tbuckley/cabot-search huggingface dataset:
A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (MAb), against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastastic, asymptomatic castration-resistant prostate cancer (CRPC)
Authors: C. Higano, J. Alumkal, C. J. Ryan, E. Y. Yu, T. M. Beer, K. Chandrawansa, T. Katz, H. Youssoufian, J. Schwartz
Journal: Journal of Clinical Oncology (2009)

5142 Background: IGF-IR-mediated signaling contributes to prostate cancer carcinogenesis and pathogenesis and may be associated with hormone resistance. IMC-A12 is a fully human IgG1 MAb that specifically targets the IGF-IR and inhibits ligand binding and signaling. In xenografts, IMC-A12 inhibits growth of both androgen-dependent and -independent prostate cancer. This phase 2, multicenter study was designed to assess the safety and antitumor activity of IMC-A12 in asymptomatic pts with metastatic CRPC who were chemotherapy-naive. Methods: Pts received IMC-A12 10 mg/kg IV every 2 wks; until evidence of progressive disease (PD), intolerable toxicity, or other withdrawal criteria were met. Radiologic evaluation was performed every 8 wks. PD by bone scan required at least 2 new lesions with confirmation at subsequent imaging per PCWG2. Results: 19 of 31 pts treated have discontinued IMC-A12, 12 due to PD. 9 of 31 pts experienced disease stabilization for ≥6 mos (range: 7.4–12.5 mos), 5 pts (3 with PSA reduction) continue on IMC-A12. The most common AEs possibly or probably related to IMC-A12, were fatigue (25.8%) and hyperglycemia (19.4%). In 4 pts cases of Grade 3 hyperglycemia was treatment related none requiring discontinuation of IMC-A12; 1 pt required insulin but continued on study. Approximately 70% of pts experienced at least transient elevation of nonfasting glucose to above normal range. Other AEs grade ≥3 at least possibly related to IMC-A12 were one case each of thrombocytopenia (requiring IMC-A12 discontinuation), hyperkalemia, fatigue, pneumonia (resulting in death), and Grade 4 pharmacokinetic and pharmacodynamic analayses are pending leukoencephalopathy (probably related; requiring IMC-A12 discontinuation). Pharmakinetic and pharmacodynamic analyses are pending. Conclusions: IMC-A12 monotherapy appears well tolerated in pts with metastatic asymptomatic CRPC. As in phase I, hyperglycemia was largely asymptomatic and manageable. Disease stabilization for &gt; 6 months in 9 of 31 pts suggests that IMC- A12 may have modest antitumor activity. Additional studies of IMC-A12 in CRPC are planned. [Table: see text]
Doctors fail to recognise acute respiratory distress syndrome, study finds
Authors: Jacqui Wise
Journal: BMJ (2016)

Acute respiratory distress syndrome (ARDS) is under-recognised and undertreated, and is associated with a high mortality rate, a study of intensive care units from 50 countries published in the journal of the American Medical Association ( JAMA ) has found.1

The observational study to understand the global impact of severe acute respiratory failure was carried out during four weeks in the winter of 2014 in a sample of 459 intensive care …
Quantitative Analyses of Early Tumor Shrinkage on Clinical Outcome in an Open, Non-Randomized, Multicenter Phase Ii Clinical Trial (Clime Study)
Authors: W. Zhang, S. Cai, W. Li, Y. Xu, W. Gu, Z. Guan, P. Chi, C. Song, J. Cai, J. Xu, J. Lin, K. Zhang, D. Li, X. Wang, H. Pei, X. Zhang, J. Wang, D. Wan, C. Dang, X. Yuan
Journal: Annals of Oncology (2014)
LSC 2011 Abstract: Production of alpha-1 antitrypsin (AAT) by pro- and anti-inflammatory macrophages and dendritic cells
Authors: Emily F.A. van 't Wout, Annemarie van Schadewijk, Nigel D.L. Savage, Jan Stolk, Pieter S. Hiemstra
Journal: European Respiratory Journal (2011)

