tbuckley/cabot-search huggingface dataset:
Curtailing the High Rate of Late-Stage Attrition of Investigational Therapeutics Against Unprecedented Targets in Patients with Lung and Other Malignancies
Authors: Eric K. Rowinsky
Journal: Clinical Cancer Research (2004)

A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.
Commentary: acne, isotretinoin and suicide attempts
Authors: D.J. Margolis
Journal: British Journal of Dermatology (2011)

Acne is a fascinating and common illness. Its importance as a severe health concern is often trivialized by the medical community. Several severe adverse events have been postulated to be associated with the use of isotretinoin as a treatment for severe acne. For example, partially based on case reports and sensational discussions in the lay press, there has been a growing concern that isotretinoin when used to treat acne is associated with depression and suicidal ideation. Because isotretinoin is often used to treat individuals with severe acne, separating a direct association between acne and this severe adverse event from one associated with isotretinoin use to treat acne using observational designs may be difficult due to several forms of selection bias including confounding by indication and protopathic bias. Sundström et al.1 hypothesized that people with severe acne may be at higher risk of attempted suicide. In their recently published study, they attempt to answer this question by carefully evaluating a population of patients who used isotretinoin as a treatment for acne. Information on attempted suicide was available before the commencement of therapy with isotretinoin, during therapy with isotretinoin, and after therapy. They also carefully compared the rates of suicide with a standard population as well as within their cohort of isotretinoin users.
Economics of Sirolimus-Eluting Stents
Authors: William S. Weintraub
Journal: Circulation (2004)

ince the development of coronary angioplasty in the late 1970s, there have been a series of technical advancements that have improved the outcome of the procedure.Clearly, the biggest advance was to move from balloon angioplasty to intracoronary stenting and now to drug-eluting stents (DES). 1,2These advances have been shown to reduce in-hospital events and to dramatically lower the incidence of restenosis, the long standing "Achilles' Heel" of percutaneous coronary intervention (PCI).As these advances have occurred, there has been concern about the ability of society to afford these new therapies.
Morphological changes induced by extensive endobronchial electrocautery
Authors: C. Verkindre, A. Brichet, C.a Maurage, P Ramon, J-P Homasson, C.h Marquette
Journal: European Respiratory Journal (1999)

Due to recent improvements of safety conditions for therapeutic devices, electrocautery is being considered with renewed interest in the field of therapeutic bronchoscopy. The efficiency of this technique for destructing intraluminal tumours is well documented and makes it an attractive alternative to Yttrium aluminium garnet (YAG) laser photo-coagulation. Little is known, however, about the morphologic changes induced by electrocautery within the bronchial wall structures. This information is, however, important since electrocautery has been proposed as an alternative to other techniques to treat superficial tumours of the bronchial wall. Soft coagulation, with autostop, using two different power setting (40 and 120 W), produced by a new generation of high frequency voltage regulated generators was applied circumferentially to the trachea or left main bronchus, in a series of 52 piglets. Early (48 h) and late effects (6 weeks) were assessed through gross examination (bronchoscopy and autopsy) and light microscopy. Early effects of electrocautery included coagulation necrosis of the mucosa only and intense acute inflammation extending deep into the bronchial structure. The inflammatory phase progressively resolved while extensive transmural fibrosis and deterioration of the cartilage plates developed. The nature and extent of these lesions did not depend upon the energy delivered (40 W versus 120 W). Retractile scar formation and loss of cartilaginous support then produced iatrogenic secondary stenoses. These results do not question the use of electrocautery to palliate endoluminal tumours but should make operators careful when treating extensive infiltration of the bronchial wall.
ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNF inhibitors
Authors: S. J. Pedersen, I. J. Sorensen, P. Garnero, J. S. Johansen, O. R. Madsen, N. Tvede, M. S. Hansen, G. Thamsborg, L. S. Andersen, O. Majgaard, A. G. Loft, J. Erlendsson, K. Asmussen, A. G. Jurik, J. Moller, M. Hasselquist, D. Mikkelsen, T. Skjodt, R. Lambert, A. Hansen, M. Ostergaard
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. <h3>Methods</h3> ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. <h3>Results</h3> Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. <h3>Conclusion</h3> Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.
Interferon is associated with type 1 interferon-inducible gene expression in dermatomyositis
Authors: A. P. Liao, M. Salajegheh, R. Nazareno, J. C. Kagan, R. G. Jubin, S. A. Greenberg
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To determine whether type 1 interferon (IFN) proteins in blood are associated with downstream type 1 IFN-inducible gene expression in blood from patients with myositis. <h3>Methods</h3> IFNα, IFNβ and IFNω concentrations were measured by ELISA in 129 blood samples (from 93 patients with dermatomyositis (DM), inclusion body myositis, polymyositis and other muscle diseases and from 36 healthy volunteers). Their concentrations were correlated with their ability to stimulate type 1 IFN-inducible gene transcription in a functional assay for 123 of these samples and the type 1 IFN-inducible blood gene expression from 70 of the same samples. <h3>Results</h3> Blood IFNβ concentration was uniquely associated with DM (p=0.0004), detectable in 64% of samples from patients with untreated or minimally treated DM and 35% of all DM samples compared with 6% of other inflammatory myopathy and 6% of healthy volunteer samples. Blood IFNβ, but not IFNα or IFNω, correlated with high blood type 1 IFN-inducible gene expression (p=0.01). Healthy volunteer samples with a high ELISA signal for IFNα and IFNω lacked functional bioassay activity and such a signal was confirmed as artefactual. <h3>Conclusion</h3> Elevated blood IFNβ protein concentration is associated with DM. Systemic and local production of IFNβ might contribute to, but may not fully explain, the marked overproduction of type 1 IFN-inducible transcripts and proteins seen in DM muscle and blood.
Tricuspid Valve Surgery in Adults With a Dysfunctional Systemic Right Ventricle
Authors: Roderick W.C. Scherptong, Hubert W. Vliegen, Michiel M. Winter, Eduard R. Holman, Barbara J.M. Mulder, Ernst E. van der Wall, Mark G. Hazekamp
Journal: Circulation (2009)

