tbuckley/cabot-search huggingface dataset:
A phase 2 study of prostate specific membrane antigen antibody drug conjugate (PSMA ADC) in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following abiraterone and/or enzalutamide (abi/enz).
Authors: Daniel Peter Petrylak, Nicholas J. Vogelzang, Gurkamal S. Chatta, Mark T. Fleming, David C. Smith, Leonard Joseph Appleman, Arif Hussain, Manuel Modiano, Parminder Singh, Scott T. Tagawa, Ira Gore, Edward Francis McClay, Anthony E. Mega, A. Oliver Sartor, Bradley G. Somer, Raymond Couric Wadlow, Neal D. Shore, Nancy Stambler, Vincent A. DiPippo, Robert Joseph Israel
Journal: Journal of Clinical Oncology (2015)

144 Background: PSMA is a validated target that is overexpressed selectively on prostate cancer cells. PSMA ADC is a fully human IgG1 antibody conjugated to the microtubule disrupting agent MMAE which binds to PSMA-positive cells, inducing cytotoxicity. A phase 1 study showed activity and tolerability at doses from 1.8-2.5 mg/kg. We have enrolled 119 mCRPC pts who progressed following abi/enz in a phase 2 trial of PSMA ADC. Methods: mCRPC pts (83 taxane experienced (TE) and 36 chemo-naïve (CN)) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 wk for up to 8 cycles. 95% of pts received prior abi and/or enz treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed. Results: In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to &lt;5 cells/7.5 ml blood in 47% (n=77) at any time during the study. For 2.3 mg/kg pts (n=82), corresponding PSA declines were 35% and 17%; CTC declines of ≥50% were seen in 81% and conversions in 46% (n=54). For CN pts, PSA declines of ≥30% and ≥50% were 31% and 20% (n=35); CTC declines of ≥50% were seen in 89% and conversion in 53% (n=19). Radiologic response by RECIST in 31 pts with measurable target lesions: PR in 4 pts, SD in 19 pts, and PD in 8 pts. Efficacy responses were associated with: low neuroendocrine serum markers (low CgA, low NSE, and high PSA), high PSMA expression (CTCs or tumor tissue). The most common treatment-related AEs ≥CTCAE grade 3 were neutropenia (TE: 25%; CN: 22%), fatigue (20%; 8%), electrolyte imbalance (16%; 11%), anemia (10%; 8%), and neuropathy (8%; 8%). Grade 1-2 neuropathy occurred in 40% (TE) and 50% (CN) of pts. Two 2.5 mg/kg pts (n=34) and one 2.3 mg/kg pt (n=85) died of sepsis. 2.3 mg/kg was better tolerated than 2.5 mg/kg. Conclusions: PSMA ADC was active in abi/enz refractory mCRPC pts. Clinically significant AEs included neutropenia and neuropathy. CTC conversions/reductions, PSA declines, and radiologic evidence of antitumor activity were seen in CN as well as heavily pretreated pts. Clinical trial information: NCT01695044.
Abstract P122: An Interactive Intervention to Increase Stroke Knowledge: Results of the SWIFT Study
Authors: Eric T Roberts, Emma K Benn, Leigh Quarles, Veronica Perez, Bernadette Boden-Albala
Journal: Circulation (2014)

