tbuckley/cabot-search huggingface dataset:
Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency.
Authors: A. Z. Badros, R. Vij, T. Martin, J. A. Zonder, A. F. Wong, T. Woo, K. Boussina, Z. Wang, R. Niesvizky
Journal: Journal of Clinical Oncology (2010)

8128 Background: Renal impairment (RI) affects >50% of patients (pts) with multiple myeloma (MM). It confers shorter survival and prevents adequate dosing by exacerbating drug side effects. Carfilzomib (CFZ) is a selective proteasome inhibitor with established single-agent activity in pts with relapsed and/or refractory (R/R) MM (even in the bortezomib-refractory setting), including those with moderate RI. Methods: This open-label, multicenter phase II trial enrolled pts with MM and varying degrees of RI (Table). Pts received CFZ 15 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 every 28 d for cycle (C) 1, escalating to 20 mg/m2 in C2 and 27 mg/m2 in C3. After response assessment, pts failing to achieve ≥PR by C2 or CR by C4 could receive dexamethasone 40 mg/week. Study objectives included PK, safety, pharmacodynamics (proteasome inhibition in blood and PBMC [PDn]), and efficacy (overall response rate [≥PR; ORR], clinical benefit response [≥MR; CBR] stable disease (SD) ≥6 wk, duration of response, and time to progression). Results: To date 39 pts have been enrolled. Pts received a median of 5 prior therapies (range 2–10). 97% had received bortezomib; all had received ≥1 immunomodulatory agent; 67% had prior stem cell transplant. Thus far, 22 pts received a median of 3 C (range 1–10+); 9 have completed ≥6 C. Side effects (AEs), including grade (G) 3/4 AEs (apparently independent of renal status), are presented in the Table. No QT/QTc prolongations were seen. PK/PDn were similar across all groups; CFZ was undetectable in plasma within 3 h (t¾ = 30–60 min) and did not accumulate after 2 C. Proteasome inhibition 1 h post-dose ranged from 75–89% at doses of 15–20 mg/m2. The CBR was 37% (8 PR and 5 MR) with an additional 37% SD (n = 13). Conclusions: Pts with MM and substantial RI can receive CFZ without dose adjustment. Responses are encouraging and toxicity is mild and manageable. Evaluable pts Cohort CrCL, mL/min Enrolled Efficacy Safety PK Normal 80 10 10 2 4 Mild RI 50-79 9 8 8 6 Moderate RI 30-49 9 7 6 6 Severe RI <30 9 8 4 6 On hemodialysis 2 2 2 2 Total 39 22 35 24 AE All G (n) G 3/4 (n) Fatigue 14 3 Anemia 10 9 Diarrhea 9 Nausea 8 Constipation 7 Thrombocytopenia 7 6 Hypokalemia 7 Creatinine increase 4 Mental status change 3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Celgene, Millennium, Onyx Onyx Celgene, Millennium Celgene, Cepahlon, Millennium, Onyx, Seattle Genetics
Implementing smoking cessation strategies in primary health care in Russia: Opportunities and challenges
Authors: Marine Gambaryan, Anna Kalinina, Tsovinar Grigoryan, Vladimir Vigodin
Journal: European Respiratory Journal (2012)

Since 3 years Russia implements FCTC and National Policy against tobacco for years 2010-2015. But yet the Health System is not prepared for effective tobacco control(TC).  The study aims to assess opportunities, challenges for smoking cessation(SC) strategies in various settings in Primary Health Care(PHC) to define algorithms for effective TC. Pilot studies in 2 various settings conducted: 1)randomized control trial for SC in outpatient clinic conducted in 60 patients. SC intensive advice plus NRT and without NRT was offered to intervention and control groups 2)prospective study to assess the impact of workplace health promotion programs (WHPP) on SC rates conducted in 348 health professionals at 4 outpatient clinics in 12-months period.  Average age of patients was 49±12. At first visit 94.8% were diagnosed with COPD GOLD II/III and 77.6%-with high blood cholesterol, of which 58.2% and 51%respectively were new findings(p  Prevention of NCD requires systematic identification of smokers and provision of SC assistance at all levels of PHC. Workplaces are ideal settings for HP interventions. Intensive assisted SC interventions significantly increase success rates.
Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.
Authors: E E Vokes, W R Panje, R L Schilsky, R Mick, A M Awan, W J Moran, M D Goldman, A G Tybor, R R Weichselbaum
Journal: Journal of Clinical Oncology (1989)

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.
The role of Syk kinase in ultraviolet-mediated skin damage
Authors: E. Papazoglou, Z.Y. Huang, C. Sunkari, J. Uitto
Journal: British Journal of Dermatology (2011)

