tbuckley/cabot-search huggingface dataset:
Continuous daily dosing (CDD) of sunitinib malate (SU) compares favorably with intermittent dosing in pts with advanced GIST
Authors: S. George, J. Y. Blay, P. G. Casali, A. Le Cesne, J. A. Morgan, J. Pokela, M. T. Quigley, V. Tassell, C. M. Baum, G. D. Demetri
Journal: Journal of Clinical Oncology (2007)

10015 Background: SU, an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, is approved multinationally for the treatment of imatinib (IM)-resistant or -intolerant GIST. SU 50 mg/d on a 4/2 schedule (6-wk cycles: 4 wks on treatment, 2 wks off) has demonstrated efficacy and acceptable tolerability in pts with advanced IM-resistant GIST. The current study assesses the efficacy and safety of CDD of SU in this pt population. Methods: In this multicenter phase (ph) II trial, pts with IM-resistant/intolerant GIST were randomized to receive morning or evening dosing of SU 37.5 mg daily. The primary endpoint was clinical benefit rate (CBR; percentage of pts with confirmed CR, PR or SD for =24 wks per RECIST). Investigator-assessed efficacy and safety data compiled in this ph II study and an earlier ph III study were compared informally, and the PK of SU and its metabolite were also analyzed. Results: Of 61 pts randomized, 60 received treatment with SU (30 pts/arm; ITT population). At a median duration on study of 30 wks (range: 4–52+), 33 pts remain on study and 27 have discontinued. The SU dose was reduced to 25 mg/d in 9 pts due to AEs. The most common non-hematologic AEs of any cause (primarily grade [gr] 1/2) were diarrhea (40%), asthenia (38%) and fatigue (35%). Gr 3 AEs were asthenia (13%), fatigue (7%) and diarrhea (7%); gr 4 abdominal pain was reported in 3% pts. Hematologic toxicities included gr 3 anemia (10%), neutropenia (17%, all non-febrile) and thrombocytopenia (7%) and gr 4 anemia (3%). Toxicities were similar in the morning and evening dosing groups. Preliminary PK data indicated no unexpected accumulation with CDD. To date, median PFS is 27 wks (CI: 24–41) and overall CBR is 24%, including 11% pts with PRs, which compares favorably with results obtained with the approved regimen of SU 50 mg/d on the 4/2 schedule (N=207; PR: 7%; CBR: 25%; PFS 28 wks [CI: 14–34]; phase III study). Conclusions: SU is well tolerated and clinically active when given as 37.5 mg CDD in pts with IM- resistant/-intolerant GIST. The AE profile for SU CDD appears similar to that of the 4/2 schedule. Morning and evening dosing seem to have similar tolerability. SU CDD appears to be a safe and effective alternative dosing strategy for pts with IM-resistant/intolerant GIST. No significant financial relationships to disclose.
Automatic breast CAD results for seven categories of abnormalities.
Authors: J. P. Brockway, W. B. Carruthers, M. Zapata, R. B. Reiling
Journal: Journal of Clinical Oncology (2011)

