tbuckley/cabot-search huggingface dataset:
Randomised, Multicentre, Phase Iii, Open-Label Study of Alectinib Vs Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (Alk)-Positive Advanced Nsclc (Alex Study)
Authors: S. Peters, T.S.K. Mok, M. Perol, S.I. Ou, R. Rosell, I. Bara, V. Henschel, D.R. Camidge
Journal: Annals of Oncology (2014)
A randomized phase II study of sequential carboplatin/paclitaxel (CP) and gefitinib (G) in chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC): Preliminary results
Authors: H. Nokihara, Y. Ohe, M. Kawaishi, T. Kato, N. Yamamoto, I. Sekine, H. Kunitoh, N. Saijo, T. Tamura
Journal: Journal of Clinical Oncology (2006)

7096 Background: G has been shown to exhibit antitumor activity against NSCLC, however, the optimal timing of its administration remains unclear. We conducted a randomized phase II study of CP followed by G or G followed by CP in chemotherapy-naïve advanced NSCLC patients in order to select the candidate arm for a subsequent phase III study. Methods: Chemotherapy-naïve patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged between 20 to74 years, performance status 0–1, were randomized to either Arm A (carboplatin (AUC 6, day 1) plus paclitaxel (200 mg/m 2 , day 1) every 3 weeks for 4 courses followed by daily G (250 mg/day)) or Arm B (daily G until disease progression followed by CP every 3 weeks for 4 courses). The primary endpoint was overall survival, and the planned sample size for this randomized phase II study was 96 patients (Liu’s selection design for pilot studies on survival). Results: From June 2003 to October 2005, 97 patients were enrolled, and 96 of these patients were treated in this study. Forty-nine patients (males/females: 28/21, median age: 63 years, adeno/non-adeno: 43/6, stageIII/IV: 11/38, smoker/non-smoker: 27/22) were randomized to Arm A and 48 patients (males/females: 28/20, median age: 61 years, adeno/non-adeno: 42/6, stageIII/IV: 11/37, smoker/non-smoker: 28/20) to Arm B. The response rate to CP in Arm A was 32.7% (16/49), and that to G in Arm B was 29.8% (14/47). The median survival was not yet reached, and the 1-year survival rates were 64.5% and 70.5% in Arm A and arm B, respectively. As of January 2006, one patient had died of treatment-related perforative peritonitis and two patients had developed interstitial lung disease. Conclusions: G exhibits similar antitumor activity to CP in chemotherapy-naïve patients with advanced NSCLC. The preliminary survival analysis is proposed to be conducted in April 2006. No significant financial relationships to disclose.
The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults
Authors: F. McGill, R.S. Heyderman, B.D. Michael, S. Defres, N.J. Beeching, R. Borrow, L. Glennie, O. Gaillemin, D. Wyncoll, E. Kaczmarski, S. Nadel, G. Thwaites, J. Cohen, N.W.S. Davies, A. Miller, A. Rhodes, R.C. Read, T. Solomon
Journal: Journal of Infection (2016)

Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis.Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults.A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system.Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.
Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G- CSF-mediated activation of signaling complexes of the p21ras route
Authors: RM Barge, JP de Koning, K Pouwels, F Dong, B Lowenberg, IP Touw
Journal: Blood (1996)
Genetic basis of myeloid transformation in familial platelet disorder/acute myeloid leukemia patients with haploinsufficient RUNX1 allele
Authors: M Sakurai, H Kasahara, K Yoshida, A Yoshimi, H Kunimoto, N Watanabe, Y Shiraishi, K Chiba, H Tanaka, Y Harada, H Harada, T Kawakita, M Kurokawa, S Miyano, S Takahashi, S Ogawa, S Okamoto, H Nakajima
Journal: Blood Cancer Journal (2016)