Ultraviolet (UV) irradiation is the main cause of skin photodamage; the resulting modulation of matrix metalloproteinases (MMPs) leads to collagen degradation. There is no easily accessible molecular indicator of early skin UV damage.In this study, we investigated the effects of Syk kinase on MMP expression and evaluated the sensitivity and usefulness of Syk as an early indicator of skin UV damage.Human dermal fibroblasts (HDFs) were transfected with Syk cDNA to overexpress Syk. MMP-1 expression and Syk activity were determined by Western blot after UV exposure. The effect of Syk on MMP-1 expression in HDFs was further explored by either Syk siRNA or a selective Syk inhibitor. Possible downstream molecules of Syk were also evaluated in HDFs upon UV exposure. The relationship between Syk and collagenase was further explored in vivo (MMP-13, hairless mice).Our studies in HDFs demonstrated that both a Syk inhibitor and Syk siRNA were able to inhibit MMP-1 expression in HDFs exposed to UV and that overexpression of Syk increased MMP-1 expression and the activity of JNK kinase, but not p38 or Erk1/2 MAP kinase. UV exposure enhanced both expression and activity of Syk in HDFs. Experiments with hairless mice suggested that Syk expression is an earlier indicator of UV exposure than MMP-13 expression.Our results demonstrate that Syk expression correlates well with increase of MMPs (MMP-1 in humans and MMP-13 in mice) in response to UV exposure. The findings suggest that Syk may be a novel target for the prevention and treatment of skin photodamage by modulating MMPs.
A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis
Authors: Doug Hanniford, Judy Zhong, Lisa Koetz, Avital Gaziel-Sovran, Daniel J. Lackaye, Shulian Shang, Anna Pavlick, Richard Shapiro, Russell Berman, Farbod Darvishian, Yongzhao Shao, Iman Osman, Eva Hernando
Journal: Clinical Cancer Research (2015)

Brain metastasis is the major cause of mortality among patients with melanoma. A molecular prognostic test that can reliably stratify patients at initial melanoma diagnosis by risk of developing brain metastasis may inform the clinical management of these patients.We performed a retrospective, cohort-based study analyzing genome-wide and targeted microRNA expression profiling of primary melanoma tumors of three patient cohorts (n = 92, 119, and 45) with extensive clinical follow-up. We used Cox regression analysis to establish a microRNA-based signature that improves the ability of the current clinicopathologic staging system to predict the development of brain metastasis.Our analyses identified a 4-microRNA (miR-150-5p, miR-15b-5p, miR-16-5p, and miR-374b-3p) prognostic signature that, in combination with stage, distinguished primary melanomas that metastasized to the brain from nonrecurrent and non-brain metastatic primary tumors (training cohort: C-index = 81.4%, validation cohort: C-index = 67.4%, independent cohort: C-index = 76.9%). Corresponding Kaplan-Meier curves of high- versus low-risk patients displayed a clear separation in brain metastasis-free and overall survival (training: P < 0.001; P < 0.001, validation: P = 0.033; P = 0.007, independent: P = 0.021; P = 0.022, respectively). Finally, of the microRNA in the prognostic model, we found that the expression of a key lymphocyte miRNA, miR-150-5p, which is less abundant in primary melanomas metastatic to brain, correlated with presence of CD45(+) tumor-infiltrating lymphocytes.A prognostic assay based on the described miRNA expression signature combined with the currently used staging criteria may improve accuracy of primary melanoma patient prognoses and aid clinical management of patients, including selection for adjuvant treatment or clinical trials of adjuvant therapies.
Probability of malignancy based on automatic segmentation and software measurements of nodules in the Danish lung cancer screening trial (DLCST)
Authors: Zaigham Saghir, Colin Jacobs, Bram van Ginneken, Marleen de Bruijne, Asger Dirksen, Jesper Holst Pedersen
Journal: European Respiratory Journal (2012)

Introduction and aim   With the widespread use of chest CT in clinical and screening settings pulmonary nodules are detected more frequently than ever, and the risk of malignancy needs to be determined.   Materials and methods   In DLCST, 4,104 current and former smokers, with a history of at least 20 pack years and age between 50-70 years, were randomized to either five annual multi-slice low-dose CT screenings or no screening. All participants had an annual visit to the screening clinic where lung function tests and questionnaires concerning health, lifestyle, smoking habits and psychosocial consequences of screening were performed. All scans were double-read by two experienced chest radiologists and the location and size were registered. Nodules between diameters of 5-15 mm were considered indeterminate, and rescanned after three months. Participants with nodules larger than 15 mm were referred to diagnostic workup, as were those with growing nodules. Lung cancer was diagnosed by pathological evaluation.  Using volumetric software nodules were segmented automatically and for the solid and sub-solid components mass and volume were calculated as well as the largest axial diameter. All automated nodule-segmentations were visually reviewed for correctness and adjusted if needed.   Results and conclusion   We are currently analyzing the data by logistic regression with malignancy as outcome and nodule measurements and risk factors such as age, sex, smoking status and history and COPD-status as explanatory variables. The results will be presented at the ERS 2012 in Vienna.
Inspiratory muscle training for asthma – A randomized controlled pilot study
Authors: Renata Delgado, Ivanízia Silva, Thaisy Elaine Silva, Tainá Fernandes, Nelson Lima Filho, Victor Hugo Oliveira, Rafaela Pedrosa, Gardenia Ferreira
Journal: European Respiratory Journal (2014)