AAT acts as an important neutrophil elastase inhibitor in the lung. Although the hepatocyte is considered as the primary source of AAT, local production by monocytes, macrophages and epithelial cells may contribute to the formation of an anti-elastase screen. Since monocytes can differentiate into a heterogeneous population of macrophages with subpopulations ranging from pro-inflammatory properties (M1) to anti-inflammatory properties (M2), and into dendritic cells (DC), we studied whether lipopolysaccharide (LPS), TNFα and oncostatin M (OSM) enhance AAT production differentially in cultured M1, M2 and DC.  Monocytes from healthy blood donors were cultured for 7 days in the presence of GM-CSF, M-CSF or GM-CSF + IL-4 to obtain M1, M2 and immature (i) DC, respectively. Next, cells were stimulated with LPS, TNFα or OSM and synthesis of AAT was assessed by quantitative RT-PCR and ELISA.  Spontaneous release of AAT was higher in M1 than in M2 and iDC after 24h (187 ng/10 6 cells vs 50 ng/10 6 c and 86 ng/10 6 c, p=0.016). LPS significantly increased AAT production in M1, M2 and DC (302 ng/10 6 c vs 97 ng/10 6 c and 248 ng/10 6 c, p=0.019), whereas TNFα and OSM did not affect AAT secretion. The secretion levels of the related proteinase inhibitor alpha-1 antichymotrypsin (ACT) were below the limits of detection by ELISA. Analysis by quantitative RT-PCR showed that 24h LPS exposure caused a maximal 2.1-fold AAT mRNA increase in M1, a 21-fold increase in M2 and 11-fold increase in DC.  We conclude that cultured M1 produce more AAT than M2 and DC, which is partly explained by a high spontaneous release of AAT by M1. This suggests that cellular differentiation is a regulator of local AAT production.
Latent Tuberculosis Infection Test Agreement in the National Health and Nutrition Examination Survey
Authors: Bijan J. Ghassemieh, Engi F. Attia, David M. Koelle, James D. Mancuso, Masahiro Narita, David J. Horne
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Latent tuberculosis infection (LTBI) test discordance is poorly understood.To determine the frequency and predictors of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFT) discordance in the U.S.We analyzed data from a representative sample of the U.S. population ages 6 years and older who participated in the 2011-2012 National Health and Nutrition Examination Survey. We determined prevalence estimates of test positivity, calculated test agreement and kappa statistics, and performed multivariable logistic regression to determine predictors of discordance.LTBI prevalence among the U.S. born ranged from 0.6% to 2.8%, depending on how LTBI was defined, with test agreement 97.0% and kappa 0.27 (95% confidence interval, 0.18-0.36). Prevalence among the foreign born ranged from 9.1% to 20.3%, depending on how LTBI was defined, with test agreement 81.6% and kappa 0.38 (95% confidence interval, 0.33-0.44). TST(+)/QFT(-) discordance was associated with age, male sex, black race, Mexican-American ethnicity, previous TB exposure, and past LTBI treatment in U.S.-born participants, but only with higher lymphocyte count in foreign-born participants. TST(-)/QFT(+) discordance was associated with older age, previous TB exposure, and past LTBI treatment in U.S.-born participants and with older age, male sex, and past LTBI treatment in foreign-born participants.In the largest population-based sample of concurrently performed TST and QFT tests in a low tuberculosis incidence population, prevalence estimates depended heavily on how LTBI was defined and test agreement was only fair. We identified several predictors of discordance warranting further study.
Proteolytic Cleavage of Recombinant Type 2A von Willebrand Factor Mutants R834W and R834Q: Inhibition by Doxycycline and by Monoclonal Antibody VP-1
Authors: Han-Mou Tsai, Ira I. Sussman, David Ginsburg, Hanneke Lankhof, Jan J. Sixma, Ronald L. Nagel
Journal: Blood (1997)
A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update
Authors: M. Von Mehren, P. Reichardt, P. G. Casali, J. Blay, M. Debiec-Rychter, H. Dumez, W. Cheung, B. Feifel, M. Veronese, G. D. Demetri
Journal: Journal of Clinical Oncology (2007)