5 Background: This prospective study was conducted to determine efficacy of preclinical use of automatic computer-aided cancer detection (CAD) system. Patients were women of high risk referred for MRI of breast with goals of assessing sensitivity/specificity of an automatic CAD platform which used kinetic and morphological (spiculation, volume, solidity, surface area, elongation, maximum extent) tools. We assessed classification of abnormality using histopathology as our gold standard. Methods: 1,976 patients with 2,149 abnormalities included were scanned from 2007 to 2010. Patient inclusion criteria were women: with dense breasts; BRCA1 or BRCA2 genes; family history of cancer; suspected of having recurrent cancer; anomalous mammogram/ultrasound; pain; or clinical suspicion. All patients included gave institutionally IRB approved HIPAA compliant informed consent. CAD software post-processing was automatically applied to dynamic contrast-enhanced MRI (DCE-MRI). One pre- and 4 post-scan series were used to calculate wash-in/out parameters. System's automatic detection was applied to entire breast(s) volume. No manually placed regions of interest were used. Results: Of 1,976 women scanned, 361 had mastectomies, 17 had bilateral mastectomies, 488 had lumpectomies/excisional biopsies, 623 had core biopsies, 166 had non-surgical approaches; radiation or chemotherapy. Mean tumor resected was 2.95 cm; SD=2.88 cm, while CAD detected breast tumor calculated size was 3.20 cm; SD=2.66 cm. Conclusions: Automatic CAD applied to breast DCE-MRI demonstrated high sensitivity, reasonable specificity, and accurate estimates for location within breast, and volume of malignancy. Automatic 3D CAD translucent display will aid oncology planners in tumor localization, volume and extent estimations. [Table: see text]
“Real-Time” Monitoring of Under-Five Mortality: A Vision Tempered by Reality
Authors: Jennifer Bryce
Journal: PLoS Medicine (2016)

Points• Civil registration and vital statistics (CRVS) systems have emerged as a major priority in the post-2015 development agenda, largely based on their assumed potential to generate population data for use in guiding investments and managing programs in low-income countries.• The evidence base on how best to design, implement, and sustain such systems is weak, especially for mortality statistics.There are global calls for new research and analysis to inform the CRVS agenda, whether the results are positive or negative.• The Real-Time Monitoring of Under-Five Mortality (RMM) project aimed to develop and test methods for producing estimates of child mortality for recent periods of one year or less.Three broad approaches were assessed: community-based reporting of vital events; calibration of facility data to represent deaths in the population; and rapid survey methods.• Between 2008 and 2013, we applied and rigorously evaluated at least two of these approaches in each of five countries in sub-Saharan Africa: Ethiopia, Ghana, Malawi, Mali, and Niger.• The RMM project, reported here as the PLOS Collection on RMM, has generated an important body of evidence that can inform efforts to strengthen CRVS in low-income countries and provides a foundation for continuing CRVS implementation research.
Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer
Authors: Scott T. Tagawa, Edwin M. Posadas, Justine Bruce, Emerson A. Lim, Daniel P. Petrylak, Weimin Peng, Thian Kheoh, Scott Maul, Johan W. Smit, Martha D. Gonzalez, Peter De Porre, NamPhuong Tran, David M. Nanus
Journal: European Urology (2016)
Expression profiles can predict both general chemotherapy and gemcitabine-specific responses in breast cancer patients receiving neoadjuvant therapy
Authors: D. S. Oh, L. A. Carey, C. Fan, L. Sawyer, Z. Hu, D. Ma, C. Perou
Journal: Journal of Clinical Oncology (2006)

10008 Background: The identification of markers predictive of neoadjuvant chemotherapy response would be an important advance. Therefore, we sought to identify gene expression profiles predictive of neoadjuvant response and evaluated their drug specificity. Methods: DNA microarray analysis was performed on pre-treatment core biopsies from two different locally advanced breast cancer patient sets receiving neoadjuvant chemotherapy; the first set (L9819) was treated with 4 cycles of doxorubicin + cyclophosphamide (AC) followed by 4 cycles of paclitaxel (T) or paclitaxel + trastuzumab (TH). The second patient set (S329) received 4 cycles of gemcitabine + doxorubicin followed by 4 cycles of gemcitabine + cisplatin. Clinical response was based on RECIST criteria. Results: We obtained successful microarrays on 44 (L9819) and 46 (S329) of the patients enrolled. Ten-fold cross-validated supervised analyses separately performed on each dataset identified gene expression patterns that accurately predicted (75–85% accuracy) response (clinical complete responders vs. others) evaluated on those patients that completed all 8 cycles of chemotherapy. The predictive expression patterns from the L9819 trial were significantly enriched for apoptosis genes, while the predictive gene set from the S329 trial was enriched for nucleotide metabolism genes. The L9819 predictor was able to accurately predict (75% accuracy) response for the S329 patients, however, the S329 predictor was not able to predict response on the L9819 trial (50% accuracy). We speculate that the L9819 predictor was able to predict response on the S329 dataset (despite the fact that only doxorubicin was common to both trials) because this profile was enriched for apoptosis genes that may reflect a general mechanism of chemotherapy response/resistance, while the S329 predictor was more tuned to gemcitabine’s specific mechanism of action. Conclusions: This study may provide the means to predict response to AC-T(H) and GA-GC neoadjuvant chemotherapy. The ability of one predictor to work on the other dataset, but not vise versa, suggests that both general chemotherapy and drug specific response profiles may have been identified. [Table: see text]
Malignant Lymphomas in Northeastern Brazill&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;
Authors: P. Correa, G. T. O'Conor, Adonis R. L. de Carvalho, M.D.
Journal: JNCI Journal of the National Cancer Institute (1973)