Background: The objective of a treatment for asthma is to achieve and maintain control of the disease for long periods. Inspiratory muscle training (IMT) appears as an alternative in care of patients with asthma, being used as a complementary treatment to the pharmacological one. Objectives: To investigate the effects of IMT on respiratory muscle strength and functional capacity in healthy and asthmatics adults. Methods: We performed a randomized controlled trial with blinding of outcome assessment. Twenty individuals healthy and asthmatics were randomly divided into four groups: experimental asthmatics (EA), experimental healthy (EH), control asthmatics (CA) and control healthy (CH). Spirometry, maximal inspiratory pressure (MIP) and distance walked during six minutes (6MWD) were measured before and after the six weeks of study. Participants performed 30 breaths, using a pressure threshold inspiratory muscle trainer (POWERbreathe®), twice a day, five days/week, for six weeks. Experimental group trained at 50% MIP and control group at 15% MIP. Training intensity was adjusted once a week. Results: EA, EH and CH groups demonstrated significant improves in MIP ( P  2 O to 136,4 ± 22,5 cmH 2 O), EH (84,0 ± 25,5 cmH 2 O to 124,5 ± 26,8 cmH 2 O) and CH (96,6 ± 24,2 cmH 2 O to 123,6 ± 29,6 cmH 2 O ) . 6MWD increases in EA (648,2 to 693,4 m;  P  P
Pneumococcal and influenza vaccine uptake in patients discharged from an acute medical hospital
Authors: Stephanie Camilleri, Martin Balzan, Kentaro Yamagata, Chrisotpher Zammit, Ramon Casha, Juanita Casingena Garcia
Journal: European Respiratory Journal (2013)

Introduction: Various guidelines recommend Pneumococcal vaccine(PV) and influenza(IV) to chronically ill patients.

Aims: To determine the proportion of patients where PV and IV was indicated, and measure the uptake of vaccine and assess attitudes in patients discharged from an acute medical hospital.

Methods: Patients discharged from Mater Dei hospital in Malta during a one week period in January 2013 were interviewed by phone 2 weeks later

Results: Of 271 discharged medical patients, 164 (50% Female, Mean age 66.5±15.5) were contacted. The PV was indicated in 90.8% (149 patients). Age >65 (61%), Diabetes Mellitus (38.9%) renal failure (27.8%, eGFR <60), Heart failure (21.6%) and lung disease (17.3%) were commonest inclusion criteria. 6 patients were advised and 4 received the PV. IV was indicated in 97.6% (160), but recommended by physician in 112(70%) this year. 74 (46.3%) vaccinated this year, 117 (63.8%) vaccinated at least once in the past. Main reasons for 2012/3 vaccination(n=74) 71.6% to protect themselves, 19.4% advised by doctor, 4.5% to protect household. Reasons for non vaccination (n=86), 30 (34.9%) fear of side effects, 15.1% felt they don’t need it, 15.1% forgot to take, 8.1% not aware of need.

Conclusion: Physician recommendation and consequent PV uptake was low. Whilst awareness of IV by patients was high, uptake was mainly limited by fear of side effects.
Independent prognostic und predictive value of blood vessel invasion (BVI) in curatively (R0) resected stage II and IIIA non-small cell lung (NSCLC) cancer patients
Authors: Dieter Wuerflein, Wolfgang M. Brueckl, Dietmar Kraus, Christian Meyer, Manfred Wagner, Joachim H. Ficker
Journal: European Respiratory Journal (2012)

Objective:  A single center study was conducted to identify the prognostic and predictive value of blood vessel invasion (BVI) in surgically R0 resected stage II and IIIA non-small cell lung cancer patients.   Methods:  A total of N=105 consecutive patients who had undergone complete (R0) resection for stage II/IIIA primary non-small cell lung cancer (NSCLC) between 01/2008 and 12/2010 at the Lung Cancer Center Nuremberg were evaluated. All pathological specimens were examined for evidence of BVI.   Results:  The baseline clinical data showed no significant differences between patients with adjuvant chemotherapy (aCTx; cisplatin/vinorelbine; N=46) and without aCTx (N=59) beside of age (aCTx treated patients were younger p=0.03). Demographic data were as follows: age   ECOG-PS 0 and no BVI were positive prognostic factors for both recurrence free survival (RFS) and overall survival (OS) in the group without aCTx and remained independent  prognostic  factors in the multivariate analysis (p predictive  factors for RFS and OS in the aCTx treated group.   Conclusion:  BVI is an independent prognostic and predictive factor in R0 resected stage II/IIIA NSCLC patients. This subset of patients may have a greater benefit from aCTx and may need to be followed-up more closely.
Is sarcoidosis associated with increased occurence ofmalingnancy? A retrospective analysis.
Authors: Martina Doubková, Ilona Binková, Jana Skřičková
Journal: European Respiratory Journal (2011)