Introduction: The majority of acute stroke patients do not seek care within the optimal 3 hour time frame. General informational strategies have not increased stroke preparedness, possibly due to a lack of attention to health literacy or cultural tailoring. Several interventions have successfully increased stroke knowledge yet there remains skepticism that knowledge alone can lead to behavior change. The Stroke Warning Information and Faster Treatment (SWIFT) trial is the first intervention to rigorously test whether an interactive educational intervention (II; 2 in-hospital educational sessions and health literate, culturally tailored materials), compared to an enhanced educational intervention (EE; only educational materials) can increase arrival times for stroke/TIA recurrence to the emergency department (ED) in 1193 participants. Aims: SWIFT found large, non-differential increases in the proportion of participants arriving to the ED within 3 hours in both the II and EE group. Here we assess the effect of SWIFT on stroke knowledge (SK), and stroke preparedness (SP), and assess differences by race. Methods: SK was assessed with the 29 item stroke knowledge scale and dichotomized as high/low SK (≥ 23/&lt; 23 correct). SP was dichotomized into those that knew the three important things to tell a health professional after the onset of stroke symptoms and those that identified less than 3 things. These scales were measured at baseline, and one and twelve months after baseline. We fit logit-linear models for high SK and high SP using generalized estimating equations. Results: We observed no difference between groups at baseline in SK (p-value = 0.44) or SP (p-value = 0.36). For SK, we observed statistically significant effect modification such that knowledge increased over time (p-value = 0.02) and the effect was differential by intervention group (p-value = 0.04). At one month the II group had 1.63 (95%CI = 1.23, 2.15) times greater odds of having high SK compared to the EE group but by twelve months there was no difference between groups (OR=1.21; 0.87, 1.67). However, for SP there is not a statistically significant effect of time (p-value = 0.07) but there is a difference in the rate of change by group. The II group had greater odds of having high SP at one month (OR=3.36; 1.86, 6.10) and twelve months (OR=7.64; 2.49, 23.49) compared to the EE group. We did not observe differences in rates of change by race for SK (p-value = 0.21) or SP (p-value = 0.86) but SK (p-value &lt; 0.01) and SP (p-value &lt; 0.01) increased over time for all races. Overall, we find that both II and EE increase SK over 12 months but that only II was able to increase SP. Moreover, this effect was observed for all race ethnic groups. Conclusions: The provision of culturally tailored, health literate information alone was able to increase SK; it did not eliminate racial disparities in SK but did improve SK for all race/ethnic groups studied.
Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease
Authors: Juan P. de Torres, Jose M. Marín, Ciro Casanova, Claudia Cote, Santiago Carrizo, Elizabeth Cordoba-Lanus, Rebeca Baz-Dávila, Javier J. Zulueta, Armando Aguirre-Jaime, Marina Saetta, Manuel G. Cosio, Bartolome R. Celli
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Little is known about the clinical factors associated with the development of lung cancer in patients with chronic obstructive pulmonary disease (COPD), although airway obstruction and emphysema have been identified as possible risk factors.To explore incidence, histologic type, and factors associated with development of lung cancer diagnosis in a cohort of outpatients with COPD attending a pulmonary clinic.A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was followed a median of 60 months(30–90). At baseline, anthropometrics, smoking history, lung function,and body composition were recorded. Time to diagnosis and histologic type of lung cancer was then registered. Cox analysis was used to explore factors associated with lung cancer diagnosis.A total of 215 of the 2,507 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person-years). The most frequent type was squamous cell carcinoma (44%). Lung cancer incidence was lower in patients with worse severity of airflow obstruction. Global Initiative for Chronic Obstructive Lung Disease Stages I and II, older age, lower body mass index,and lung diffusion capacity of carbon monoxide less than 80%were associated with lung cancer diagnosis.Incidence density of lung cancer is high in outpatients with COPD and occurs more frequently in older patients with milder airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease Stages I and II) and lower body mass index. A lung diffusion capacity of carbon monoxide less than 80% is associated with cancer diagnosis. Squamous cell carcinoma is the most frequent histologic type. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.
Does the model of parallel connected bronchi in each generation functionally correspond to the true dichotomy structure of the bronchial tree
Authors: Liubov Barbinova, Xaver Baur
Journal: European Respiratory Journal (2012)

Background: The structure of the bronchial tree is described in Weibel's model as a dichotomy pattern of the airways branching. The classic calculation of airways resistance (Raw) is, however, based on the assumption of parallel connected bronchi in each generation. We investigated the conditions, under which this assumption correctly represents the dichotomy.

Methods: We calculated Raw by a classical model (parallel connected bronchi (PM)) und compared it with Raw obtained by a dichotomous model (DM). In the latter, Raw was calculated consecutively by pairs of branching in 23 generations. We simulated an obstruction of 50% of the bronchi to 0.5 (half) of their radius.

Results: In case of normal structure (all bronchi of each generation have ideal radius) provided both models identical Raw.

