tbuckley/cabot-search huggingface dataset:
CTLA-4 blockade with ipilimumab increases peripheral CD8+ T cells: Correlation with clinical outcomes.
Authors: A. Yang, R. F. Kendle, B. A. Ginsberg, R. Roman, A. I. Heine, E. Pogoriler, J. D. Yuan, J. D. Wolchok
Journal: Journal of Clinical Oncology (2010)

2555 Background: Increasing doses of ipilimumab, an antibody to CTLA-4, is associated with a higher likelihood of clinical benefit. Analysis of pharmacodynamic biomarkers shows the magnitude of absolute lymphocyte count (ALC) increase correlates with dose. Identifying the lymphocyte subpopulations specifically increased may further elucidate the mechanism of action of CTLA-4 blockade. In a pooled analysis of four phase II trials (CA184-045, -008, -078, -042), peripheral blood lymphocytes subsets were analyzed from 35 patients (pts) with advanced melanoma treated with ipilimumab at Memorial Sloan-Kettering. Methods: Ipilimumab was administered (10 mg/kg every 3 weeks × 4 doses) and eligible pts continued to receive ipilimumab maintenance therapy every 12 weeks starting at week 24 in the setting of disease control. Under an institutional IRB- approved correlative blood drawing protocol, peripheral blood was obtained at weeks 1 (pre-treatment) and 7 (just before 3rd dose) and lymphocyte counts determined and evaluated for CD8/CD4/CD25+ populations using multiparametric flow cytometry. Response-evaluable pts with lymphocyte subpopulation analysis (n = 35) were classified by clinical activity (complete, partial response, stable disease 24 weeks, or progression of disease). Results: Increases in CD8+ T cells between weeks 1 and 7 were larger than changes in CD4+ or CD4+CD25+ cells. Pts with clinical benefit were noted to have a statistically significant increase in CD8+ T cells (p = 0.0294) but not CD4+ T cells (p = 0.2237) compared with nonclinical benefiters. There was a trend between degree of objective response and absolute change of CD8+ T cells and CD4+ T cells. Changes in CD4+/CD25+ T cells did not correlate with clinical response (p = 0.2912). Conclusions: Increased rate of ALC change during ipilimumab therapy is associated with clinical activity in this retrospective analysis. Specifically, increased CD8+ T cells were associated with improved clinical outcome, while absolute change in CD4+ CD25+ T cells did not appear to differ between the clinical outcome groups. This clinical correlation needs to be confirmed prospectively in trials of CTLA-4 blockade with ipilimumab. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Epstein-Barr virus polymorphic B-cell lymphoma associated with leukemia and with congenital immunodeficiencies.
Authors: J H Joncas, P Russo, P Brochu, P Simard, J Brisebois, J Dubé, D Marton, J M Leclerc, H Hume, G E Rivard
Journal: Journal of Clinical Oncology (1990)

Polymorphic B-cell lymphoma seen in four patients with congenital immunodeficiencies and in two patients with leukemia receiving chemotherapy was associated with the Epstein-Barr virus (EBV). The tumors had characteristic histologic features: they were polymorphic consisting of a mixture of lymphoblasts and differentiated cells including plasma cells, and areas of hemorrhagic necrosis were prominent. The tumors were either polyclonal, monoclonal, or multiclonal. Patients with congenital immunodeficiencies who developed these tumors died despite radiotherapy, corticosteroids plus acyclovir, or a combination of intravenous (IV) immunoglobulins and alpha 2 interferon. Patients with leukemia recovered when immunosuppressive drugs were discontinued and leukemia has not recurred over a period of 2 and 4 years, respectively, in the two patients.
Right heart volume load response in patients with chronic thromboembolic pulmonary hypertension (CTEPH)
Authors: Nicolay Khorokhordin, Pyotr Yablonsky, Andrey Boyarkin, Vladimir Golovin, Tatyana Fedorova, Evgeny Pavlushkov, Ignatij Karmamov, Olga Karmanov
Journal: European Respiratory Journal (2011)

Aim: To assess the influence of volume load on right heart hemodynamics in pts with moderate and severe CTEPH.

Patients and methods: 20 patients (mean age - 47±11, 15 males and 5 females). The 1 group consisted of 9 pts with PAP≤30 mm Hg, the 2 group – 11 pts with PAP>30 mm Hg. Right ventricular end-diastolic volume and ejection fraction were evaluated by thermodilution method [Lichtwarck-Aschoff, 2002].

Results: Results are summarized in the following table.

View this table:



After volume load: The difference in RVEDVI between the groups was not significant. The difference in CI between the groups became significant. This confirmed that there was no increase in CI in group 2. The increase of CI in group 1 was accompanied by PVRI rise. PVRI in group 2 remained high. Right ventricle stroke work dynamic (RVSWI1/2) indicated the presence of diastolic reserves of the RV in moderate CTEPH.