We performed a retrospective analysis in our cohort of 170
patients. We compared the incidence and prevalence of
malignancies in sarcoidosis patients with the incidence and
prevalence of malignancies throughout our population. Data from
years 2005-2007 were analysed. We do not prove the
statistically significant difference in the incidence and
prevalence of malignancies between sarcoidosis patients and
general population.
Increased polysialylation in lung tissue of patients with idiopathic pulmonary fibrosis
Authors: Christina Ulm, Martina Korfei, Sandra Mueller, Susanne Rinné, Hildegard Geyer, Rita Gerardy-Schahn, Martina Muehlenhoff, Andreas Guenther, Rudolf Geyer, Sebastian Galuska
Journal: European Respiratory Journal (2011)

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease of unknown etiology. The disease is characterized by alveolar destruction, uncontrolled fibroblast proliferation and excess matrix production, resulting in progressive dyspnea, a decline in lung function and loss of gas exchange properties. So far, only pirfenidone has been shown to exert some efficacy in IPF and lung transplantation represents the only option to prevent death.  Polysialic acid (polySia) is a developmentally regulated negative charged glycan which is predominantly found in neural tissue and tumours, where polySia is involved in the modulation of cell adhesion and migration processes. Therefore, we asked the extent of polysialylation in IPF (n=22) and donor (n=20) lung tissues obtained during lung transplantation.  We observed an up-regulation of the polysialyltransferases ST8SiaII and ST8SiaIV, the key enzymes of polySia biosynthesis, using quantitative real time PCR in IPF patients. In agreement with an increased mRNA expression level of both transferases we detected increased polySia levels in tissue samples of IPF patients in comparison to donor tissue by Western blotting. Using a glycoproteomics approach we were able to identify NCAM as the polySia carrier which could be confirmed by Western blot analysis. Surprisingly, polySia-NCAM was located intracellularly in vesicles of ciliated bronchiolar epithelial cells as well as clara cells. However, the role of polySia-NCAM in the bronchoalveolar system and especially during the development and the pathophysiology of IPF needs to be further investigated.
Recent Findings from the 1970 Child Health and Education Study: Preliminary Communication
Authors: N R Butler, Mary Haslum, Jean Golding, Sarah Stewart-Brown
Journal: Journal of the Royal Society of Medicine (1982)

The progress is described of the longtudinal cohort study based on all children born in England, Scotland and Wales in one week of April 1970. The children and their mothers have been surveyed at birth, at five, and recently, at ten. Analyses of the data presented include the finding of improved intellectual outcome in children who had been immunized against pertussis, compared with poor intellectual outcome in children who had had hospital admissions for the disease itself. Preliminary data collected at 10 show that routine hearing and vision testing during the child's school life fell short of recommended standards. The major aim of the 10-year-old contact, however, is to establish details of the national prevalence and pathogenesis of disability. The identification of disability uses a life skills questionnaire, medical history and examination.
Decisions to withhold or withdraw life-sustaining treatment in a Norwegian intensive care unit
Authors: Stein Arve Skjaker, Henrik Hoel, Rolf Haagensen, Nils Smith-Erichsen, Knut Stavem
Journal: European Respiratory Journal (2013)

Background: To withhold or withdraw therapies are important decisions made in intensive care units (ICUs). Few studies have investigated these processes.  Objectives: To investigate the incidence of withholding or withdrawing therapy, what characterizes the patients and how these decision processes are handled in a general ICU in a University Hospital in Norway, from 2007 to 2009.  Methods: Age, sex, reason for admission to the hospital, length of stay, diagnostic category, SAPS II, invasive mechanical ventilation time, outcome of stay, and if therapy was withheld or withdrawn were prospectively registered in a database. For this study we retrospectively reviewed the medical records for all information on restrictions in therapy.  Results: In total, 1287 patients were admitted to the ICU, and 72% received mechanical ventilation. ICU mortality was 208 (16%), and 341 (27%) died before hospital discharge. In total, 301 patients (23%) had restrictions in therapy and higher in-hospital mortality than the 986 patients without restrictions (79% vs. 11%, p  Conclusion: Withholding or withdrawing therapy in the ICU was common. The patients with restrictions in therapy were older and had more severe illnesses than patients with no restrictions. Consultant physicians made the decision in most cases.