tbuckley/cabot-search huggingface dataset:
Value of educational visits in obstetrics
Authors: J. Pannikar, A. Farkas, R. Edmondson, P. Banfield
Journal: BMJ (1999)

Editor—We are not surprised by the conclusions drawn by Wyatt et al that educational visits added little to the uptake of evidence into practice.1 We question whether randomised controlled trials can be applied to studies evaluating education, which may use qualitative as well as quantitative methods.

A controlled trial may not be the appropriate tool to reflect changes of interventions in childbirth over time. It is not possible to isolate clinicians to one educational intervention (in this case an educational visit). Practice may also change as a result of experience as well as more formal learning such as reading journals and continuing medical education. Even if a change in practice had been shown by this study, a more qualitative approach would be required to determine if the change was due to the intervention being investigated. 

The practice of evidence based medicine is the integration of individual expertise with the best available external clinical evidence from systematic research.2 Research, whether primary or review, needs to be appraised critically. Only four interventions from the 600 reviews contained in the Cochrane Database of Systematic Reviews were studied. This included a systematic review on forceps versus ventouse delivery by one of the main researchers. This review is open to criticism since many of the papers selected were written by the author of the review.3 It would be disappointing if the practice of educational visits were to be discontinued solely on the evidence of this study.
Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors
Authors: T. Mekhail, T. Rich, L. Rosen, F. Chai, Z. Semic-Suka, R. E. Savage, N. Senzer
Journal: Journal of Clinical Oncology (2009)

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC 50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]
CD8 immunomagnetic selection and interleukin-15 (IL-15) facilitate the isolation of human CD8<sup>+</sup> cytotoxic T-lymphocytes (CTL) genetically engineered to express an anti-CD20 chimeric T-cell receptor (cTCR)
Authors: E. Y. Chen, O. W. Press, M. C. Jensen
Journal: Journal of Clinical Oncology (2004)

2542 Background. Primary human CD8+ CTL can be genetically modified to express a CD20-specific cTCR. We electroporated human peripheral blood mononuclear cells (PBMC) with an anti-CD20 cTCR expressing plasmid and cultured them with interleukin-2 (IL-2). G418-resistant transfectants were cloned and screened by flow cytometry for surface cTCR expression. To optimize the yield of cTCR-expressing clones for a planned phase I clinical trial treating patients with relapsed follicular non-Hodgkin's lymphoma (FL), we compared the utility of CD8 pre-selection and IL-15 with our standard culture method. Methods. CD8+ PBMC were selected by CliniMACS™ anti-CD8 immunomagnetic beads (Miltenyi Biotec) at 99% purity, electroporated with the cTCR plasmid and cultured with IL-2 or IL-15. Clones were phenotyped by flow cytometry. Cytotoxicity was assessed in vitro by a 51Cr release assay and in SCID mice by delay of hind limb paralysis (HLP) induced by a CD20+ Burkitt's lymphoma cell line (Ramos). Results. All IL-2 and IL-15 cultured clones (213/213) from CD8 selected PBMC were CD8+ CTL. Replacing IL-2 with IL-15 in our standard method (without CD8 selection) improved the percentage of CD8+ CTL clones obtained (9% vs. 56% or 9/105 vs. 31/55, respectively). Further analysis of 11 CD8+ clones derived from CD8+ PBMC showed that 9 had a natural killer-T cell phenotype. IL-15 cultured clones (n=54) exhibited greater mean anti-CD20 cytotoxicity than IL-2 cultured clones (n=12), measured by percentage of maximum 51Cr release in vitro (53% vs. 28%, respectively; p=0.00002). 7/7 SCID mice injected intravenously with Ramos cells developed HLP after a mean of 24 days (range 21–27 days); however only 1/5 mice treated with anti-CD20 CTL developed HLP after 79 days (p=0.001). Conclusions. CD20-specific CTL are cytotoxic in vitro and in vivo and CD8 selection and IL-15 facilitate the isolation of these clones. The methods described here are anticipated to improve the yield of anti-CD20 clones for a planned phase I clinical trial for the treatment of patients with relapsed FL. No significant financial relationships to disclose.
Abstract 16277: Hyperglycemia in Congestive Heart Failure Patients is Associated to Sympathetic Overactivity
Authors: Francesco Della Rosa, Fabien Despas, Marc Labrunee, Angelica Vaccaro, Michel Galinier, Jean-Michel Senard, Gianfranco Parati, Atul Pathak
Journal: Circulation (2013)