Familial platelet disorder/acute myeloid leukemia (FPD/AML) is an autosomal dominant inherited disorder characterized by thrombocytopenia and high propensity to various hematological malignancies.FPD/AML is caused by monoallelic mutations of RUNX1, which are in many cases point mutations disrupting DNA-binding or transactivating capacities of RUNX1, and these mutations are considered to act in dominant-negative manner to various degrees for residual wild-type allele. 1,2Interestingly, some FPD/AML traits present monoallelic loss of RUNX1 gene by microdeletion of chromosome 21. 1 In such cases, no mutations were found in the residual RUNX1 allele, thus suggesting that haploinsufficiency of RUNX1 is sufficient to cause FPD/AML.Genetic basis of leukemic transformation in FPD/AML patients still remains elusive.We have recently reported recurrent mutation of CDC25C in FPD/AML patients, and suggested that this mutation is one of the early events, which defines pre-leukemic state. 3owever, all pedigrees that we examined carried point mutations of RUNX1, and no cases with monoallelic RUNX1 loss were present.We suspected that the dosage of RUNX1 activity may affect the transforming processes, and FPD/AML with haploinsufficient RUNX1 allele might require unique genetic events for transformation that are distinct from cases with RUNX1 point mutation.In order to identify collaborating mutations with haploinsufficient RUNX1 allele, we performed genome-wide mutational analyses of two transformed cases of FPD/AML with monoallelic RUNX1 loss.
Abstract 13086: Microrna-34a Regulates Smooth Muscle Cell Differentiation from Stem Cells by Targeting Sirtuin 1
Authors: Li Zhang, Xiaoye Zheng, Yutao Wu, Qishan Chen, Jianhua Zhu, Qingzhong Xiao
Journal: Circulation (2012)

Background: Smooth muscle cell (SMC) differentiation is a critical process during vascular development and disorders. MicroRNAs (miRNAs) have been reported to be involved in SMC differentiation. Re...
Accelerated Concomitant Boost Radiotherapy and Chemotherapy for Advanced Nasopharyngeal Carcinoma
Authors: Suzanne L. Wolden, Michael J. Zelefsky, Dennis H. Kraus, Kenneth E. Rosenzweig, Lanceford M. Chong, Ashok R. Shaha, Haige Zhang, Louis B. Harrison, Jatin P. Shah, David G. Pfister
Journal: Journal of Clinical Oncology (2001)

To evaluate the feasibility and efficacy of concomitant boost radiotherapy (RT) plus cisplatin-based chemotherapy compared with standard fractionation RT for patients with advanced nasopharyngeal cancer.From 1988 through 1999, 50 patients with American Joint Committee on Cancer stage II-IVb nasopharyngeal carcinoma were treated with 70-Gy concomitant boost RT (1.8 Gy/d, weeks 1 through 6; 1.6 Gy second daily fraction, weeks 5 through 6) and two cycles of concurrent cisplatin 100 mg/m(2) days 1 and 22. Thirty-seven patients also received three cycles of cisplatin-based adjuvant chemotherapy. These 50 patients were compared with a nonrandomized cohort of 51 patients with nasopharyngeal cancer treated with 70-Gy standard fractionation RT (1.8 Gy/d) without chemotherapy from 1988 through 1995. The groups were well matched for prognostic factors except stage, for which the concomitant boost RT/chemotherapy group was more advanced (54%, T3-4; 54%, N2-3; 44%, stage IV) compared with the standard RT group (31%, T3-4, P =.03; 22%, N2-3, P <.001; 20%, stage IV, P <.01).With a median follow-up of 42 months (range, 12 to 129 months), the 3-year actuarial local control, progression-free survival, and survival rates were 89% v 74% (P <.01), 66% v 54% (P =.01), and 84% v 71% (P =.04) for the concomitant boost RT/chemotherapy group and the standard RT patients, respectively. Acute grade 3 mucositis was more prevalent with combined therapy, 84% v 43% (P <.001), resulting in a higher rate of temporary gastrostomy tube placement, 46% v 20% (P <.01).Concomitant boost RT with cisplatin-based chemotherapy is feasible and improves local-regional control as well as survival for patients with advanced nasopharyngeal cancer compared with standard RT alone.
Epidermal Growth Factor Receptor Expression in Human Lung Carcinomas Defined by a Monoclonal Antibody&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R E Sobol, R W Astarita, C Hofeditz, H Masui, R Fairshter, I Royston, J Mendelsohn
Journal: JNCI Journal of the National Cancer Institute (1987)