Background— In patients with a right ventricle (RV) in the systemic position, tricuspid valve surgery for regurgitation beyond adolescence is a subject of debate. The aim of the present study was to evaluate the complications, survival, and benefit of tricuspid surgery in adult patients with an atrium-level correction for transposition of the great arteries or congenitally corrected transposition of the great arteries. Methods and Results— All adult patients (n=16; 7 men, 9 women; age 35±11 years) who underwent tricuspid valvuloplasty (n=8) or replacement (n=8) in the period 1999 to 2008 were included. Complications and survival were analyzed, and postoperative changes in RV function and functional class were evaluated. Tricuspid regurgitation was graded 1 to 4 according to its severity, RV dysfunction was graded as 1 to 4 (1=no dysfunction to 4=severe dysfunction), and functional status was determined according to New York Heart Association class. Although complications occurred in 11 patients, all could be managed adequately. Three patients died 109, 180, and 659 days after surgery, respectively, the first patient after tricuspid valve replacement and the latter 2 after tricuspid valvuloplasty. Overall, tricuspid valve function improved (from grade 3.1±0.8 to 0.9±1.0; P =0.001) and functional class improved (from 2.7±0.6 to 2.1±0.8; P =0.007), whereas RV function remained unchanged. After tricuspid valvuloplasty, however, recurrent moderate tricuspid valve regurgitation was observed frequently (n=3; 37%). Conclusions— Mortality is rather low after tricuspid surgery in adult patients with mild to moderate RV dysfunction. In general, tricuspid valve function and functional class improve significantly after surgery, and systemic RV function is preserved. Tricuspid valvuloplasty, however, is associated with a high rate of recurrence of regurgitation.
Amphetamine Intoxication with Coagulopathy, Hyperthermia, and Reversible Renal Failure
Authors: MYRON D. GINSBERG
Journal: Annals of Internal Medicine (1970)

After ingesting approximately 2 g of amphetamine sulfate, a 21-year-old man was admitted in delirium with a temperature above 108 F. He subsequently developed acute self-limited renal failure and a coagulopathy with intramuscular hemorrhages producing entrapment neuropathies. The association of amphetamines with reversible renal failure has not been previously described. The resemblance of the features in this case to instances of heatstroke is striking and suggests a similar pathophysiology.
Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study
Authors: Laurent Spahr, Laura Rubbia-Brandt, Jean-Louis Frossard, Emile Giostra, Anne-Laure Rougemont, Jérôme Pugin, Maria Fischer, Hanspeter Egger, Antoine Hadengue
Journal: Journal of Hepatology (2002)
Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled?
Authors: P. He
Journal: Cardiovascular Research (2010)

In response to infections or tissue injury, circulating leucocytes adhere to and migrate from the vessel lumen to interstitial inflammatory sites to combat invading pathogens. However, these defensive actions may also cause host tissue injury and microvascular dysfunction through oxidative bursts or enzyme release. For decades, the interaction between leucocytes and microvessel walls has been considered as a critical event leading to organ dysfunction. Extensive investigations have therefore focused on blocking specific adhesive ligands to prevent tissue injury. However, anti-adhesion therapies have shown limited success in preventing vascular dysfunction in clinical trials. Numerous studies have demonstrated temporal and spatial dissociations of leucocyte adhesion and/or emigration from permeability increases. The mechanisms that initiate the adhesion cascade have been found to be distinct from those that trigger the leucocyte oxidative burst responsible for increasing microvessel permeability. Recent studies demonstrated that endothelial activation by inflammatory mediators is critical for initiating platelet adhesion and platelet-dependent leucocyte recruitment resulting in augmented increases in microvessel permeability. These new developments suggest that targeting endothelial activation via directly enhancing endothelial barrier function might be a more efficient strategy than focusing on anti-adhesion or platelet/leucocyte depletion to prevent vascular damage during inflammation. Owing to space limitations and the wide range of studies in the field, this article will not serve as a comprehensive review. Instead, it will highlight the emerging evidence of adhesion-uncoupled permeability changes and establish a basis for re-evaluating the coupled relationship between leucocyte/platelet activation and microvessel permeability to achieve a better understanding of permeability regulation during inflammation.
Five-Year Outcomes of a Randomized Phase III Trial Comparing Adjuvant Chemotherapy With S-1 Versus Surgery Alone in Stage II or III Gastric Cancer
Authors: Mitsuru Sasako, Shinichi Sakuramoto, Hitoshi Katai, Taira Kinoshita, Hiroshi Furukawa, Toshiharu Yamaguchi, Atsushi Nashimoto, Masashi Fujii, Toshifusa Nakajima, Yasuo Ohashi
Journal: Journal of Clinical Oncology (2011)

