tbuckley/cabot-search huggingface dataset:
Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study
Authors: M. Saunders, E. Van Cutsem, R. Wilson, M. Peeters, R. Smith, A. Godwood, S. Oliver
Journal: Journal of Clinical Oncology (2007)

4085 Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1 st - or 2 nd -line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m 2 1.5-hr and leucovorin 400 mg/m 2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg 2 i.v. bolus and 5-FU 2400 mg/m 2 46–48-hr i.v. infusion). If &lt;2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.
The effect of prostaglandin E2 on mRNA expression and secretion of collagens I, III, and IV and fibronectin in cultured rat mesangial cells.
Authors: G Zahner, M Disser, F Thaiss, G Wolf, W Schoeppe, R A Stahl
Journal: Journal of the American Society of Nephrology (1994)

The possible role of prostaglandin E2 (PGE2) on the formation of collagens and fibronectin in cultured rat mesangial cells (MC) was studied. The effect of exogenous PGE2 was analyzed by the measurement of steady-state mRNA levels of the extracellular matrix components and by the secretion of these matrix components into cell culture supernatants. PGE2, in a dose-dependent manner, reduced mRNA levels of alpha 1(I) and alpha 1(III) procollagens but had little effect on alpha 1(IV) procollagen and fibronectin mRNA. In addition to its role on mRNA levels, PGE2 reduced the secretion of all studied collagen types into the cell culture supernatants. To evaluate a possible role of intracellular cAMP in the mediation of the PGE2 effects, MC were incubated with the cAMP analogue 8-bromo-cAMP (8brcAMP). In contrast to PGE2, 8brcAMP (1 mM) had no effect on mRNA expression of procollagen Types I and III over the studied time period (1 to 48 h). Furthermore, 8brcAMP stimulated collagen secretion into the cell supernatant after 48 h of incubation. These data demonstrate that PGE2 reduces mRNA levels of procollagen Types I and III in cultured MC, although the biosynthesis of all studied extracellular matrix components is inhibited. These alterations seem to be independent of intracellular cAMP, because the cAMP analogue 8brcAMP does not mimic the PGE2 effects on steady-state mRNA expression and collagen secretion of the studied extracellular matrix components.(ABSTRACT TRUNCATED AT 250 WORDS)
Definitive chemoradiation therapy with capecitabine in locally advanced pancreatic cancer
Authors: S. Yi, H. S. Kim, J. Lee, S. Park, Y. Park, H. Lim, W. Kang, H. Park, D. Lim, J. O. Park
Journal: Journal of Clinical Oncology (2009)

e15558 Background: We evaluated safety and efficacy of concurrent chemoradiotherapy (CCRT) with capecitabine in patients with locally advanced pancreatic cancer (LAPC). We also tried to devise a prognostic model for LAPC undergoing definitive CCRT. Methods: Between January 2004 and January 2008, 39 patients with LAPC treated with capecitabine CCRT were reviewed. Capecitabine was administered at 850 mg/m 2 bid every day for 5 weeks. Radiotherapy was given 5 days per week, at 1.8 Gy fractions, over the 5 weeks. Results: Thirty seven (94.8%) patients completed CCRT, and 2 patients removed during the treatment for toxicity issues. Of the 36 evaluable patients, 15 (41.7 %) patients achieved partial response, and 13 (36.1 %) had a stable disease with 77.8% of disease control rate. Among the 28 patients who had achieved disease control after CCRT, 8 patients (21.6 %) received gemcitabine-based post-CCRT chemotherapy without dose reduction or delay. With median 1.8 years of follow- up, the overall survival was 14.3 months (95% confidence interval [CI]; 10.6–17.9 months). Median progression free survival was 11.1 (95% CI 7.2–15.1) for all patients, and 7.9 months (95% CI 6.6–9.2) for those not received post-CCRT chemotherapy. No patient had grade 4 hematologic or non-hematologic toxicity. Eight patients (21.6%) had severe grade 3 toxicities, 7 (18.9%) with gastrointestinal toxicity and 1 (2.7%) with hematologic toxicity. Prognostic factors for survival were serum albumin (P=0.014; relative risk [RR], 3.4; 95% CI, 1.4, 8.6), and adjuvant gemcitabine treatment (P = 0.005; RR, 3.5; 95% CI, 1.2, 10.6). The prognostic grouping resulted in three groups with significantly different prognosis: group 1 (0 adverse factor; n=8; 1-year survival, 87.5%), group 2 (1 adverse factor; n=23; 1-year survival, 52.9%) and group 3 (2 adverse factors; n=8; 1-year survival, 25.0%). Conclusions: Combined therapy with capecitabine CCRT was well tolerated. Capecitabine seems to be a promising regimen in the treatment of LAPC, in terms of response, survival, and tolerable adverse effects. No significant financial relationships to disclose.
Pulmonary fungal infection in immunocompetent vs immunocompromised patients - a retrospective study
Authors: Ana Silva, Rui Tomé, Maria Alcide Marques
Journal: European Respiratory Journal (2014)