Acetone-fixed frozen tissue sections from 56 cases of human lung carcinoma were tested for reactivity by an indirect immunoperoxidase technique with a monoclonal antibody (MAb 528) specific for the external domain of the epidermal growth factor receptor (EGFR). MAb 528 reacted with all epidermoid (22/22) and large-cell (4/4) lung carcinomas evaluated. The antibody was also positive with a subset of lung adenocarcinomas (13/21) and did not react with small-cell lung cancers (SCLCs) (0/9). MAb 528 also stained normal bronchial epithelium identified within the tumor sections of 5 cases. Thus EGFR was expressed by all epidermoid and large-cell lung carcinomas examined, a subset of lung adenocarcinomas, and normal bronchial epithelium. EGFR expression was not identified in any of the SCLCs tested. These data imply that immunohistochemical detection of EGFR expression may find future application in distinguishing epidermoid, large-cell, and some adenocarcinomas of the lung from SCLCs.
Vinorelbine as second or third-line therapy in pemetrexed-pretreated malignant pleural mesothelioma (MPM) patients
Authors: G.L. Ceresoli, P.A. Zucali, F. Grosso, M. Mencoboni, M.G. Sauta, H.J. Soto Parra, G. Pasello, D. Cortinovis, M. Perrino, A. Muzio, A. Bruzzone, F. De Vincenzo, D. Degiovanni, M. Bonomi, M. Simonelli, G.D. Beretta, L. Giordano, A. Santoro
Journal: Annals of Oncology (2015)
Tobacco use in Sussex asbestos workers
Authors: Thomas Medveczky, Charles Turton
Journal: European Respiratory Journal (2011)

Introduction:  Asbestos related lung disease is likely to increase. Smoking, apart from being the major risk factor for lung cancer, may be a co-factor in the development of asbestos in lung disease. The Health and Safety Executive report mentions the high rate of smokers in asbestos related industry [1]. We reviewed our local population of asbestos workers to explore that.   Methods:  Between 1994 and 2007, 268 workers were seen for clinical assessment, spirometry, health safety advice and smoking cessation. A retrospective analysis of records,spirometry, smoking habits,effect of smoking cessation advice, was undertaken.   Results:  268 subjects were seen, 65 on multiple occasions. 214 (79%) were involved with asbestos handling or removal. 42 (16%) worked in supervisory or managerial capacities. 12 (5%) were laboratory analysts.Current smoking rates for handlers was 67% (144/214), mnagerial group 36%, and analysts 33% (p=0.015). Ex smoking rates were 11% for removers, 38% for the supervisory and managerial group and 8% for analysts. Non-smoking rates were 22% for handlers and removers, 46% for supervisors and managers and 58% for analysts.The rate of decline in FEV1 for current smoking handlers/asbestos removers was 52.8 ml per year, and for supervisors 22.3 ml per year (p=0.0023). The mean FEV1 decline in non-smokers and ex-smokers was 37.5 ml/year.   Conclusions:  Workers with highest asbestos exposure are significantly more likely to be current smokers and to have greater decline in FEV1, conferring greater disease risk [2]. Smoking behaviour has not changed since 1983. Consultant advice on cessation was ineffective for the group most at risk.   References:   1HSE asbestos related database 2007.  2HSE Executive report, mesothelioma deaths Great Britain, 1981-2005.
Evaluating if darbepoetin alfa efficacy and safety in patients with chemotherapy-induced anemia is affected by the disease stage of the patient
Authors: L. S. Schwartzberg, J. Glaspy, D. Tomita, T. Lillie
Journal: Journal of Clinical Oncology (2006)