Further analysis showed that PM is not sensitive for the spatial distribution of obstructive bronchi. It operates only with their number in each generation regardless whether the obstruction occurs in the same or in different segments.

DM is sensible to the heterogeneity of obstruction. The simulations of random distributed obstruction showed that DM leads to a 2.1fold higher Raw compared to PM. Primarily vertical bronchial heterogeneity plays an essential role. By simulation of different patterns of topographical heterogenous obstruction, estimated Raw is in DM on the average 4.3fold higher than in PM.

Conclusions: The classical model of parallel connected bronchi of each generation disregards the topography of obstruction that leads to falsely decreased Raw estimation. Spatial heterogeneity of the obstruction is an important factor of Raw increase.
Tobacco smoking alters the relationship between airway inflammation and airway hyperresponsiveness in asthma
Authors: Christian Grabow Westergaard, Celeste Porsbjerg, Vibeke Backer
Journal: European Respiratory Journal (2012)

Background: Smoking in asthma patients constitutes a major health problem, due to impaired steroid responsiveness, poor symptom control and an accelerated loss of lung function. This may relate to alterations in the airway inflammation. The aim of the present study was to evaluate the effect of smoking on the relationships between airway inflammation and airway hyperresponsiveness in asthma patients not on steroid treatment.  Material and methods: A group of smoking asthma patients (n=27) was compared to a group of non smoking asthma patients (n=34) with induced sputum, exhaled nitrogenous oxide (eNO) and airway hyperresponsiveness with a bronchial challenge with mannitol. Airway eosinophilia was defined as a sputum % eosinophils > 2 %.  Results: A significantly higher proportion of patients with non-eosinophilic asthma was observed in the smoking group than in the non-smoking group (44% and 18%, p=0.023). The mean eNO was lower in the smoker group compared to the non-smoker group (11.7 ppb vs 38.2 ppb (p=0.001)). The proportion of subjects with a positive mannitol test was comparable among smokers (68%), and non-smokers (50%) (p=0.19). Smokers with a positive mannitol test (n=15) had a lower mean eNO (15.4 ppb) than the non-smokers (mean eNO=46.3 ppb, n=15), p=0.006.  Conclusion: Our data showed that despite of a lower proportion of eosinophilic phenotype amongst the smoking asthma patients than amongst the non-smokers, no reduced degree of airway hyperresponsiveness to mannitol in the smoker group was observed, indicating that pathogenetic mechanisms other than eosinophilic airway inflammation are responsible for the tendency to airway narrowing in smoking asthma patients.
Anaesthesia and Monitoring for Paediatric Radiotherapy
Authors: W F Casey, Vanessa Price, H S Smith
Journal: Journal of the Royal Society of Medicine (1986)

Four hundred and sixty-nine anaesthetics were given to 27 children between the ages of 18 months and 5 years so that they could receive radiotherapy. When ketamine was used as the sole anaesthetic agent, the induction of anaesthesia was frequently stressful and traumatic, with problems and difficulties being encountered during 24% of anaesthetics. A change to an entirely gaseous method of inducing and maintaining anaesthesia resulted in a much more acceptable service being offered to the children and the incidence of complications fell to only 4%. The problems of monitoring children whilst they receive radiotherapy under general anaesthesia are discussed, the merits of different methods are reviewed and the use of the capnograph is commended.
Doctors who smoke
Authors: P. Sudbury
Journal: BMJ (1995)

Why not exclude doctors with other unhealthy habits too?

EDITOR,--I am encouraged by Simon Chapman's suggestion that doctors who smoke are undesirable in primary care.1 Perhaps it is important that we preserve the fantasy that doctors are fundamentally different from their patients rather than acknowledging that we have all of the same human failings and using our joint experience of imperfection to understand the difficulties we all face in balancing the costs and benefits of our behaviour. We should also …
Targeting Angiogenesis in Advanced Non-Small Cell Lung Cancer
Authors: Philip E. Lammers, Leora Horn
Journal: Journal of the National Comprehensive Cancer Network (2013)

Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer.
BALL-SNP: combining genetic and structural information to identify candidate non-synonymous single nucleotide polymorphisms
Authors: Sabine C. Mueller, Christina Backes, Olga V. Kalinina, Benjamin Meder, Daniel Stöckel, Hans-Peter Lenhof, Eckart Meese, Andreas Keller
Journal: Genome Medicine (2015)