Introduction: Fungal infection is a rare condition in immunocompetent individuals and it is associated with high rates of morbimortality. Aims and objectives : To determine the prevalence of pulmonary infections in immunocompetent (ICT) and immunocompromised (ICP) patients with a purpose of identifying risk factors and compare parameters that allow a better characterization of these patients. Methods : A retrospective study of all patients diagnosed with pulmonary fungal infections, during the year 2012, at Coimbra University Hospital. The following data was assessed: Epidemiology, laboratory and radiological features, microbiology, treatment and risk factors. Results : The medical sample consisted of 62 patients, 30 ICT and 32 ICP. There was a female predominance (62.5%) in the first group and male (73%) in the latter. The average age ranged between 65.97±16 years in ICT and 61.5±15 in ICP. We observed a high frequency of Aspergillus fumigatus in both groups. The presence of other non-fungal infectious agents affected 22% ICT and 33% ICP. Regarding the radiological findings, the majority of patients showed bilateral parenchymal infiltrates. The main diagnoses in ICP were hematologic malignancies (27%), while structural abnormalities (bronchiectasis) and COPD were observed in ICT patients in 13% of cases each. In most patients the choice was monotherapy. Conclusions : There is similar prevalence of this type of infection in immunocompetent patients; non fungal infectious agents are invariably present in this fungal infection in both groups; of the patients with lung pathology, the most affected had COPD or bronchiectasis.
Abstract 12743: Prolonged Duration of Myocardial Early Systolic Lengthening Predicts Late Coronary Restenosis and New Coronary Lesion after Coronary Intervention
Authors: Jun Koyama, Masatoshi Minamisawa, Ayako Kozuka, Hirohiko Motoki, Atsushi Izawa, Takeshi Tomita, Yusuke Miyashita, Uichi Ikeda
Journal: Circulation (2013)

Introduction: Recent study suggested that ischemic myocardium with reduced active force will lengthen when left ventricular (LV) pressure rises during early systole before onset of systolic shorten...
Phase II trial of bleomycin, ifosfamide, and carboplatin in metastatic cervical cancer.
Authors: A M Murad, S A Triginelli, J C Ribalta
Journal: Journal of Clinical Oncology (1994)