18568 Background: Cancer patients (pts) often develop chemotherapy-induced anemia (CIA), resulting in increased transfusion incidence and fatigue. Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent that can reduce the incidence of transfusions, increase hemoglobin (Hb) levels to a range of 11 to 13 g/dL (as recommended by evidence-based guidelines), and decrease fatigue in pts with CIA. The 74-hour half-life of DA allows it to be effectively administered weekly (QW), every 2 weeks (Q2W), or every 3 weeks (Q3W). DA treatment can also be synchronized with chemotherapy (Glaspy et al., 2005). Here we examined if the efficacy and safety of DA for treating CIA is affected by the disease stage of the pt. Methods: Eight clinical trials (including single-arm, active-controlled, and placebo-controlled studies) were analyzed that described the administration of DA QW (2 studies), Q2W (3 studies), or Q3W (3 studies) to pts with CIA. Tumor-Nodes-Metastases (TNM) classification was used to define disease stage of I, II, III, or IV. A clinically meaningful endpoint evaluated was the proportion of pts achieving a target Hb of ≥ 11 g/dL. Other endpoints included incidence of transfusions, change in FACT-F score at end of study from baseline, and incidence of adverse events. Results: A high percentage of pts in all disease stages achieved a target Hb of ≥ 11 g/dL in response to DA treatment (see Table ). Early stage pts were seen to benefit at least as much as later stage pts. A similar trend was seen for the other efficacy and safety endpoints (data will be presented). Conclusions: The present analysis suggests that DA administered QW, Q2W, or Q3W can effectively correct anemia when administered to pts in either early or late disease stages. The potential to synchronize DA treatment and chemotherapy regardless of disease stage may increase pt convenience by reducing the number of clinic visits. [Table: see text] [Table: see text]
68Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer
Authors: Annika Herlemann, Vera Wenter, Alexander Kretschmer, Kolja M. Thierfelder, Peter Bartenstein, Claudius Faber, Franz-Josef Gildehaus, Christian G. Stief, Christian Gratzke, Wolfgang P. Fendler
Journal: European Urology (2016)
Endocardial Tumors in Rats Exposed to Durable Fibrous Materials&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C Hoch-Ligeti, B Sass, H J Sobel, H L Stewart
Journal: JNCI Journal of the National Cancer Institute (1983)

Endocardial tumors in the rat found in association with intrathoracic implantation of durable fibrous materials are reported here for the first time. In Osborne-Mendel female rats, endocardial tumors occurred in 3 of 50 rats associated with the implantation of fiberglass greater than 5 µm in length and 1–3 µm in diameter, in 1 of 15 rats associated with fiberglass of 0.03x3 µm, and in 1 of 15 rats associated with pulverized glass fiber. The intrathoracic administrations of pulverized chrysotile, of cigarette smoke condensate and crocidolite, and of coarse cotton lint, and of intravenous injections of air particulate extract were associated with endocardial tumor in 1 of 15 rats each. The dimensions of the durable fibers associated with endocardial tumors were similar to those of carcinogenic asbestos. Endocardial tumors were not observed in concurrently studied control rats.
Effect of oral magnesium on hot flashes in breast cancer survivors.
Authors: H. Park, T. J. Smith, G. L. Parker, P. Dodson, C. Boardman, M. M. Morris
Journal: Journal of Clinical Oncology (2010)

9151 Background: Hot flashes can affect up to 40% of cancer survivors and lead to discomfort, altered sleep, and poor quality of life. Magnesium is vasoactive, neuroactive, safe, inexpensive, and has anecdotal evidence of effect (Smith T, J Clin Oncol. 2009 27:1151). We tested if magnesium would diminish hot flashes in breast cancer patients who were bothered by them. Trial MCC-12062, NCT01008904. Methods: Breast cancer patients with at least 14 hot flashes a week were eligible. Oral magnesium oxide 400 mg (250 mg magnesium) for two weeks was given, escalating to 800 mg for two weeks if needed. Hot flash score (frequency × severity) at baseline was compared to the end of the 5 weeks using a one-sided paired t-test. Results: 31 patients enrolled, 29 started the study drug, and 25 completed treatments. The average age was 53.5 years. 6 patients were African-American, the rest Caucasian. Of the 29, 8 were on tamoxifen, 9 were on aromatase inhibitors, and 14 were on anti-depressants. 17 patients escalated the magnesium dose after two weeks of treatment. Hot flash frequency and score were both reduced significantly. Results from 25 patients are shown in Table 1 below. Out of 25 patients, 14 patients (56%) had a >50% reduction in hot flash score, and 19 patients (76%) had a >25% reduction. There was no change in formal quality of life. Side effects were minor: 3 women stopped the drug for adverse effects including 1 person with migraine headache and 2 with nausea; 2 women had grade 1 diarrhea. Compliance was excellent and many patients continued treatment after the trial ended. Conclusions: Oral magnesium appears to have helped more than half of the patients with hot flashes and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo-controlled trial is planned, with explorations of mechanism of action. Baseline Week 5 Difference Reduction % p value Frequency (SE) 52.2 (13.7) 27.7 (5.7) 24.6 (9.6) 41.4% 0.009 Score (SE) 109.8 (40.9) 47.8 (13.8) 62.0 (28.5) 50.4% 0.020 No significant financial relationships to disclose.
Clinical characteristics and outcomes in biclonal gammopathies
Authors: Trey C. Mullikin, S. Vincent Rajkumar, Angela Dispenzieri, Francis K. Buadi, Martha Q. Lacy, Yi Lin, David Dingli, Ronald S. Go, Suzanne R. Hayman, Steven R. Zeldenrust, Stephen J. Russell, John A. Lust, Nelson Leung, Prashant Kapoor, Robert A. Kyle, Morie A. Gertz, Shaji K. Kumar
Journal: American Journal of Hematology (2016)

