle of therapy. A full neurologic nursing assessment of 24 signs and symptoms including a hand writing sample was done at baseline and a basic assessment evaluating alertness, orientation, sense of well being and a hand writing sample was repeated every 12 hours. In the event N was identified, a full assessment was repeated; observed N was graded using the NCI CTC, version 3. Other variables collected were demographic traits, dose per day, hydration, and potential risk factors for N: renal function, albumin, largest pelvic tumor dimension, prior Ifos or cisplatin, use of other medications with potential for N, and alcohol use history. Individual factors were analyzed using Fisher’s exact test or the Wilcoxon two-sample test. Results: Eighty patients were accrued from 5/09-1/12. Median age was 54.5 (range: 21-85), 51% were males, PS 0 in 26.3%, 1 in 65%, 2 in 6.3% and 3 or 4 in 1.3% each. Diagnosis was sarcoma in 73.75%, lymphoma 22.5%, or germ cell tumor 3.75%. N was observed in 47.5% of patients. Toxicities in &gt;15% of patients were sleepiness (25%), lethargy and restlessness (16.25% for each), and dizziness (15%). The majority were grade 1-2 (89.6%). Factors associated with N included generic versus brand formulation of Ifos (p=0.041) and prior history of a drug related neurotoxicity (p=0.047). BSA, performance status, gender, age, dose per m2, total planned dose, pretreatment Cr, and pretreatment albumin were not associated. Conclusions: The incidence of Ifos N is common using this nursing assessment tool, although usually low grade. We identified the formulation of Ifos and a prior history of drug related N as statistically correlated with developing N.
Gemcitabine and capecitabine synergism and biomodulation with dipridamole in a mouse tumor model
Authors: G. Demir, H. O. Klein, S. Yildirim, I. Esen, T. Altug
Journal: Journal of Clinical Oncology (2006)

12034 Background and Aim: Gemcitabine and capecitabine are antimetabolites that are effective in the pyrimidine pathway of the DNA synthesis. Capecitabine through a 3-step activation process is transformed to 5-FU in the tumor cell by thymidine phosphorilase. On the other hand, gemcitabine interacts with the enzymes thymidine kinase, tymidine phosphorilase ve ribonucloetide reductase. Our hypothesis is based on a possible synergistic blockade by concurrent administration of these two antimetabolites. Additionally, dipridamole is an inhibitor of the nucleoside transport; and that can prolong the accumulation of antimetabolites within the tumor cell. In this study, combinations of these drugs are tested on an animal model. Methods and Results: 80 male balb-c mice were inoculated dorsally with 0.1 cc Ehrlich ascites tumor, and 10 days later the animals were separated into 5 groups having a similar tumor load. The control group received no treatment, while in the gemcitabine arm the animals received 50 mg/d gemcitabine on day 1. In the capecitabine arm, the animals received 1mg/day capecitabine administered in drinking water on days 1–4. In the gemcitabine + capecitabine combination arm, the animals received both treatments. In the gemcitabine + capecitabine + dipridamole arm, in addition to both of the drugs, dipridamole was also given 2mg/day in drinking water on days 1–4. In the control group (n=16) median survival was 17 days, while it was 33 days in gemcitabine arm (n=11), 35 days in capecitabine arm (n=14), and 44 days in the gemcitabine + capecitabine combination arm (n=22) which was significantly higher (p&lt;0.007). Dipridamole added to this combination (n=17) did not prolong survival any further. Conclusion: combination of gemcitabine with capecitabine suggests favorable results in an animal model. Testing of this combination in clinical trials seems to be justified. No significant financial relationships to disclose.
Association of epithelial to mesenchymal transition with efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild type.
Authors: Shengxiang Ren, ChunXia Su, Xiaoxia Chen, Jiayu Li, Bing Li, Xuefei Li, Caicun Zhou
Journal: Journal of Clinical Oncology (2012)

7535 Background: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype, it has a profound impact on cancer progression and treatment. The purpose of this study was to investigate the role of EMT to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) patients. Methods: We evaluated the correlation between EMT and sensitivity to EGFR-TKIs in advanced NSCLC patients. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, fibronectin, N-cadherin and vimentin and ARMs was used to detect the EGFR mutation in tumor specimens obtained before the treatment. The EMT phenotype status was determined according to the expression of E-cadherin, fibronectin, N-cadherin and vimentin. Results: 101 patients enrolled into this study and 97 had enough tissue to perform the EMT examination. The median age was 59 years old, male/female:56/45, never smoker/smoker: 71/30, adenocarcinoma/non-adeno: 73/28, PS 0-1/2-3: 83/18, Stage IIIB/IV: 2/99, 1st /2nd-4th line: 13/88. The response rate and progression free survival(PFS) in the whole population were 45.5% and 7.6 months respectively. EMT test revealed that 46(47.4%) samples were epithelial phenotype, while 51(52.6%) were mesenchymal phenotype. 38 of 79 patients harbour activating EGFR mutation. Among the patients with EGFR wild type or unknown status, patients with an epithelial phenotype had a higher response rate(40% Vs 17.6%, P=0.056) and significantly longer PFS(7.6 m Vs 3.8 m, P=0.045) than these with a mesenchymal phenotype. However, the response rate(85.7% Vs 64.7%, P=0.249) and PFS(15.2 m Vs 12.2 m, P=0.420) were similar in the patients with activated EGFR mutation. Conclusions: Patients with an epithelial phenotype got more benefit from the treatment of EGFR-TKIs in the advanced EGFR wild type NSCLC patients, which indicated that the EMT might be a potential marker to guide the individual therapy of EGFR-TKIs in this subpopulation.
Gastric acid suppressants are associated with risk of<i>C difficile</i>infection
Authors: Jacqui Wise
Journal: BMJ (2017)

Gastric acid suppressants should be stopped in patients with Clostridium difficile infection, researchers suggest in JAMA Internal Medicine .1

Their meta-analysis found that the use of proton pump inhibitors and histamine H2 receptor blockers was associated with a 50% higher risk of recurring C difficile infection than in patients who were not taking gastric acid …