tbuckley/cabot-search huggingface dataset:
<i>K-ras</i>Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Authors: Christos S. Karapetis, Shirin Khambata-Ford, Derek J. Jonker, Chris J. O'Callaghan, Dongsheng Tu, Niall C. Tebbutt, R. John Simes, Haji Chalchal, Jeremy D. Shapiro, Sonia Robitaille, Timothy J. Price, Lois Shepherd, Heather-Jane Au, Christiane Langer, Malcolm J. Moore, John R. Zalcberg
Journal: New England Journal of Medicine (2008)

Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value.We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups.Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97).Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. (ClinicalTrials.gov number, NCT00079066.)
<i>TMPRSS2-ERG</i> Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair
Authors: Alan Dal Pra, Emilie Lalonde, Jenna Sykes, Fiona Warde, Adrian Ishkanian, Alice Meng, Chad Maloff, John Srigley, Anthony M. Joshua, Gyorgy Petrovics, Theodorus van der Kwast, Andrew Evans, Michael Milosevic, Fred Saad, Colin Collins, Jeremy Squire, Wan Lam, Tarek A. Bismar, Paul C. Boutros, Robert G. Bristow
Journal: Clinical Cancer Research (2013)

Abstract Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) &amp;lt; 8, prostate-specific antigen (PSA) &amp;lt; 20 ng/mL; &amp;gt;7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response. Clin Cancer Res; 19(18); 5202–9. ©2013 AACR.
The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats
Authors: N.R. Simler, D.C.J. Howell, R.P. Marshall, N.R. Goldsack, P.S. Hasleton, G.J. Laurent, R.C. Chambers, J.J. Egan
Journal: European Respiratory Journal (2002)

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg·kg −1 ·day −1 ) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182±11% (mean±sem) compared with saline controls at 14 days (p&lt;0.001). The increase in lung-collagen accumulation was reduced by 75±12% (p&lt;0.01) in animals given SDZ RAD and was accompanied by a concomitant 56±6% (p&lt;0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.
Immunologic and Clinical Responses after Vaccinations with Peptide-Pulsed Dendritic Cells in Metastatic Renal Cancer Patients
Authors: Jan Wierecky, Martin R. Müller, Stefan Wirths, Edith Halder-Oehler, Daniela Dörfel, Susanne M. Schmidt, Maik Häntschel, Wolfram Brugger, Stephen Schröder, Marius S. Horger, Lothar Kanz, Peter Brossart
Journal: Cancer Research (2006)

Abstract A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell–based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-A2-binding MUC1 peptides (M1.1 and M1.2). For the activation of CD4+ T-helper lymphocytes, dendritic cells were further incubated with the PAN-DR-binding peptide PADRE. Dendritic cell vaccinations were done s.c. every 2 weeks for four times and repeated monthly until tumor progression. After five dendritic cell injections, patients additionally received three injections weekly of low-dose interleukin-2 (1 million IE/m2). The induction of vaccine-induced T-cell responses was monitored using enzyme-linked immunospot and Cr release assays. Twenty patients were included. The treatment was well tolerated with no severe side effects. In six patients, regression of the metastatic sites was induced after vaccinations with three patients achieving an objective response (one complete response, two partial responses, two mixed responses, and one stable disease). Additional four patients were stable during the treatment for up to 14 months. MUC1 peptide–specific T-cell responses in vivo were detected in the peripheral blood mononuclear cells of the six patients with objective responses. Interestingly, in patients responding to the treatment, T-cell responses to antigens not used for vaccinations, such as adipophilin, telomerase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. This study shows that MUC1 peptide–pulsed dendritic cells can induce clinical and immunologic responses in patients with metastatic RCC. (Cancer Res 2006; 66(11): 5910-8)
Frequency of replication errors in colorectal cancer and their association with family history
Authors: S R Brown, P J Finan, L Cawkwell, P Quirke, D T Bishop
Journal: Gut (1998)