PURPOSE A bleomycin, carboplatin, and ifosfamide (BIC) chemotherapy protocol was designed to evaluate tumor response and palliation in patients with advanced cervical cancer. PATIENTS AND METHODS Forty patients with stage IV primary or recurrent squamous cell carcinoma of the cervix (19 previously irradiated and 21 nonirradiated) were assigned to treatment with six cycles of BIC: bleomycin, 30 mg bolus on day 1; carboplatin, 200 mg/m2 bolus on day 1; and ifosfamide, 2g/m2 for 3 consecutive days, infused over 2 hours. Mesna was administered as a bolus 15 minutes, and 4 and 8 hours after ifosfamide at 20% (intravenous [IV]), and 40% (orally, at home) of the ifosfamide dose, respectively. RESULTS Thirty-five patients (27 stage IVA and eight stage IVB) were considered eligible for response and toxicity evaluation. After a median of four cycles (maximum of six in responders), we observed objective responses in 21 patients (60%), with eight complete responses (CRs; 23%), including two histologically documented by laparotomy, and 13 (37%) partial responses (PRs) (95% confidence limits, 44% to 76%, 9% to 37%, and 21% to 53%, respectively). Median overall survival duration was 11 months (range, 3 to 24+). Median overall survival duration in the nonirradiated group was 17 months versus 4 months in the previously irradiated group (P = .005). The median progression-free survival duration of the responders was 12 months, and the median disease-free survival duration of the complete responders was 14 months. Toxicity was acceptable and included manageable alopecia, vomiting, and neutropenia. There was one toxic death due to febrile neutropenia and sepsis. CONCLUSION BIC can be administered on an outpatient basis and seems to be effective in inducing tumor response and palliation in patients with disseminated squamous cell carcinoma of cervix, with a possible survival benefit for previously nonirradiated patients, with an acceptable toxicity profile.
Early life exposure to traffic-related air pollution and lung function in adolescence
Authors: Erica Sofia Schultz, Jenny Hallberg, Tom Bellander, Anna Bergström, Matteo Bottai, Olena Gruzieva, Per Thunqvist, Magnus Wickman, Göran Pershagen, Erik Melén
Journal: European Respiratory Journal (2013)

Introduction: Exposure to air pollution during infancy has been related to lung function decrements in 8-year old children (Schultz et al AJRCCM 186(12):1286-91.), but whether the negative effect remains into adolescence is unknown.

Aims and objectives: To assess the role of long-term exposure to air pollution on lung function at 16 years of age.

Methods: Over 1600 children in the Swedish birth cohort BAMSE performed dynamic spirometry at 16 years of age. Outdoor concentrations of nitrogen oxides (NOx) from road traffic were estimated for residential, daycare and school addresses from birth up to 12 years of age using an emission inventory and dispersion modelling. The relationship between time-weighted average exposure during different time windows and forced expiratory volume in one second (FEV1) was analyzed by linear regression.

Results: A 5-95th percentile difference (corresponding to 48 µg/m3) in average traffic NOx exposure during the first year of life was associated with a reduced FEV1 of -111 ml, 95% confidence interval (CI) -210 to -12, at 16 years of age. Exposure after the first year of life showed no clear effects. The negative association between first year exposure to NOx and FEV1 appeared particularly pronounced in boys (-192 ml, 95% CI: -192 to -28). Associations were also suggested between first year of life exposure to NOx and clinically important lung function deficits of less than 80% of predicted FEV1 with an odds ratio of 2.6 (95% CI 0.9 to 7.4).

Conclusions: Our results indicate that exposure to traffic-related air pollution during infancy negatively affects lung function in adolescents at 16 years of age.
Creeping censorship occurs
Authors: S. J Rose
Journal: BMJ (1995)

EDITOR,—I was appalled to hear the response of Alan Langlands, the chief executive of the NHS Executive, on BBC Radio 4's Today programme (16 December 1994) to Naomi Craft and colleagues' articles.1 He accused the BMJ of sensationalism and said that there was no place for secrecy (I believe that he qualified this to commercial secrecy) within the NHS. I …
Results of subset analyses on overall survival (OS) from study CA184-043: Ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC).
Authors: Charles G. Drake, Eugene D. Kwon, Karim Fizazi, Alberto Bossi, Alfons JM van den Eertwegh, Christopher Logothetis, Howard I. Scher, Tomasz M. Beer, Brent McHenry, David Liu, Winald R. Gerritsen
Journal: Journal of Clinical Oncology (2014)