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for &gt; 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to &gt; 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD &gt; 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.
Cyclophosphamide, doxorubicin and fluorouracil (CAF) plus the treatment of premenopausal women with metastatic breast cancer
Authors: C.I. Falkson, H.C. Falkson, G. Falkson
Journal: Annals of Oncology (1992)

A phase II study was undertaken to assess the effect of CAF plus depo-buserelin, as first-line treatment, in premenopausal women with breast cancer. Of 66 patients entered 60 are eligible and evaluable; their median age was 45, estrogen receptor (ER) was positive in 9, negative in 11 and unknown in 40. The median disease free interval (DFI) was 11 months. Metastatic sites were visceral in 14, bone in 34 and soft tissue in 37. Twenty-nine patients had metastatic disease of one site, while 31 had 2-4 sites. An objective response of 82% was documented (29 complete responders and 20 partial responders). Median time to treatment failure was 11.5 months and median survival 37 months. Most commonly encountered side effects attributable to CAF were alopecia, nausea and vomiting, leucopenia and thrombocytopenia. Side effects attributable to buserelin were hot flashes. After one cycle baseline mean serum estradiol fell from premenopausal levels to postmenopausal levels. This study showed that CAF plus buserelin is well tolerated, with a very high response rate in selected premenopausal patients with advanced breast cancer.
A phase I/II study of 24-hour infusional irinotecan (CPT-11) therapy in metastaic colorectal cancer
Authors: A. Tsuji, K. Kobayashi, Y. Shima, M. Hamada, Y. Nishioka, S. Morita, T. Horimi
Journal: Journal of Clinical Oncology (2005)

3673 Background: The efficacy of Irinotecan (CPT-11) for metastatic colorectal cancer (MCRC) is widely known. However 90-minute drip infusional CPT-11 therapy results in fair response rate compared to severe toxicity such as diarrhea and bone marrow suppression, because of low conversion rate from CPT-11 into SN-38 as active component of CPT-11. Therefore we conducted Phase I/II trial for MCRC 24-hour infusional Method: We survey the blood concentration of CPT-11, SN-38 and SN-38 for recommended dose of CPT-11. Material: MCRC patients who had received prior chemotherapy with 5-fluoropyrimidine are entered into this trial. Method: CPT-11 was administered 24-hour infusion weekly on day 1,8, and 15 every four weeks with weekly dose-up at 25 mg/m2 (Level 1), 40 mg/m2 (Level 2), 50 mg/m2 (Level 3), 65 mg/m2 (Level 4) according to response and toxicity. When object response is acquired or more than grade 2 toxicity, the dose-up is terminated. RESIST criteria was used to assess tumor response. The toxicity was estimated by NCI-CTC (ver.2). Median survival time was calculated by the Kaplan-Meier method. Pharmacokinetic profile: Blood concentrations of CPT-11, SN38 and SN-38G were measured before and 24, 72, 168, 336 hrs after administration of each course. Results: 25 patients were entered into this trial. Information is available for all patients. Characteristics were: mean age 58.0 (36- 79): male 17 (68%). The tumor shrinking effects were PR in 7 patients, SD in 2 and PD in the other 4 at Level 1 (n=13) and PR in 1 and SD in 5 at Level 2 (n=6) and PR in 4, SD in the other 1 at Level 3 (n=5) and PD in 1 at Level 4 (n=1), resulting in an overall response rate of 48.0%. Alopesia, general fatigue and appetite loss were chiefly occurred, while bone marrow suppression and diarrhea was rarely experienced. No Grade 3 or severe adverse events were noted at all Levels. Personal difference of Blood concentration of CPT-11, SN38 and SN38G was wide. Conclusion: Twenty-four hour infusion of CPT-11 has good anti-cancer effect and low toxicity. Step by step dose escalation from Level 1 brought to good anti-cancer effect without more than grade 3 toxicity. CPT-11 chemotherapy by using this method is promising for treatment as outpatient basis. No significant financial relationships to disclose.
Survivin protein expression predicts poor outcome in patients with primary breast cancer
Authors: B. Ryan, G. Konecny, S. Kahlert, H. Wang, J. Crown, M. Untch, M. Pegram, D. J. Slamon, M. J. Duffy
Journal: Journal of Clinical Oncology (2005)