Background —Replication errors (RERs) characterise tumours of hereditary non-polyposis colorectal cancer (HNPCC). RER status may therefore improve identification of such families previously diagnosed by family history alone. Aims —To assess RER and HNPCC frequency within a population of colorectal cancer patients and a regional population of family history defined (Amsterdam criteria) HNPCC families. Methods —Family history was assessed by personal interview in a population of 479 patients with colorectal cancer attending one follow up clinic. Seven fluorescently labelled microsatellites were used to investigate RER frequency in colorectal cancers from 89 patients of this population with varying degrees of family history and 20 Amsterdam criteria positive families (four with a known germline mutation, 16 with unknown mutation status) from the regional population. Results —Only four of the follow up population (0.8%) came from families meeting the Amsterdam criteria with only one showing RERs. The frequency of RERs was similar in the early onset cancer group (less than 50 years of age), those with a family history, and those with no family history of colorectal cancer. From the regional population, RERs were identified in 4/4 families with a mutation but only 8/16 families with unknown mutation status. Conclusions —No correlation was seen between RER status and strength of family history except in HNPCC families. Results also indicate that half of the Amsterdam criteria defined families do not exhibit RERs, perhaps suggesting a different mechanism of tumorigenesis.
Conditional Targeting of Tumor Necrosis Factor Receptor–Associated Factor 6 Reveals Opposing Functions of Toll-Like Receptor Signaling in Endothelial and Myeloid Cells in a Mouse Model of Atherosclerosis
Authors: Apostolos Polykratis, Geert van Loo, Sofia Xanthoulea, Martin Hellmich, Manolis Pasparakis
Journal: Circulation (2012)

Previous studies implicated Toll-like receptor signaling as a critical pathogenic pathway in atherosclerosis, but the cell-specific mechanisms by which Toll-like receptors act to control atherosclerotic plaque development remain poorly understood.To study the cell-specific role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in atherosclerosis, we generated ApoE(-/-) mice with endothelial cell- or myeloid cell-specific TRAF6 deficiency using Cre/LoxP-mediated gene targeting. Endothelial TRAF6 deficiency reduced atherosclerosis in female ApoE(-/-) mice by inhibiting nuclear factor-κB-dependent proinflammatory gene expression and monocyte adhesion to endothelial cells. In contrast, myeloid cell-specific TRAF6 deficiency caused exacerbated atherosclerosis, with larger plaques containing more necrotic areas in both male and female ApoE(-/-) mice. TRAF6-deficient macrophages showed impaired expression of the antiinflammatory and atheroprotective cytokine interleukin-10, elevated endoplasmic reticulum stress, increased sensitivity to oxidized low-density lipoprotein-induced apoptosis, and reduced capacity to clear apoptotic cells. Thus, the reduced antiinflammatory properties, coupled with increased sensitivity to apoptosis and impaired efferocytosis capacity of TRAF6-deficient macrophages, result in exacerbated atherosclerosis development in TRAF6(MYKO)/ApoE(-/-) mice.Toll-like receptor-mediated TRAF6 signaling acts in endothelial cells to promote atherosclerosis but displays atheroprotective, antiinflammatory and prosurvival functions in myeloid cells.
An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib
Authors: Christina Danial, Kavita Y. Sarin, Anthony E. Oro, Anne Lynn S. Chang
Journal: Clinical Cancer Research (2015)

Abstract Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449). Experimental Design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location. Results: The median duration of treatment with sonidegib was 6 weeks (range, 3–58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib. Conclusions: Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors. Clin Cancer Res; 22(6); 1325–9. ©2015 AACR.
Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial
Authors: Ulrich H Thome, Orsolya Genzel-Boroviczeny, Bettina Bohnhorst, Manuel Schmid, Hans Fuchs, Oliver Rohde, Stefan Avenarius, Hans-Georg Topf, Andrea Zimmermann, Dirk Faas, Katharina Timme, Barbara Kleinlein, Horst Buxmann, Wilfried Schenk, Hugo Segerer, Norbert Teig, Corinna Gebauer, Roland Hentschel, Matthias Heckmann, Rolf Schlösser, Jochen Peters, Rainer Rossi, Wolfgang Rascher, Ralf Böttger, Jürgen Seidenberg, Gesine Hansen, Maria Zernickel, Gerhard Alzen, Jens Dreyhaupt, Rainer Muche, Helmut D Hummler
Journal: The Lancet Respiratory Medicine (2015)
Association of Human Papillomavirus Type 58 Variant With the Risk of Cervical Cancer
Authors: Paul K S Chan, Ching-Wan Lam, Tak-Hong Cheung, William W H Li, Keith W K Lo, May Y M Chan, Jo L K Cheung, Augustine F Cheng
Journal: JNCI Journal of the National Cancer Institute (2002)