A single monoclonal protein typically characterizes monoclonal gammopathies, but a small proportion may have more than one M protein identifiable. In the setting of symptomatic multiple myeloma (MM), the development of a new monoclonal protein following therapy is associated with better outcomes. As for the precursor conditions, monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM), there is limited information on the impact of a second monoclonal protein on the disease course, including progression and response to treatment. The outcomes of patients with MGUS and SMM with more than one monoclonal protein, after identifying 539 patients with biclonal proteins on electrophoresis and/or immunofixation, were reported. About 22 of 393 patients with MGUS/biclonal gammopathy of undetermined significance (BGUS) progressed to SMM (6), MM (11), AL (3), or WM (2), and 5 of 16 patients with biclonal SMM progressed to MM. The rate of progression for BGUS was approximately 1% per year, which is similar to MGUS with one monoclonal protein. The median estimated time of progression of biclonal SMM was 2.6 years; similar to monoclonal SMM. For patients with biclonal MM, both M spikes responded to treatment and, upon relapse, the original dominant M protein remained dominant as the disease progressed. In conclusion, the presence of a second monoclonal protein does not appear to affect the progression of precursor states and suggests multiple monoclonal proteins do not clinically impact one another in the course of the disease.
Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD
Authors: Claudia Costa, Suzanne L. Traves, Susan J. Tudhope, Peter S. Fenwick, Kylie B.R. Belchamber, Richard E.K. Russell, Peter J. Barnes, Louise E. Donnelly
Journal: European Respiratory Journal (2016)

Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8 + cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C-C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5. Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays. There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression. However, isolated lymphocytes failed to migrate and isolated monocytes from COPD patients lost their enhanced migratory capacity. Both monocytes and lymphocytes cooperate to enhance migration towards CXCR3 chemokines and CCL5. This may contribute to increased numbers of macrophages and T-cells in the lungs of COPD patients, and inhibition of recruitment using selective antagonists might be a treatment to reduce the inflammatory response in COPD.
Heme-oxygenase (HO)-1 inhibits TNF-α induced CXCL10 secretion by airway smooth muscle cells
Authors: Petra Seidel, Katrin Hostettler, Margaret Hughes, Michael Tamm, Michael Roth
Journal: European Respiratory Journal (2011)

Background and purpose: CXCL10 induces mast cell migration towards airway smooth muscle bundles in asthma. In blood mononuclear cells, induction of heme oxygenase (HO)-1 inhibited pro-inflammatory cytokine secretion. Dimethylfumarate (DMF), which is clinically used as an anti-inflammatory medication, induced HO-1 and thereby inhibited proliferation in airway smooth muscle cells (ASMC).

Experimental approach: Here we assessed the anti-inflammatory effect of DMF on TNF-α induced CXCL10 secretion in human primary ASMC and the involvement of HO-1 and mitogen activated protein kinases (MAPK). ASMC were pre-incubated with DMF and/or glutathione ethylester (GSH-OEt), SB203580, or the HO-1 inducers hemin, or cobalt-protoporphyrin (CoPP) 1 hour before stimulation with TNF-α (10 ng/ml).

Key results: TNF-α induced the secretion of CXCL10, which was inhibited by DMF as well as by the HO-1 inducers hemin, or CoPP. Interestingly, DMF amplified the TNF-α induced phosphorylation of p38 MAPK and thereby induced the expression of HO-1. Inhibition of p38 MAPK by SB203580 reduced DMF-induced HO-1. Importantly, GSH-OEt supplementation: (i) abrogated the inhibitory effect of DMF on TNF-α induced CXCL10 secretion, (ii) counteracted DMF-induced HO-1 expression, and (iii) p38 MAPK activation.

Conclusion and implications: Our data indicate that DMF inhibits TNF-α induced CXCL10 by altering intracellular GSH, leading to activation of p38 MAPK and subsequent synthesis of HO-1 in ASMC. Thus, DMF might help to reduce airway inflammation in asthma.