547 Introduction: Survivin plays multiple roles in malignancy including inhibition of apoptosis, stimulation of proliferation and promotion of angiogenesis, and is up regulated in malignant tissues. Survivin is currently being investigated both as a target for new anticancer treatments and as a new tumor marker. The aim of this work was to study the expression and potential clinical value of survivin in breast cancer. Methods Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 399 patients with a median clinical follow up of 48 months. Results Survivin levels were significantly increased in high grade compared to low grade tumors (p<0.001), in hormone receptor-negative compared to receptor-positive tumors (p=0.011), in HER-2 positive versus HER-2 negative tumors (p<0.047) and in VEGF-positive versus VEGF-negative tumors (p<0.0001). Using Spearman correlation analysis, survivin levels correlated weakly but significantly with numbers of nodal metastases (r=0.11, p=0.024, n=388), total VEGF levels (r=0.23, p<0.0001, n=386) and VEGF165 levels (r=0.23, p<0.0001, n=386). Using the median value as a cut-off point, high levels of survivin were associated with both shortened disease-free (Log Rank test p=0.014) and overall survival (Log Rank test p=0.015). When categorized using the 25th, 50th and 75th percentiles as cut-off points, survivin was an independent predictor of disease-free survival (p=0.037), i.e., patients with the highest quartile of survivin levels had a significantly shorter disease-free survival period than those with the lowest quartile. Conclusions We conclude that increased expression of survivin is associated with adverse outcome in patients with primary breast cancer. These patients with high levels of survivin are potential candidates for treatment with new anti-survivin (e.g, antisense oligonucleotides) therapies. No significant financial relationships to disclose.
AB0140 Pathogenicity of Antibody Against Cyclic Citrullinated Peptide in Experimental Arthritis in Mice
Authors: S.M. Jung, J.H. Koh, H.K. Min, J.Y. Lee, J. Lee, J.H. Kim, S.-K. Kwok, J.H. Ju, K.-S. Park, C.-H. Yoon, S.-H. Park
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Antibodies against citrullinated peptides are specific to rheumatoid arthritis (RA), although its pathologic relevance has not been clearly understood. <h3>Objectives</h3> This study was undertaken to develop a novel anti-citrullinated petide antibody (ACPA) and to investigate the arthritogenecity of the ACPA in collagen-induced arthritis (CIA) model, the commonly used murine model of RA. <h3>Methods</h3> The novel ACPA, 12G1 was developed by injecting cyclic citrullinated antigen to mice and subsequently hybridizing the B cells producing citrullinated peptide-specific antibodies with myeloma cell line. Arthritic joints of mice with CIA and collagen antibody induced arthritis (CAIA) and IL-1Ra knockout mice underwent immunohistochemical staining with 12G1 antibody, and the staining pattern was compared. Confocal immunostaining was used to identify co-localization of 12G1 with various citrullinated peptides. 12G1 in the presence or absence of chelating bead was administered to mice with CIA on day 21 and 28 after type II collagen (CII) immunization to investigate the arthritogenecity of 12G1. <h3>Results</h3> 12G1 could detect citrullinated peptides in the arthritic joints of various experimental arthritis models. On confocal immunostaining of arthritic joints with 12G1, it was found to be co-localized with well-known citrullintaed peptides including vimentin, collagen, anti-immunoglobulin binding protein (BiP), and fibronectin. There was no difference in the staining pattern of citrullinated peptides between the different arthritis models. The injection 12G1 apparently showed comparable effect of a booster immunization in CIA mice with single immunization of CII, which was abolished when 12G1 was injected with chelating beads. <h3>Conclusions</h3> The novel ACPA, 12G1 identified various citrullinated peptides in the arthritic joints of various experimental arthritis models. 12G1-treated mice develop arthritis with single immunization of CII, which suggested arthritogenic potential of ACPA in CIA mice. <h3>References</h3> Sakkas, L. I., et al. (2014). Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment. Autoimmun Rev 13(11): 1114-1120. Vossenaar, E. R., et al. (2003). Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48(9): 2489-2500. <h3>Disclosure of Interest</h3> None declared
Screening for germline mutations in families at-risk for hereditary breast cancer in Southern Brazil
Authors: E. I. Palmero, P. Hainaut, S. A. Camey, C. M. Filho, D. R. da Cunha, P. K. dos Santos, S. L. Cossio, L. Schuler- Faccini, M. Caleffi, P. Ashton-Prolla
Journal: Journal of Clinical Oncology (2008)