The main features of malignant lymphoma in Northeastern Brazil are: 1) an incidence of 4.30 per 100,000 populatiom 2) a Hodgkin's disease distribution pattern of Type II (Correa and O'Conor system); and 3) a low incidence of the so-called Burkitfs lymphoma. The paper includes general data on malignant tumors, in Brazil, for comparison.
Abstract P128: Type II Deiodinase Upregulation in Patients with End-Stage Dilated Cardiomyopathy
Authors: Kyle K Henderson, Andrew McElligott, Miensheng Chu, Nilam Patel, Jennifer T Paul
Journal: Circulation Research (2011)

Background: Dilated cardiomyopathy (DCM) is the most common form of heart disease, with a 50% survival rate 5yrs after diagnosis. Low thyroid hormone levels are an independent risk factor for heart failure progression. Recent studies in animal models with heart failure have shown re-expression of a fetal enzyme, type III deiodinase (D3) that functions to reduce thyroid hormone concentrations. Alternatively, an increase in β-adrenergic stimulation during heart failure may increase expression of type II deiodinase (D2) that would function to increase thyroid hormone concentration. We hypothesized that human hearts in end-stage dilated heart failure would have increased D3/D2 expression and lower myocardial and serum thyroid hormone concentrations. Methods and Results: Serum and left ventricular (LV) tissue from patients with dilated heart failure undergoing heart transplantation, and organ donors not meeting the criteria for heart donation were obtained with full consent and Institutional Review Board approval. Deiodinase expression was measures with real time rtPCR and thyroid hormone concentrations measured with radioimmunoassay. Interestingly, D3 expression and protein levels were not elevated in DCM patients vs. “non-failing” heart samples. On the other hand, D2 expression and protein levels were increased in DCM hearts and tended to have greater myocardial thyroid hormone concentrations (P =0.10). In spite of the increase in D2 expression in DCM patients, serum thyroid hormone concentrations were significantly lower than serum obtained from healthy volunteers, (P&lt;0.05). Changes in thyroid hormone receptors and thyroid hormone dependent downstream signaling changes for Akt, mTOR, and ERK are currently being investigated. Conclusions: Contrary to our hypothesis, patients with end-stage DCM have a reduced D3/D2 expression ratio and tend to have elevated myocardial thyroid hormone concentrations. Compensatory increases in D2 expression may enhance myocardial T3 production in DCM patients; however changes in thyroid hormone receptors and downstream signaling may negate this effect. Importantly, serum T3 concentrations were significantly reduced which likely contributed to patients progression toward end stage heart failure.
Abstract 12972: Reduction of Unnecessary Radiation Exposure for Cardiovascular Patients by Adoption of a Stress-First Protocol for Nuclear-Based Cardiac Stress Testing
Authors: Robert J Russo, Jordan Allem, Heather S Costa, Patricia D Silva
Journal: Circulation (2014)