High-throughput genetic testing is increasingly applied in clinics. Next-Generation Sequencing (NGS) data analysis however still remains a great challenge. The interpretation of pathogenicity of single variants or combinations of variants is crucial to provide accurate diagnostic information or guide therapies.To facilitate the interpretation of variants and the selection of candidate non-synonymous polymorphisms (nsSNPs) for further clinical studies, we developed BALL-SNP. Starting from genetic variants in variant call format (VCF) files or tabular input, our tool, first, visualizes the three-dimensional (3D) structure of the respective proteins from the Protein Data Bank (PDB) and highlights mutated residues, automatically. Second, a hierarchical bottom up clustering on the nsSNPs within the 3D structure is performed to identify nsSNPs, which are close to each other. The modular and flexible implementation allows for straightforward integration of different databases for pathogenic and benign variants, but also enables the integration of pathogenicity prediction tools. The collected background information of all variants is presented below the 3D structure in an easily interpretable table format.First, we integrated different data resources into BALL-SNP, including databases containing information on genetic variants such as ClinVar or HUMSAVAR; third party tools that predict stability or pathogenicity in silico such as I-Mutant2.0; and additional information derived from the 3D structure such as a prediction of binding pockets. We then explored the applicability of BALL-SNP on the example of patients suffering from cardiomyopathies. Here, the analysis highlighted accumulation of variations in the genes JUP, VCL, and SMYD2.Software solutions for analyzing high-throughput genomics data are important to support diagnosis and therapy selection. Our tool BALL-SNP, which is freely available at http://www.ccb.uni-saarland.de/BALL-SNP, combines genetic information with an easily interpretable and interactive, graphical representation of amino acid changes in proteins. Thereby relevant information from databases and computational tools is presented. Beyond this, proximity to functional sites or accumulations of mutations with a potential collective effect can be discovered.
Rasch analysis for evaluating abbreviated World Health Organization quality of life questionnaire (WHOQOL-Bref) in north Indian patients with bronchial asthma
Authors: Ashutosh Aggarwal, Ritesh Agarwal, Dheeraj Gupta
Journal: European Respiratory Journal (2011)

Introduction: A disease-specific instrument to describe health-related quality of life (HRQoL) in Indian asthmatics is not available. A generic Hindi HRQoL measure - abbreviated World Health Organization Quality of Life questionnaire (WHOQOL-Bref) - has however been developed and validated in India. We evaluated the WHOQOL-Bref in adult patients of asthma, and tested possible modifications to the instrument to improve its psychometric adequacy.

Methods: 67 asthmatics completed the WHOQOL-Bref. Rasch analysis was used to explore the psychometric performance of the four domains (physical, psychological, social relationships, and environment) of the scale. Overall fit of data to model expectations, appropriate category ordering, presence of differential item functioning (DIF), individual item fit, and targeting of item difficulty to patient ability were explored for each domain. Item deletion and rescoring were applied to misfitting items to improve overall performance.

Results: Overall fit of the WHOQOL-Bref data was adequate. Item 3 had a large positive fit residual value resulting in poor construct validity for physical domain. No item exhibited DIF. Ten items had disordered thresholds. The WHOQOL-Bref was modified by dropping item 3, and rescoring category structures of 16 items. The modified scale had good construct validity for all domains, ordered thresholds for all items, and good targeting of items to persons.

Conclusion: WHOQOL-Bref proved a psychometrically inadequate scale in our study group. However, the scale, when modified through Rasch analysis, proved better at describing HRQoL in the asthmatics studied.
Epirubicin/paclitaxel (EP) vs. capecitabine/paclitaxel (XP) in first-line metastatic breast cancer (MBC): A prospective, randomized multicentre phase III study of the AGO breast cancer study group
Authors: H. Lueck, G. V. Minckwitz, A. Du Bois, I. Schrader, J. Huober, V. Heilmann, M. Beckmann, A. Stähle, C. Jackisch, C. Marth, B. Richter
Journal: Journal of Clinical Oncology (2006)