2 Background: The CA184-043 phase 3 study did not reach statistical significance for its primary endpoint of OS (HR=0.85, p=0.053). However, antitumor activity was observed in other efficacy endpoints, including progression-free survival. Prespecified subset analyses were performed to understand if any prognostic features may identify mCRPC patients (pts) more likely to benefit from Ipi treatment. Methods: 799 pts were randomized to receive a single dose of radiotherapy (RT) followed by either Ipi (N=399) or Pbo (N=400). Prespecified subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Prespecified subset analyses suggested that Ipi may be more active in pts with favorable prognostic factors, including no visceral disease, alkaline phosphatase &lt;1.5 ULN, and hemoglobin ≥11 g/dL (Table). The safety profile in this study was consistent with previous reports of Ipi. Conclusions: Based on these subset analyses, Ipi added to RT appears to have greater activity than RT alone in pts with a favorable prognostic profile. These results support continued investigation of Ipi in the ongoing CA184-095 study in chemotherapy-naive mCRPC pts. Clinical trial information: NCT00861614. [Table: see text]
Long Term Effects of Telmisartan on the Inflammation, Oxidative Stress and Myocardial Impairment Induced by Epirubucin
Authors: A Piras, Christian Cadeddu Dessalvi, M Dessì, G Binaghi, Martino Deidda, Elena Massa, Clelia Madeddu, G Mantovani, Giuseppe Mercuro
Journal: Circulation (2010)
GP leaders vow to secure more money for general practice
Authors: Matthew Limb
Journal: BMJ (2016)

General practice is in a “state of emergency” and needs more cash as well as a major investment plan to save it from long term decline, GP leaders have warned.

Maureen Baker, chair of the Royal College of General Practitioners, and Chaand Nagpaul, head of the BMA’s General Practitioners Committee, described the scale of the problem and the need for action at a special BMA conference of local medical committees, the local representative bodies for GPs, in London on 30 January.

Nagpaul called for a “fightback” by GPs against the lack of resources in general practice that threatened patient safety. “Patients are being short changed on a daily basis, with nine out of 10 GPs stating that workload pressures …
A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13.
Authors: Karim Fizazi, Lance C. Pagliaro, Aude Flechon, Jozef Mardiak, Lionnel Geoffrois, Pierre Kerbrat, Christine Chevreau, Remy Delva, Frederic Rolland, Christine Theodore, Guilhem Roubaud, Gwenaelle Gravis, Jean-Christophe Eymard, Jean-pierre Malhaire, Claude Linassier, Muriel Habibian, Florence Journeau, Christopher Logothetis, Stephane Culine, Agnes Laplanche
Journal: Journal of Clinical Oncology (2013)

LBA4500 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
A novel traction method using an endoclip attached to a nylon string during colonic endoscopic submucosal dissection
Authors: Yasushi Yamasaki, Yoji Takeuchi, Noboru Hanaoka, Koji Higashino, Noriya Uedo, Ryu Ishihara, Hiroyasu Iishi
Journal: Endoscopy (2015)

Colorectal endoscopic submucosal dissection (ESD) is considered to be a difficult procedure that has a high risk of adverse events [1]. Endoscopic procedures should be performed under direct visualization, but it is often difficult to maintain appropriate visualization during submucosal dissection. A traction method using an endoclip attached to a string was developed in order to maintain good visualization of the submucosal layer during esophageal and gastric ESD [2] [3]. However, this method was not applicable to colonic ESD because the colonoscope required reinsertion in order to mount the endoclip. We designed a novel traction method that did not require reinsertion of the colonoscope.
The effect of TAE226 on the non-small cell lung cancer including Japanese origin lung cancer
Authors: H. Otani, M. Jida, M. Takaoka, T. Kubo, T. Hayashi, H. Yamamoto, K. Kiura, Y. Naomoto, S. Toyooka
Journal: Journal of Clinical Oncology (2009)