Background: sympathetic activation is a hallmark of acute and chronic heart failure (CHF). Recently, abnormalities of blood glucose concentrations at presentation, among patients with CHF, have bee...
Shared decision making for older, poor, newly diagnosed prostate cancer patients may not be feasible
Authors: A. Arseven, M. S. Wolf, E. A. Lyons, S. Pickard, R. M. Golub, S. J. Knight, K. Kramer, K. Colella, C. L. Bennett
Journal: Journal of Clinical Oncology (2004)

6086 Background: Shared decision making may be difficult for older prostate cancer patients of lower SES. Although physicians and patients make shared treatment decisions about the option of radiation, surgery, or watchful waiting, functional and psychosocial obstacles may limit the effectiveness of this process among older men of lower socioeconomic status with newly diagnosed prostate cancer. Methods: A cohort (n= 85) of lower socioeconomic status White (25%) and African American patients (75%), 65 year and older with newly diagnosed prostate cancer were queried on social support and evaluated for health literacy, hearing, vision, activities of daily living, nutrition, depressive mood, and cognitive and mobility function using validated tools including the Rapid Estimate for Adult Literacy in Medicine, Mini Nutritional Assessment Short Form, and the Vulnerable Elderly Survey. Results: Subjects were mainly low SES (29% within the poverty range) and African American (74.2%). Mean age was 72 years (SD = 5), and one third lived alone. Impairments identified included: <7th grade health literacy (30%); cognitive impairment (32%); vulnerable (increased risk of decline in activities of daily living and death) (15%); mobility (19%); poor nutrition (22%); visual impairment (8%); hearing impairment (21%); depressive mood (10%); and lack of social support (4%). Overall, 73% of patients had at least one impairment. Conclusions: We conclude that among older, lower SES prostate cancer patients, three quarters have functional and psychosocial impairments that may limit the feasibility of shared decision making approaches. No significant financial relationships to disclose.
The CXC-Chemokine Neutrophil-Activating Peptide-2 Induces Two Distinct Optima of Neutrophil Chemotaxis by Differential Interaction With Interleukin-8 Receptors CXCR-1 and CXCR-2
Authors: Andreas Ludwig, Frank Petersen, Stefan Zahn, Otto Götze, Jens-Michael Schröder, Hans-Dieter Flad, Ernst Brandt
Journal: Blood (1997)
Modeling targeted inhibition of wild type and mutated c-MET receptor
Authors: P. C. Ma, S. Jiang, R. Du, S. Dietrich, Z. Tang, J. A. Kern
Journal: Journal of Clinical Oncology (2007)

14010 Background: c-MET belongs to the semaphorin superfamily of signaling proteins, containing three protein families (semaphorins, plexins, c-MET and RON) that have central roles in cell signaling. The c-MET receptor tyrosine kinase is involved in regulating cell growth/proliferation, survival, angiogenesis, cell scattering, cell motility and migration. Mutations in c-MET have been identified in various human cancers including lung cancer and papillary renal cell carcinomas. c-MET mutations occur within the extracellular seven-blade β-propeller fold sema domain (E168D, L229F, S325G, N375S), juxtamembrane domain (R988C, T1010I), and kinase domain (M1268T). We hypothesized that these mutations would have differential effects on the kinase inhibition. Methods: We modeled the various c-MET mutations from different functional domains of the receptor using a G418-resistant stable Cos-7 transfection cell system to determine their effect on sensitivity to a selective c-MET kinase inhibitor SU11274. Sensitivity to SU11274 inhibition was assayed by phospho-immunoblotting using phospho- specific antibody against the major tyrosine kinase phosphorylation epitopes pY1234/1235 of the c-MET kinase in vitro. Results: First, we identified that mutations in the sema and juxtamembrane domain were activating as defined by ligand-independent constitutive receptor activation. SU11274 was capable of inhibiting ligand induced signaling through the wild-type c-MET as well as mutant c-MET receptors harboring mutations in the sema, juxtamembrane and tyrosine kinase domain. However, SU11274 inhibition of mutant c-MET was mutation-dependent, with the juxtamembrane domain mutations R988C and T1010I resulting in a receptor form that was less sensitive to SU11274. Mutations in the sema and kinase domain also resulted in varying sensitivity to inhibition by SU11274 inhibition. Conclusions: Mutations in the sema and juxtamembrane domain of c-MET result in receptor activation. The small molecule inhibitor SU11274 is active against wild type and mutated c- MET receptor. Further studies to characterize the signaling effects and the mechanism of sensitivity and resistance of c-MET mutations to specific inhibitors are crucial in the successful development of therapeutic c-MET and mutant c-MET inhibitors. No significant financial relationships to disclose.
A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor
Authors: Marc Jacquemin, Renaud Lavend'homme, Abdellah Benhida, Beatrijs Vanzieleghem, Roseline d'Oiron, Jean-Maurice Lavergne, Hans H. Brackmann, Rainer Schwaab, Thierry VandenDriessche, Marinee K. L. Chuah, Marc Hoylaerts, Jean Guy G. Gilles, Kathelijne Peerlinck, Jos Vermylen, Jean-Marie R. Saint-Remy
Journal: Blood (2000)
OCOG-ALMERA: A phase II trial investigating the ability of metformin to chemo-radio-sensitize and prevent recurrence in locally advanced (LA) non-small cell lung cancer (NSCLC)∗
Authors: T. Tsakiridis, P. Ellis, J.-C. Cutz, G. Pond, M. Wierzbicki, P. Kavsak, J. Wright
Journal: Journal of Thoracic Oncology (2016)
Randomized phase III study of 5-fluorouracil continuous infusion (5FUci) versus methotrexate and 5-FU sequential therapy (MF) in gastric cancer with peritoneal metastasis (JCOG0106)
Authors: K. Shirao, N. Boku, Y. Yamada, K. Yamaguchi, T. Doi, H. Takiuchi, J. Nasu, K. Nakamura, H. Fukuda, A. Ohtsu
Journal: Journal of Clinical Oncology (2009)