517 Background: Anthracyline-taxane combinations have the highest response rates in high risk MBC. Recently, anthracyclines and taxanes have become standards for adjuvant breast cancer chemotherapy. The addition of capecitabine to docetaxel improved overall survival in MBC. This regime was associated with a high rate of side effects (actually FN was not different from Taxotere mono - it was more the addition of cape AEs to Taxotere AEs). Earlier phase II studies with XP are able to show efficacy with better tolerability including less febrile neutropenia. Methods: Our aim was to show non-inferiority of XP to EP. The primary endpoint was progression-free survival (PFS). Secondary endpoints were toxicity and overall survival (OS).Patients (pts) were treated with 6x E 60 mg/m 2 and P 175 mg/m 2 d1 q21d, or with 6× X 2×1000 mg/m 2 d1–14 q 21d and P 175 mg/m 2 d1 q21d. Results: During a period of 2.5 y the planned 340 pts (170 in each arm) in 63 centres were recruited. The median number of cycles was 6 in both arms. The median PFS for EP was 11.8 months, and 12.3 for XP (p=ns). OS also was not different between the arms. The response rate (RECIST) was 41.0% (CR 6.6%, PR 34.4%) for EP and 41.5% (CR 8.5%, PR 33.1%) for XP. The main toxicity was myelosuppression (10% of cycles grade 3/4). Febrile neutropenia was seen in 5 cases in EP and in 1 case in XP. Skin toxicity grade 3 was observed in 5 of XP pts. Two patients stopped treatment for cardiological reasons in EP, and 4 patients for GI reasons in XP. Conclusions: This first analysis shows a comparable efficacy of the non-anthracycline regimen XP to the EP combination in first-line MBC. The toxicity is relatively low compared to other non-anthracycline containing combination therapies. XP is therefore an appropriate option for pts with anthracycline pretreated first line MBC. [Table: see text]
Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells
Authors: Dongmei Fan, Wei Li, Yuqi Yang, Xiaolong Zhang, Qing Zhang, Yan Yan, Ming Yang, Jianxiang Wang, Dongsheng Xiong
Journal: Journal of Hematology & Oncology (2015)

B-acute lymphoblastic leukemia (B-ALL) is derived from B cell progenitors. Recently, the development of appropriate combinations of chemotherapy and immunotherapy represents a promising approach for eliminating cancer. We previously constructed an anti-CD3 × anti-CD19 bi-specific antibody in a diabody configuration and its disulfide-stabilized format (ds-diabody). The combination of the diabody or ds-diabody and Ara-C was highly effective in enhancing the cytotoxicity of T cells against the CD19+ human leukemia cell-line, Nalm-6, both in vitro and in vivo. This study verified whether B-ALL patient-derived cells were sensitive to the diabody or ds-diabody and low-dosage Ara-C combination. This study aimed to detect the B7 family members B7.1 (CD80) and B7.2 (CD86) that were expressed in B-ALL patient-derived cells pre-treated by Ara-C (0.25 μM) and to determine the targeted killing ability of T cell subtypes induced by the diabody or ds-diabody combination with Ara-C both in vitro and in vivo. We also determined the levels of the cytokines that were released by activated CD4+ or CD8+ T cells during therapy. Low-dose Ara-C enhanced CD80 and CD86 expression in nearly 50 % of specimens of B-ALL patient-derived cells. A combination of diabody or ds-diabody and Ara-C enhanced T cell against B-ALL cells in vitro and in vivo. Both CD8+ and CD4+ T cells were potently activated. Expression of CD25 and CD69 was augmented equally by CD4+ or CD8+ T cells. However, CD8+ T cells made the major contribution by redirecting target cell lysis in a granzyme B and perforin-dependent mechanism. CD4+ T cells played an important immunomodulatory role by secreting IL2. Consequently, IL3, IL6, TNFα, and IFNγ were also released by CD4+ or CD8+ T cells following diabody-mediated T cell activation. T cell therapy induced by diabody or ds-diabody combined with low dose of Ara-C was effective against cancer cell-lines and in clinical trials. In vivo, the ds-diabody was more efficient than its parent diabody due to its enhanced stability.