Background: In 2010, the FDA issued the Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging. The purpose of this study was to determine the total radiation exposure for cardiovascular patients and the relative contribution of nuclear-based cardiac stress testing. Method: The electronic medical record was reviewed to identify all patients who underwent cardiac stress testing in 1 institution over a 10-year period. The type and number of all radiation-based diagnostic tests were identified, and a hospital-determined or published radiation dose was used to calculate each patient’s gender-specific total annualized radiation exposure expressed in mSv. Therapeutic radiation-based procedures were excluded. Results: Between 2003 and 2012, a total of 50,737 patients underwent 88,108 stress tests, 501,239 diagnostic radiology exams, and 17,194 diagnostic coronary angiograms, with 177,957 patient years of follow-up. Mean age at first stress test was 60±14 years, 56% of the patients were men, and the total number of stress tests per patient was 1.8±1.4 (range 1-18). When patients undergoing a nuclear-based stress test (PET-Rb/SPECT) at any time were compared to those who never had a nuclear-based stress test, 0.8±0.6 vs 0.7±0.4 total stress tests/year were performed, respectively (p&lt;.001), with a total radiation exposure (including stress tests, all radiology exams, and diagnostic coronary angiography) of 16.2±18.5 vs. 6.0±15.5 mSv/patient-year (p&lt;.001), and an aggregate total radiation exposure from diagnostic angiography of 16 vs. 11%. For patients undergoing a nuclear-based stress test at any time, the total aggregate radiation exposure from nuclear stress testing was 37% (for both men and women). If a stress-first/stress-only protocol was adopted, which would decrease isotope exposure by 75% as a result of administering only a single dose of isotope, using an institutional normal test rate of 57% over the study period, the aggregate radiation exposure from radiation-based testing dropped to 25% for the group. Conclusion: Adoption of a stress-first/stress-only protocol for nuclear-based cardiac stress tests results in a significant reduction in unnecessary radiation exposure for patients undergoing cardiac stress testing.
"Free" medical publishing venture gets under way
Authors: G. Eysenbach
Journal: BMJ (2003)

Medical staff need to be aware of major incident planningEditor-Last month the BMA warned that too few people in the United Kingdom know how to respond to a terrorist attack. 1 Its concerns about too few senior officials being aware of plans and recommendations to improve preparedness are sensible, but we believe that not enough medical staff are aware of their role in the event of a terrorist attack.We recently carried out a survey in the largest acute NHS trust of the south west of England to assess medical staff's knowledge about the local major incident plan.We sent questionnaires to the 107 doctors in North Bristol NHS Trust with a potential role in the mobile medical team if they were on duty during a major incident.Seventy seven doctors replied (72%).Sixty nine were aware of the existence of the local major incident plan, but only 26 had read part or all of it.Only 11 of the responding doctors were aware of their potential role in the mobile medical team.Of these 11 doctors, only three thought themselves adequately trained for this position, and all three had been trained as medical incident officers.Last year's National Audit Office report highlighted deficiencies in NHS plans to deal with major incidents in England. 2 It recommended upgrading training arrangements.Five months later some doctors are still unaware of their roles in the event of a terrorist attack.As a trust we are currently considering several measures to improve on our results.We suspect, however, that our findings are not unique and encourage other acute trusts to look closely at their staff's knowledge and training and act accordingly.
Transformation of Rat Lymph Node Cells By Simian Virus 40: Attempt to “Fix” Specialized Function&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Jeffrey J. Collins, Kurt J. Bloch, Paul H. Black
Journal: JNCI Journal of the National Cancer Institute (1970)