4545 Background: Gastric cancer (GC) with peritoneal metastasis (PM) often complicates ascites or intestinal stenosis and the prognosis is still poor. Anti-cancer drugs generally can not be administered for such patients (pts) due to the risk of serious and prolonged adverse events. However, 5FU-based chemotherapy is reportedly relatively safe for PM. We conducted a phase III study to investigate the superiority of MF over 5FUci for GC with PM with a primary endpoint of overall survival (OS) and secondary endpoints of toxicities, ingestion-possible survival (IPS) in pts with initially possible ingestion and proportion of ingestive improvement (%II) in pts requiring nutrition support. Methods: Eligibility criteria included pts with histologically proven gastric adenocarcinoma; inoperable or recurrent GC; PM with radiologically confirmed intestinal stenosis or ascites; 20–75 years old; PS 0–2; no prior treatment except surgery or adjuvant chemotherapy. Treatment with 5FUci (800mg/m 2 /d, civ, d1–5, q4w) or MF (methotrexate, 100mg/m 2 , iv, followed 3 h later by 5FU, 600mg/m 2 , iv, with leucovorin rescue, q1w) were continued until disease progression or unacceptable toxicities. Projected sample size was 236 in total, which had 80% power to detect 40% increase of median OS in MF with 1-sided alpha 0.05. Results: A total of 237 pts were randomized between Oct 2002 and Apr 2007. Final analysis was performed in Dec 2008 when 224 pts (95%) were dead. Results of OS are shown in Table . Median IPS was 8.1M for 5FUci(n=102) and 9.0M for MF(n=103) (p=0.60). %II was 41%(7/17) for 5FUci and 57%(8/14) for MF (p=0.48). Frequencies (%) of grade 4 neutropenia, grade &gt;3 febrile neutropenia, infection with neutropenia, anemia, anorexia, diarrhea, abdominal pain within 6M, and treatment related death (5-FUci/MF) were 0/9, 0/3, 0/5, 10/16, 27/34, 1/10, 5/10 and 2/1, respectively. Conclusions: MF could not become new standard therapy for GC with PM. [Table: see text] No significant financial relationships to disclose.
Neoplastic meningitis in unknown primary neoplasms
Authors: M. E. Loghin, M. D. Groves
Journal: Journal of Clinical Oncology (2006)

11517 Background: Neoplastic meningitis (NM) is diagnosed in 5–8% of patients with solid tumors. Unknown primary cancers (UPC) constitute 1% to 7% of NM cases. There is scattered data addressing NM in the context of UPC. Here we characterize the clinical manifestations, prognostic factors and survival outcomes in patients with NM from UPC. Methods: Through an IRB-approved, retrospective chart-review, spanning 1944–2002, we identified 38 patients with UPC, with NM either the presenting feature or a later manifestation of their systemic cancer. Imaging studies were also reviewed. Results: Median age at UPC diagnosis was 44 (13–72 years); for those patients not presenting with NM, time from UPC diagnosis to NM diagnosis was 10 weeks (range 3–60 weeks). Five patients presented with NM as the first and only manifestation of cancer, 1 presented with NM simultaneously with UPC, and 32 patients presented with UPC, followed by NM. Sixteen of those 32 patients presented with central nervous system (CNS) metastases concomitantly with their UPC diagnosis. The final cancer diagnoses were: melanoma (n=21), adenocarcinoma (n=12), small cell undifferentiated carcinoma (n=2), undifferentiated malignant tumor (n=1), Ewing sarcoma (n=1) and sarcomatoid carcinoma (n=1). The median overall survival after the initial diagnosis of UPC was 54 weeks (range: 6–344 weeks), and the median survival after the diagnosis of NM was 10.7 weeks (range: 2–132 weeks). Thirteen patients had a prolonged survival after the diagnosis of NM (24–132 weeks), 8 with melanoma, 3 with adenocarcinoma, 2 with small cell cancer. Six of the 8 melanoma patients with prolonged survival presented with only CNS disease, and none developed other metastatic sites during the course of their disease. Conclusions: Patients with NM and UPC have a poor prognosis. The most commonly identified primary tumors in patients with NM and UPC are melanoma and adenocarcinoma. UPC presenting as NM, and found to be melanoma limited to the CNS and or meninges, carries a better prognosis than other UPCs with NM where systemic tumor burden is identified. This may aid in the systemic diagnostic evaluation and treatment of such patients. No significant financial relationships to disclose.
True Evidence-Based Care for Posttraumatic Stress Disorder in Military Personnel and Veterans
Authors: Maria M. Steenkamp
Journal: JAMA Psychiatry (2016)