Human papillomavirus (HPV) type 58 has been found to be prevalent among Chinese patients with cervical cancer. This study examined the oncogenic risk of HPV58 variants in Hong Kong, a southern part of China. Altogether, 1924 women were studied: 42.8% with a normal cervix, 16.2% with cervical intraepithelial neoplasia (CIN) I, 12.7% with CIN II, 20.8% with CIN III, and 7.6% with invasive cervical cancer (ICC). The overall prevalence of HPV58 was 11.4% (220) and increased statistically significantly with the severity of neoplasia (Ptrend<.001, χ2 test for trend). Among HPV58-positive women, the occurrence of E7 632C→T (T20I) and E7 760G→A (G63S) variants (T20I/G63S) showed a positive trend of association with the severity of neoplasia (Ptrend<.001, χ2 test for trend). HPV58 variants carrying these two substitutions showed an odds ratio (OR) for ICC of 26.79 (95% confidence interval = 10.14 to 74.72), and this OR was 6.9-fold higher than the ORs of variants without these substitutions. Patients with CIN III or ICC who were also infected with T20I/G63S variants had a statistically significant younger age at diagnosis than those infected with other variants (median age = 37 years versus 48 years; P = .038, two-sided Mann–Whitney U test). Thus, HPV58 variants carrying E7 T20I/G63S substitutions may be associated with an increased risk for cervical cancer.
Subclinical Inflammation and Diabetic Polyneuropathy
Authors: Christian Herder, Mark Lankisch, Dan Ziegler, Wolfgang Rathmann, Wolfgang Koenig, Thomas Illig, Angela Döring, Barbara Thorand, Rolf Holle, Guido Giani, Stephan Martin, Christa Meisinger
Journal: Diabetes Care (2009)

Subclinical inflammation represents a risk factor of type 2 diabetes and several diabetes complications, but data on diabetic neuropathies are scarce. Therefore, we investigated whether circulating concentrations of acute-phase proteins, cytokines, and chemokines differ among diabetic patients with or without diabetic polyneuropathy.We measured 10 markers of subclinical inflammation in 227 type 2 diabetic patients with diabetic polyneuropathy who participated in the population-based MONICA/KORA Survey F3 (2004-2005; Augsburg, Germany). Diabetic polyneuropathy was diagnosed using the Michigan Neuropathy Screening Instrument (MNSI).After adjustment for multiple confounders, high levels of C-reactive protein and interleukin (IL)-6 were most consistently associated with diabetic polyneuropathy, high MNSI score, and specific neuropathic deficits, whereas some inverse associations were seen for IL-18.This study shows that subclinical inflammation is associated with diabetic polyneuropathy and neuropathic impairments. This association appears rather specific because only certain immune mediators and impairments are involved.
Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation
Authors: M.R. Bishop, R.M. Dean, S.M. Steinberg, J. Odom, S.Z. Pavletic, C. Chow, S. Pittaluga, C. Sportes, N.M. Hardy, J. Gea-Banacloche, A. Kolstad, R.E. Gress, D.H. Fowler
Journal: Annals of Oncology (2008)
A population-based study of the costs of care for community-acquired pneumonia
Authors: M. Bartolomé, J. Almirall, J. Morera, G. Pera, V. Ortún, J. Bassa, I. Bolíbar, X. Balanzó, A. Verdaguer
Journal: European Respiratory Journal (2004)