An attempt was made to obtain a continuous cell line able to produce monospecific antibody. Lymph node cells from rats hyperimmunized with dinitrophenyl bovine γ-globulin were infected in vitro with the oncogcnic DNA virus, simian virus 40 (SV40), under varying conditions in order to “fix” their specialized function. Some lymph node cell cultures were infected immediately, while others were first stimulated with either phytohemagglutinin or specific antigen. Four transformed cell lines were obtained 5–7 weeks after infection. No specific antibodies, rat immunoglobulins, or immunoglobulin fragments were detected in the culture medium or in extracts of transformed cells. The transformed cells resembled fibroblasts and produced small amounts of collagen. They did not produce reticulum nor did they have the staining properties of mast cells. The identity of the target cell for SV40 transformation is discussed, and the relationship between lymphocytes and fibroblasts is considered.
Clinical Activity of Crizotinib in Ros1-Rearranged Non-Small Cell Lung Cancer
Authors: A. Shaw, S.I. Ou, Y. Bang, R. Camidge, B. Solomon, R. Salgia, G.J. Riely, M. Varella-Garcia, G. Shapiro, D. Costa, R. Doebele, L.P. Le, Z. Zheng, P. Stephenson, S.M. Shreeve, L. Tye, J. Christensen, K. Wilner, J. Clark, A. Iafrate
Journal: Annals of Oncology (2014)
Randomized phase II/III trial comparing gemcitabine/carboplatin (GC) and methotrexate/carboplatin/vinblastine (M-CAVI) in patients (pts) with advanced urothelial cancer (UC) unfit for cisplatin-based chemotherapy (CHT): Phase III results of EORTC study 30986.
Authors: M. De Santis, J. Bellmunt, G. Mead, J. M. Kerst, M. G. Leahy, G. Daugaard, T. Gil, J. P. Maroto, S. Marreaud, R. Sylvester
Journal: Journal of Clinical Oncology (2010)

LBA4519 Background: About 50% of pts with advanced UC are not eligible for cisplatin based CHT (“unfit”) due to impaired renal function, performance status (PS) or comorbidity. This is the first randomized phase II/III trial comparing two chemotherapy regimens in this pts group. Methods: The primary objective of the phase III part of this study was to compare the overall survival (OS) of CHT naïve pts with measurable disease and an impaired renal function (GFR&lt;60 but &gt;30 ml/min) and/or PS 2 who were randomized to receive either GC (G 1000 mg/m 2 d1 and 8 and C AUC 4.5) q21 days or M-CAVI (M 30 mg/m 2 d1 and 15 and 22, C AUC 4.5 d1 and VI 3 mg/m 2 d1 and 15 and 22) q28 days. In order to detect an increase of 50% in median survival on GC compared to M-CAVI (13.5 versus 9 months) based on a two sided logrank test at error rates alpha=0.05 and beta=0.20, 225 pts were required. Secondary endpoints were overall response rate (ORR) and progression free survival (PFS). Results: 238 pts, 119 in each arm, were randomized between January 2001 and March 2008 by 29 institutions. The median follow-up is 4.5 years. Two pts were ineligible and two other pts never started treatment. Best ORRs (CR + PR) were 41.2% (36.1% confirmed response) on GC versus 30.3% (21.0% confirmed response) on M-CAVI (p = 0.08). Median OS was 9.3 months on GC and 8.1 months on M-CAVI (p = 0.64). There was no difference in PFS between the two arms (p = 0.78). OS, PFS and ORR were similar in each of the risk groups (reason unfit for cisplatin and Bajorin risk group). Severe acute toxicity (SAT) (death, grade 4 thrombocytopenia with bleeding, or grade 3/4 renal toxicity, neutropenic fever or mucositis) was observed in 9.3% of pts on GC (2 toxic deaths) and 21.2% on M-CAVI (4 toxic deaths). The most common grade 3/4 toxicities were leucopenia (44.9%, 46.6%), neutropenia (52.5%, 63.5%), febrile neutropenia (4.2%, 14.4%), thrombocytopenia (48.3%, 19.4%), and infection (11.8%, 12.7%) on GC and M-CAVI, respectively. Conclusions: There were no significant differences in efficacy between the two treatment groups. The incidence of SATs was slightly higher on M-CAVI. [Table: see text]
Induction of the TGF-beta pseudoreceptor BAMBI by nontypeable haemophilus influenzae (NTHi) and its impact on TGF-beta induced effects
Authors: Dorothee Wilpsbaeumer, Kristina Rohmann, Jan Rupp, Peter Zabel, Sebastian Marwitz, Torsten Goldmann, Klaus Dalhoff, Daniel Droemann
Journal: European Respiratory Journal (2014)

NTHi is the most frequently isolated pathogen in acute exacerbations of COPD. NTHI induces the TGF-beta Pseudoreceptor BAMBI, which has been shown to act as an antagonist on TGF-beta signaling.