22128 Background: In this study, we investigated the prevalence of hereditary breast cancer (HBC) syndromes and of germilne mutations in breast cancer predisposition genes, in a population-based cohort of women attending primary health care units in Brazil´s southernmost capital, Porto Alegre. Methods: All women were submitted to a questionnaire about family history (FH) of breast, ovarian and colorectal cancer. Those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis elicited criteria for the major HBC syndromes (hereditary breast and ovarian cancer, hereditary breast and colorectal cancer, and Li-Fraumeni/Li- Fraumeni-like syndromes), genetic testing was offered to the family, including BRCA1, BRCA2, TP53, and CHEK2 mutation analysis. Results: Of 902 women submitted to GCRA, 214 (23.7%) women from 183 families had pedigrees suggestive of HBC. Fifty of these families underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 germline mutations, respectively, and 7 for the CHEK2 1100delC mutation. No known deleterious mutations were identified in the HBOC families. In the LFL group, the R273C mutation was found in one family. The CHEK21100delC mutation was found in one of the seven families with hereditary breast and colorectal cancer phenotype. Conclusions: In spite of the relatively strict inclusion criteria, aimed at testing high risk families for HBC, the risk posed to most of these families remains unexplained. To our knowledge this is the first report of the prevalence of HBC phenotypes and germline mutations in corresponding breast cancer predisposition genes in a sample of at-risk individuals identified in a community-based cohort in South America. No significant financial relationships to disclose.
A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease
Authors: Jagpal Singh Klair, Ju Dong Yang, Manal F. Abdelmalek, Cynthia D. Guy, Ryan M. Gill, Katherine Yates, Aynur Unalp‐Arida, Joel E. Lavine, Jeanne M. Clark, Anna Mae Diehl, Ayako Suzuki
Journal: Hepatology (2016)

Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self‐reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of &lt;40 years) and time from menopause (age at study enrollment ‐ age at menopause, years) with fibrosis severity (stage 0‐4) were assessed using multiple ordinal logistic regression models with and without adjusting for clinical confounders. Among the participants (age at menopause 43.7 ± 8.6 years), women with premature menopause (29.3%) were younger at enrollment ( P &lt; 0.001) and used hormone replacement therapy more often ( P &lt; 0.003). After adjusting for age at enrollment, race, waist circumference standardized by body mass index, current smoking, current alcohol use, hypertension, diabetes/impaired fasting glucose, homeostatic model assessment of insulin resistance, and hormone replacement therapy, premature menopause was associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio = 1.9, 95% confidence interval 1.3‐2.7, P = 0.001), while time from menopause was directly associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio for 5‐year unit = 1.2, 95% confidence interval 1.1‐1.3, P = 0.002). Conclusion : Duration of estrogen deficiency in postmenopausal state confers fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. (H epatology 2016;64:85–91)
Abstract 13956: The Effect of Transfer Distance on Reperfusion Time of ST-Elevation Patients Transferred for Primary Percutaneous Coronary Intervention
Authors: Sa'ar Minha, Joshua P Loh, Lowell F Satler, Israel M Barbash, Marco A Magalhaes, Itsik Ben-Dor, Salem Badr, Alfazir Omar, Lakshmana K Pendyala, Hideaki Ota, Hironori Kitabata, Rebecca Torguson, Fang Chen, Kenneth M Kent, William O Suddath, Augusto D Pichard, Ron Waksman
Journal: Circulation (2013)