In a population-based study, the consumption of resources for treating adult patients with community-acquired pneumonia was determined. During a 2‐yr period, all cases with a clinical and radiological suspicion of community-acquired pneumonia that occurred in patients aged &gt;14 yrs in a community of 74,610 inhabitants were investigated prospectively. Of 292 cases with a suspicion of community-acquired pneumonia, 224 were included (18.5% misdiagnoses). The mean number of visits per patient was 4.5 (72% in the primary care setting). Inpatient care was recommended in 59.8% of cases; after discharge, 44% of patients were managed in outpatient clinics. The mean direct cost of pneumonia treated in the hospital setting was (euros)1,553, whereas the mean cost of cases treated as outpatients was 196. A total of 15.7% of admissions were considered inappropriate and the length of stay could have been reduced by 3.5 days in the most severe cases. A reduction in inappropriate admissions and lengths of hospital stay would result in a decrease in cost of 17.4%. Community-acquired pneumonia in Maresme, Spain, occurs at a low incidence, although with a high percentage of hospitalisations (in part inappropriate), resulting in considerable costs.
Neural respiratory drive in obesity
Authors: J Steier, C J Jolley, J Seymour, M Roughton, M I Polkey, J Moxham
Journal: Thorax (2009)

<h3>Background:</h3> The load imposed on ventilation by increased body mass contributes to the respiratory symptoms caused by obesity. A study was conducted to quantify ventilatory load and respiratory drive in obesity in both the upright and supine postures. <h3>Methods:</h3> Resting breathing when seated and supine was studied in 30 obese subjects (mean (SD) body mass index (BMI) 42.8 (8.6) kg/m<sup>2</sup>) and 30 normal subjects (mean (SD) BMI 23.6 (3.7) kg/m<sup>2</sup>), recording the electromyogram of the diaphragm (EMGdi, transoesophageal multipair electrode), gastric and oesophageal pressures. <h3>Results:</h3> Ventilatory load and neural drive were higher in the obese group as judged by the EMGdi (21.9 (9.0) vs 8.4 (4.0)%max, p&lt;0.001) and oesophageal pressure swings (9.6 (2.9) vs 5.3 (2.2) cm H<sub>2</sub>O, p&lt;0.001). The supine posture caused an increase in oesophageal pressure swings to 16.0 (5.0) cm H<sub>2</sub>O in obese subjects (p&lt;0.001) and to 6.9 (2.0) cm H<sub>2</sub>O in non-obese subjects (p&lt;0.001). The EMGdi increased in the obese group to 24.7 (8.2)%max (p&lt;0.001) but remained the same in non-obese subjects (7.0 (3.4)%max, p = NS). Obese subjects developed intrinsic positive end-expiratory pressure (PEEPi) of 5.3 (3.6) cm H<sub>2</sub>O when supine. Applying continuous positive airway pressure (CPAP) in a subgroup of obese subjects when supine reduced the EMGdi by 40%, inspiratory pressure swings by 25% and largely abolished PEEPi (4.1 (2.7) vs 0.8 (0.4) cm H<sub>2</sub>O, p = 0.009). <h3>Conclusion:</h3> Obese patients have substantially increased neural drive related to BMI and develop PEEPi when supine. CPAP abolishes PEEPi and reduces neural respiratory drive in these patients. These findings highlight the adverse respiratory consequences of obesity and have implications for the clinical management of patients, particularly where the supine posture is required.
Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel
Authors: Mirte M. Malingré, Dick J. Richel, Jos H. Beijnen, Hilde Rosing, Franciska J. Koopman, Wim W. Ten Bokkel Huinink, Margaret E. Schot, Jan H.M. Schellens
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m 2 with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m 2 . RESULTS: The mean (± SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m 2 without CsA was 0.37 ± 0.33 mg·h/L and 2.71 ± 1.81 mg·h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m 2 was 4.41 ± 2.10 mg·h/L. The absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.
Depression, Euthanasia, and Improving End-of-Life Care
Authors: Ezekiel J. Emanuel
Journal: Journal of Clinical Oncology (2005)

As a result [of medical progress], Americans are living longer, and when they finally succumb to illness, lingering longer, either in great pain or in a stuporous, semi-comatose condition that results from the infusion of vast amounts of pain killing medications. . .The now recognized right to refuse or terminate treatment and the emergent right to receive medical assistance in hastening one’s death are inevitable consequences of [these] changes.