Conclusion: There are two main haemodynamic consequences in CTEPH: RV systolic dysfunction due to afterload increase and diastolic impairment as a response to volume load leading to RVEF decrease. The severity of right heart changes could be used in preoperative risk stratification in CTEPH patiens.
Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma
Authors: Ahmad A. Tarhini, Haris Zahoor, Yan Lin, Usha Malhotra, Cindy Sander, Lisa H. Butterfield, John M. Kirkwood
Journal: Journal for ImmunoTherapy of Cancer (2015)

We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS.Thirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18 months. Among 33 evaluable patients, median PFS was 11 months (95 % CI = 6.2-19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (p = 0.02) with a trend towards significance at 6 weeks (p = 0.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- β1 (ρ = 0.19) and IL-10 (ρ = -0.34)] was significantly associated with PFS (HR 2.66; p = 0.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines.Baseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- β1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation.ClinicalTrials.gov Identifier NCT00972933.
Clinical Tests of Respiratory Function.
Authors: V. Brusasco
Journal: Annals of Internal Medicine (1985)

Edited by G.J. Gibson    Published by Hodder Arnold, UK    Pages: 432. Price: £85.00. ISBN: 978-0340925614

Knowledge of clinical physiology is unquestionably a major step in the understanding of most respiratory disorders. Despite the abundance of knowledge gained in this field over the past 60 years, the value of pulmonary function testing in clinical practice has not been fully appreciated. This is possibly due to the complexity of respiratory function and a lack of clear communication between pulmonary physiologists and clinicians. After an outburst of enthusiasm for …
Benefits of teaching mindfulness at school will be assessed:
Authors: Ingrid Torjesen
Journal: BMJ (2015)

Schools already teach children about the importance of regular exercise and a balanced diet in reducing the risk of physical health ill health, but now UK researchers plan to investigate whether a similar strategy can be used for mental illness. Researchers funded by the Wellcome Trust will assess whether mindfulness training at school improves mental health in teenagers.

Mindfulness training has been found to be effective at preventing relapse in depression in adults, and its use is recommended by the National Institute for Health and Care Excellence.1 The study will look at whether this training can improve attention and mental resilience in teenagers and, as a result, have a positive effect on their current and future mental health.

The teenage years are a …
Increased Risk of Acute Leukemia After Adjuvant Chemotherapy for Breast Cancer: A Population-Based Study
Authors: Gilles Chaplain, Chantal Milan, Catherine Sgro, Paule-Marie Carli, Claire Bonithon-Kopp
Journal: Journal of Clinical Oncology (2000)

To quantify the risk of acute leukemia after adjuvant therapy, especially chemotherapy with topoisomerase II inhibitors.We performed a population-based study in a cohort of 3,093 women younger than 85 years who resided in the French administrative area of the Côte d'Or, who were given a first diagnosis of primary breast cancer between 1982 and 1996, and who received a curative treatment. Information about therapy and follow-up events was obtained from records of cancer registries that covered this area.Until December 1998, 10 cases of acute leukemia, including nonlymphoid acute leukemia and refractory anemia with excess of blasts, occurred in patients before any local or distant recurrence. All cases developed in the first 4 years of follow-up. Compared with the general female population, the incidence rate of leukemia was significantly increased in women who received radiotherapy and chemotherapy (standardized incidence ratio, 28.5; P <.0001). A dose-dependent increase in the risk of leukemia was observed in women treated with mitoxantrone. Cox regression analysis showed that the risk of leukemia was significantly lower in patients treated with anthracyclines than in those treated with mitoxantrone at cumulative doses >/= 13 mg/m(2).The combination of adjuvant radiotherapy and chemotherapy with mitoxantrone induces a high risk of acute leukemia in patients with breast cancer. A leukemogenic effect of chemotherapy with anthracyclines cannot be ruled out with certainty. However, there are some suggestions that these topoisomerase II inhibitors might be less leukemogenic than mitoxantrone and could be preferred in an adjuvant setting.
Risk of Stroke at the Time of Carotid Occlusion
Authors: Catherine Yang, Chrysi Bogiatzi, J. David Spence
Journal: JAMA Neurology (2015)

IMPORTANCEMany patients with asymptomatic carotid stenosis are offered carotid stenting for the prevention of carotid occlusion.However, this treatment may be inappropriate if the risk of stroke is low at the time of occlusion and with intensive medical therapy.OBJECTIVES To determine the risk resulting from progression to occlusion among patients with asymptomatic carotid stenosis and to assess the role of severity of carotid stenosis or the presence of contralateral occlusion as factors that may predict the risk of stroke or death after occlusion of a previously asymptomatic carotid stenosis.
Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain
Authors: Hugh MacPherson, Helen Tilbrook, Stewart Richmond, Julia Woodman, Kathleen Ballard, Karl Atkin, Martin Bland, Janet Eldred, Holly Essex, Catherine Hewitt, Ann Hopton, Ada Keding, Harriet Lansdown, Steve Parrott, David Torgerson, Aniela Wenham, Ian Watt
Journal: Annals of Internal Medicine (2015)