e22103 Background: Mutations in the epidermal growth factor receptor (EGFR) gene is the predictive factor for sensitivity of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. Focal adhesion kinase (FAK) that is the downstream molecule of EGFR has been reported to be highly expressed in NSCLC suggesting novel therapeutic target of NSCLC. TAE226, dual inhibitor for FAK and insulin like growth factor-I receptor (IGF-IR), have been developed as anticancer reagent. In this study, we examined the effect of TAE226 on NSCLC from the view point of EGFR mutation status. Methods: We used NSCLC cell lines consisting of 4 EGFR mutant cell lines (PC9, H3255, HCC827, H1975) and 3 EGFR wild type cell lines (H1819, H1299, A549). We also used PC9 derived resistant cell line (RPC9). Antiproliferative effect of TAE226 on NSCLC cell lines was examined with MTS assay. The status of EGFR related molecules including its downstream signal pathway was investigated by western blotting analysis. The effect of TAE226 on xenograft mouse models was also examined. Results: TAE226 was effective on NSCLC cell lines with EGFR mutation including T790M mutation, compared to those with EGFR wild type. The value of IC50 (μmol/L) for PC-9, H3255, HCC827, H1975, RPC-9 and H1819, H1299, A549 was 0.16, 0.12, 0.086, 0.17, 0.31 and 4.7, 2.8, 1.4, respectively. Western blotting assay showed that TAE226 preferentially inhibited phosphor-EGFR and its downstream signaling mediators. We could confirm the anticancer effect of TAE226 on EGFR mutant cells was confirmed in xenograft mouse models. Conclusions: We indicated that TAE226 showed antitumor effect on EGFR mutant cell lines even T790M mutant cells. Further study is necessary to understand the mechanism of TAE226 effect on EGFR mutant cell lines. Our results suggest that TAE226 will be expected as the novel strategy for NSCLC. No significant financial relationships to disclose.
Abstract 245: Assessing Proarrhythmic Potential of Drugs Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes and Optical Recordings With Voltage-sensitive Dyes
Authors: Ksenia Blinova, Jayna Stohlman, Dulciana Chan, Maria Hortigon, Victor Z Rodriquez, Godfrey Smith, William Crumb, Li Pang, Beverly Lyn-Cook, Jose Vicente, Lars Johannesen, Norman Stockbridge, Norman Stockbridge, David Strauss
Journal: Circulation Research (2015)

Background: Drug-induced arrhythmias have been a leading reason for withdrawing drugs from the market and abandoning the development of new drugs. For the past decade FDA has required new drugs to be tested for block of the hERG potassium channel and QT interval prolongation. While these requirements have prevented arrhythmia-related drug recalls, some new drugs affecting multiple ion channels are being dropped from development inappropriately. Human induced pluripotent stem cell derived cardiomyocytes (iPS-CMs) are a new technology for preclinical risk assessment; however they have not been fully characterized or validated. Methods: We studied 26 drugs and 3 drug combinations that block multiple cardiac ion channels with two commercially available iPS-CM lines from Axiogenesis and Cellular Dynamics using optical recordings of action potentials with voltage-sensitive dyes. Drug-induced action potential duration (APD) prolongation was compared to clinical QT prolongation from two FDA-sponsored clinical trials. The effects of the drugs on multiple individual cardiac ion channels were assessed using manual patch clamp of overexpressed cell lines. Cardiac ion channel gene expression in the iPS-CMs was quantified and compared to primary human heart cell controls. Results: Of 19 drugs with an FDA label of clinical QT prolongation, 15 exhibited iPS-CM APD prolongation after acute drug exposure. None of the 6 drugs without clinical QT prolongation caused iPS-CM APD prolongation. Of 14 drugs with arrhythmia risk on the FDA label, nine caused arrhythmias in iPS-CMs. iPS-CM response had good correlation with clinical QT data for drugs that block hERG and calcium channels, while drugs blocking the late sodium current had variable response. This was in line with gene expression data, which showed most robust expression of hERG and calcium channels. Conclusion: Optical recordings from iPS-CMs with voltage sensitive dyes is a promising technology for high-throughput toxicity assessment for drug-induced arrhythmias. This study provides a comprehensive characterization of the cardiac ion channel properties of multiple commercially available iPS-CMs to support a potential new paradigm for assessing the arrhythmia risk of all new drugs.