To investigate the effects of BAMBI expression, experiments were performed in A549 cells and lung tissue of a mouse model (BAMBI+/+mouse vs. BAMBI-/-mouse). A549 cells were transfected with BAMBI-si-RNA and murine lung tissue was cultivated ex vivo . The cytokine release has been investigated by ELISA and Multiplexanalysis of cell- and tissue-supernatants.

After in vitro and ex vivo -infection, marked proinflammatory effects of A549 cells and murine lung tissue, measured as the secretion of CXCL-8, were observed (A549: Med 24h 507+96 pg/ml vs. NTHi 106 cfu/ml 24h 1391+250 pg/ml, p<0,01, n=7; lung BAMBI +/+mouse Med 24h 15902+7277 pg/ml vs. NTHI 106 cfu/ml 24h 98622+ 11709 pg/ml, p<0,01, n=6; lung BAMBI -/-mouse: Med 24h 26662+5640 pg/ml vs. NTHI 106 cfu/ml 24h 102954+8642 pg/ml, p<0,01, n=10).

Furthermore we demonstrated that there was a significant decrease of TGF-beta secretion after stimulation (Med 24h 1188+148 pg/ml vs. NTHi 106cfu/ml 24h 1004+98 pg/ml, p<0,05), whereas the TGF-beta secretion increased after transfection with BAMBI-si-RNA (Med 24h 1112+107 pg/ml vs. NTHi 106cfu/ml 24h 1252+134 pg/ml, p=0,05, n=5).

Our results show the inhibitory effect of BAMBI on TGF-beta signalling after infection with NTHi. Additionally there are indications of antinflammatory effects of BAMBI in the knockout model.

This mechanism moght have relevant influence on lung tissue remodeling and repair functions after chronic infections in COPD patients.
Development and deployment of a rapid recombinase polymerase amplification Ebola virus detection assay in Guinea in 2015
Authors: Oumar Faye, Ousmane Faye, Barré Soropogui, Pranav Patel, Ahmed Abd El Wahed, Cheikh Loucoubar, Gamou Fall, Davy Kiory, N’Faly Magassouba, Sakoba Keita, Mandy Kader Kondé, Alpha Amadou Diallo, Lamine Koivogui, Helen Karlberg, Ali Mirazimi, Oliver Nentwich, Olaf Piepenburg, Matthias Niedrig, Manfred Weidmann, Amadou Alpha Sall
Journal: Eurosurveillance (2015)

In the absence of a vaccine or specific treatments for Ebola virus disease (EVD), early identification of cases is crucial for the control of EVD epidemics. We evaluated a new extraction kit (SpeedXtract (SE), Qiagen) on sera and swabs in combination with an improved diagnostic reverse transcription recombinase polymerase amplification assay for the detection of Ebola virus (EBOV-RT-RPA). The performance of combined extraction and detection was best for swabs. Sensitivity and specificity of the combined SE and EBOV-RT-RPA were tested in a mobile laboratory consisting of a mobile glovebox and a Diagnostics-in-a-Suitcase powered by a battery and solar panel, deployed to Matoto Conakry, Guinea as part of the reinforced surveillance strategy in April 2015 to reach the goal of zero cases. The EBOV-RT-RPA was evaluated in comparison to two real-time PCR assays. Of 928 post-mortem swabs, 120 tested positive, and the combined SE and EBOV-RT-RPA yielded a sensitivity and specificity of 100% in reference to one real-time RT-PCR assay. Another widely used real-time RT-PCR was much less sensitive than expected. Results were provided very fast within 30 to 60 min, and the field deployment of the mobile laboratory helped improve burial management and community engagement.