Management of chronic neck pain may benefit from additional active self-care-oriented approaches.To evaluate clinical effectiveness of Alexander Technique lessons or acupuncture versus usual care for persons with chronic, nonspecific neck pain.Three-group randomized, controlled trial. (Current Controlled Trials: ISRCTN15186354).U.K. primary care.Persons with neck pain lasting at least 3 months, a score of at least 28% on the Northwick Park Questionnaire (NPQ) for neck pain and associated disability, and no serious underlying pathology.12 acupuncture sessions or 20 one-to-one Alexander lessons (both 600 minutes total) plus usual care versus usual care alone.NPQ score (primary outcome) at 0, 3, 6, and 12 months (primary end point) and Chronic Pain Self-Efficacy Scale score, quality of life, and adverse events (secondary outcomes).517 patients were recruited, and the median duration of neck pain was 6 years. Mean attendance was 10 acupuncture sessions and 14 Alexander lessons. Between-group reductions in NPQ score at 12 months versus usual care were 3.92 percentage points for acupuncture (95% CI, 0.97 to 6.87 percentage points) (P = 0.009) and 3.79 percentage points for Alexander lessons (CI, 0.91 to 6.66 percentage points) (P = 0.010). The 12-month reductions in NPQ score from baseline were 32% for acupuncture and 31% for Alexander lessons. Participant self-efficacy improved for both interventions versus usual care at 6 months (P < 0.001) and was significantly associated (P < 0.001) with 12-month NPQ score reductions (acupuncture, 3.34 percentage points [CI, 2.31 to 4.38 percentage points]; Alexander lessons, 3.33 percentage points [CI, 2.22 to 4.44 percentage points]). No reported serious adverse events were considered probably or definitely related to either intervention.Practitioners belonged to the 2 main U.K.-based professional associations, which may limit generalizability of the findings.Acupuncture sessions and Alexander Technique lessons both led to significant reductions in neck pain and associated disability compared with usual care at 12 months. Enhanced self-efficacy may partially explain why longer-term benefits were sustained.Arthritis Research UK.
A functional polymorphism in XRCC1 gene is associated with lung cancer risk in a Korean population
Authors: Seung Soo Yoo, Chengcheng Jin, Keum Ju Choi, So Yeon Lee, Yong Dae Lee, Shin Yup Lee, Jaehee Lee, Seung Ick Cha, Chang Ho Kim, Jae Yong Park
Journal: European Respiratory Journal (2014)

Defects on DNA repair system are associated with carcinogenesis. It has been reported that a number of  XRCC1  polymorphisms are related with lung cancer risk. We investigated the relationship between 5 potentially functional polymorphisms and lung cancer risk in a Korean population. In total, 610 lung cancer patients and 610 healthy controls were enrolled in this case-control study. Among 5 polymorphisms, the rs25489G>A was significantly associated with lung cancer risk (codominant model, odds ratio = 0.65, 95 % confidence interval = 0.49-0.87,  P  value = 0.003). When stratified according to smoking status, age, gender and tumor histology, the rs25489G>A was associated with lung cancer risk in never smoker, young age, female and adenocarcinoma ( P  value = 0.004, 0.003. 0.001 and  XRCC1  may contribute to genetic susceptibility to lung cancer.
Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer.
Authors: H M Lazarus, R H Herzig, J Graham-Pole, S N Wolff, G L Phillips, S Strandjord, D Hurd, W Forman, E M Gordon, P Coccia
Journal: Journal of Clinical Oncology (1983)

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.
Ultrasound evaluation of diaphragmatic function in obstructive sleep apnea
Authors: George Matziaras, Katerina Vlami, Argiro Antaraki, Anastasia Papastefanou, Vaggelis Balafas, Nikos Kostomitsopoulos, Spiros Papiris, Alkiviadis Kostakis
Journal: European Respiratory Journal (2011)