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Characteristics, oncogene dependency, and response to ponatinib of a novel transgenic mouse model of KIF5B-RET-induced lung adenocarcinoma
Authors: Qingling Huang, Valentina E. Schneeberger, Noreen Luetteke, Roha Afzal, Mikalai M. Budzevich, Rikesh Makanji, Gary V. Martinez, Domenico Coppola, Jie Wu
Journal: Journal of Thoracic Oncology (2016)
Osteopontin (OPN) vs. prostate-specific antigen (PSA) in benign prostatic conditions and prostate cancer (PCa)
Authors: P. Betta, F. Montefiore, F. Bonini, C. Rossi, N. Gastaldo, E. Arnolfo, M. Paganuzzi, R. Filiberti, D. Ugolini, R. Puntoni
Journal: Journal of Clinical Oncology (2008)

16062 Background: OPN is an integrin-binding protein over-expressed in various experimental models of malignancy and involved in tumourigenesis and metastasis. Increased levels of OPN have been also detected in a wide variety of human tumours from different body sites, including the prostate. OPN alterations occur early in tumour formation with dysregulated expression observed in lesions of low-grade prostatic intraepithelial neoplasia. To our knowledge the usefulness of plasma OPN determination in the early detection of PCa is yet to be established. On the other hand using the PSA test to screen men for prostate cancer is controversial because it is not yet known if this test actually saves lives. Our study aims at evaluating the hypothesis that combined plasma OPN and serum PSA determinations may improve the specificity of PSA alone and help distinguish men with PCa from those with benign prostatic hyperplasia (BPH). Methods: Serum total PSA using a chemiluminescent immunoassay system (Hybritech PSA, DxI Beckman Coulter, Inc.) and plasma OPN using an ELISA technique (R&D Systems, Inc.) were measured in 83 men referred for diagnostic prostate biopsy, including 35 patients with chronic prostate inflammation, 15 patients with BPH and 33 PCa patients. Results: A progressive increase of plasma OPN mean levels was observed from chronic prostate inflammation (31.83 ± 26.30 ng/ml) to BPH (38.29 ± 25.59 ng/ml) and PCa (41.94 ± 44.66 ng/ml), while PSA values are higher in PCa (12.92 ± 12.29 ng/ml) and lower in BPH (7.80 ± 5.77 ng/ml) with respect to chronic prostate inflammation (9.67 ± 7.07 ng/ml). OPN appears to better discriminate between chronic inflammation and BPH when compared to PSA. Conclusions: These preliminary findings point to a different role of OPN in the natural history of prostate cancer with respect to PSA and emphasize the need to further explore these two markers in a larger study, including healthy men, to better understand their meaning in the setting of the early diagnosis of PCa. (the study was funded by the Alessandria branch of the Italian League for the Fight against Cancer through a grant from the Cassa di Risparmio di Alessandria Foundation) No significant financial relationships to disclose.
Clinical Significance of HLA-DRB1*0410 in Japanese Patients With Idiopathic Thrombocytopenic Purpura
Authors: Shosaku Nomura, Tatsunori Matsuzaki, Yoshio Ozaki, Manabu Yamaoka, Chie Yoshimura, Kaoruko Katsura, Gui Lan Xie, Hideo Kagawa, Tomoko Ishida, Shirou Fukuhara
Journal: Blood (1998)
MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome
Authors: Joseph W. Wragg, Jonathan P. Finnity, Jane A. Anderson, Henry J.M. Ferguson, Emilio Porfiri, Rupesh I. Bhatt, Paul G. Murray, Victoria L. Heath, Roy Bicknell
Journal: Cancer Research (2016)

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.