Background:  Little is known about diaphragmatic function during obstructive sleep apnea syndrome. On the other hand ultrasonography has been used to image the diaphragm diagnostically but not in obstructive sleep apnea. The aim of this study was to use ultrasound technique to evaluate and quantify diaphragm function in a rat model during sleep apnea under condition of normoxia.   Methods:  Experiments were conducted in ten male adult Wistar rats weighing 350 gr, which were anaesthetized with Ketamine-Xylazine intraperitoneally. Animals were breathing after being tracheostomized and connected in a circuit with an electromagnetic valve which was closing periodically every minute for 10 sec for two hours, mimicking obstructive apnoeas. Supplemental oxygen was added to keep normal arterial saturation (SaO2:97%). Diaphragm Inspiratory Amplitude (DIA) (cm), Diaphragm Inspiratory Time (Ti) (sec), breathing period (Ttot) (sec), Diaphragm Motion Time (DMT) (sec) and Diaphragm Resting Time (DRT) (sec) were measured from the M- mode sonographic images. Data analyzed and compared between quite breathing (time 0) and breathing after two hours of airway obstructions (time 0+2).   Results:  All diaphragmatic measurements (DIA,Ti,Ttot, DMT and DRT) from time 0 to time 0+2 were compared using the Wilcoxon signed-rank test and showed a statistically significant reduction (p   Conclusions:  These findings suggest that diaphragmatic function is affected acutely during obstructive sleep apnea. It is also indicated that diaphragmatic fatigue as expressed via DIA,DMT,DRT,Ti and Ttot is present independently of hypoxeamia after two hours of airway obstructions during sleep.
Management of chronic thromboembolic pulmonary hypertension (CTEPH): A physician-based perception study
Authors: Henning Tiede, Barbara Hinzmann, Nicholas Bawden, Ioana Preston
Journal: European Respiratory Journal (2012)

Background:  Therapeutic approach to CTEPH includes surgical and medical management. Pulmonary endarterectomy (PEA) is the standard of care in eligible patients (pts). Medical therapy with pulmonary arterial hypertension (PAH)-specific drugs has not been formally studied in this population.   Objectives:  To compare therapeutic management of CTEPH between different countries.   Methods:  Quantitative online survey conducted in 7 countries in Europe and North America, during 2010, of 331 physicians with experience in managing CTEPH for ≥2 years and who were treating ≥3 pts.   Results:  CTEPH pts were mostly treated by cardiologists (38%) and pulmonologists (34%) and 59% of physicians were affiliated with a pulmonary hypertension (PH) centre. Only 26% of pts were evaluated for PEA; 10% of all pts had undergone or were awaiting PEA. The proportion of pts who had been evaluated for and undergone/awaiting PEA was higher in PH centres compared with non-specialist centres (31% vs 17%; 12% vs 6%, respectively). A subset of physicians in the US was found to 9self-screen9 pts for PEA using subjective criteria. 59% of CTEPH pts were receiving PAH-specific therapies with little variation between countries. Comparison with a similar perceptual study in PAH pts demonstrated that the treatment of CTEPH mirrors that of PAH in terms of PAH-specific therapy usage and combination therapy.   Conclusions:  Despite PEA being the standard of care and a potentially curative treatment for CTEPH, a low referral rate for PEA evaluation was observed in clinical practice. There is a need for education about CTEPH, implementation of specific CTEPH management guidelines, and an established referral process after diagnosis.
Differential Frequencies of p16<sup>INK4a</sup> Promoter Hypermethylation, p53 Mutation, and K-ras Mutation in Exfoliative Material Mark the Development of Lung Cancer in Symptomatic Chronic Smokers
Authors: M. Kersting, C. Friedl, A. Kraus, M. Behn, W. Pankow, M. Schuermann
Journal: Journal of Clinical Oncology (2000)

PURPOSE: The aim of this study was to investigate the frequency of three (epi)genetic alterations (p53 and K-ras mutations and p16 INK4a promoter hypermethylation) in symptomatic chronic smokers compared with patients with lung cancer and to evaluate the use of exfoliative material for such analyses. PATIENTS AND METHODS: Fifty-one patients with histologically confirmed lung cancer and 25 chronic smokers (&gt; 20 pack-years) were investigated for mutations in the K-ras (codon 12) and p53 (codons 248, 249, and 273) genes and for allelic hypermethylation of the p16 INK4a gene. DNA was isolated from sputum and bilateral bronchial lavage, and brushings were taken at bronchoscopy. RESULTS: Forty-one genetic lesions were detected within exfoliative material from the group of 51 patients with lung cancer and 10 lesions in the chronic smoker group. K-ras mutations occurred exclusively in the lung cancer group, whereas p53 mutations and p16 INK4a promoter hypermethylation were also found in chronic smokers. Three of eight chronic smokers who harbored an (epi)genetic alteration were subsequently diagnosed with lung cancer. Analysis of sputum yielded information equivalent to that of samples obtained during bronchoscopy. CONCLUSION: p16 INK4a promoter hypermethylation and p53 mutations can occur in chronic smokers before any clinical evidence of neoplasia and may be indicative of an increased risk of developing lung cancer or of early disease. K-ras mutations occur exclusively in the presence of clinically detectable neoplastic transformation. Molecular analysis of sputum for such markers may provide an effective means of screening chronic smokers to enable earlier detection and therapeutic intervention of lung cancer.