The first planned interim analysis (median follow-up, 3 years) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival, the primary end point. The results were therefore opened at the recommendation of an independent data and safety monitoring committee. We report 5-year follow-up data on patients enrolled onto the ACTS-GC study.Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 after surgery or surgery only. S-1 (80 to 120 mg per day) was given for 4 weeks, followed by 2 weeks of rest. This 6-week cycle was repeated for 1 year. The primary end point was overall survival, and the secondary end points were relapse-free survival and safety.The overall survival rate at 5 years was 71.7% in the S-1 group and 61.1% in the surgery-only group (hazard ratio [HR], 0.669; 95% CI, 0.540 to 0.828). The relapse-free survival rate at 5 years was 65.4% in the S-1 group and 53.1% in the surgery-only group (HR, 0.653; 95% CI, 0.537 to 0.793). Subgroup analyses according to principal demographic factors such as sex, age, disease stage, and histologic type showed no interaction between treatment and any characteristic.On the basis of 5-year follow-up data, postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy.
Good Metabolic Control Is Associated With Better Quality of Life in 2,101 Adolescents With Type 1 Diabetes
Authors: Hilary Hoey, Henk-Jan Aanstoot, Francesco Chiarelli, Denis Daneman, Thomas Danne, Harry Dorchy, Michael Fitzgerald, Patrick Garandeau, Stephen Greene, Reinhard Holl, Philip Hougaard, Eero Kaprio, Mirjana Kocova, Helle Lynggaard, Pedro Martul, Nobuo Matsuura, Hannah M. McGee, Henrik B. Mortensen, Kenneth Robertson, Eugen Schoenle, Oddmund Sovik, Peter Swift, Rosa Maria Tsou, Maurizio Vanelli, Jan Åman
Journal: Diabetes Care (2001)

OBJECTIVE—It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families. RESEARCH DESIGN AND METHODS—The study involved 2,101 adolescents, aged 10–18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA1c was analyzed centrally (normal range 4.4–6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires. RESULTS—Mean HbA1c was 8.7% (range 4.8–17.4). Lower HbA1c was associated with lower impact (P &amp;lt; 0.0001), fewer worries (P &amp;lt; 0.05), greater satisfaction (P &amp;lt; 0.0001), and better health perception (P &amp;lt; 0.0001) for adolescents. Girls showed increased worries (P &amp;lt; 0.01), less satisfaction, and poorer health perception (P &amp;lt; 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P &amp;lt; 0.0001). Patients from ethnic minorities had poorer scores for impact (P &amp;lt; 0.0001), worries (P &amp;lt; 0.05), and health perception (P &amp;lt; 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores. CONCLUSIONS—In a multiple regression model, lower HbA1c was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.
Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis
Authors: Enrico Tortoli, Cristina Russo, Claudio Piersimoni, Ester Mazzola, Paola Dal Monte, Michela Pascarella, Emanuele Borroni, Alessandra Mondo, Federica Piana, Claudio Scarparo, Luana Coltella, Giulia Lombardi, Daniela M. Cirillo
Journal: European Respiratory Journal (2012)

Extrapulmonary tuberculosis (EPTB) accounts for more than 20% of tuberculosis (TB) cases. Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, CA, USA) is a fully automated amplification system, for which excellent results in the diagnosis of pulmonary TB in highly endemic countries have been recently reported. We aimed to assess the performance of the Xpert system in diagnosing EPTB in a low incidence setting. We investigated with Xpert a large number of consecutive extrapulmonary clinical specimens (1,476, corresponding to 1,068 patients) including both paediatric (494) and adult samples. We found, in comparison with a reference standard consisting of combination of culture and clinical diagnosis of TB, an overall sensitivity and specificity of 81.3% and 99.8% for Xpert, while the sensitivity of microscopy was 48%. For biopsies, urines, pus and cerebrospinal fluids the sensitivity exceeded 85%, while it was slightly under 80% for gastric aspirates. It was, in contrast, lower than 50% for cavitary fluids. High sensitivity and specificity (86.9% and 99.7%, respectively) were also obtained for paediatric specimens. Although the role of culture remains central in the microbiological diagnosis of EPTB, the sensitivity of Xpert in rapidly diagnosing the disease makes it a much better choice compared to smear microscopy. The ability to rule out the disease still remains suboptimal.
Early Catheter Removal after Robot-assisted Radical Prostatectomy: Surgical Technique and Outcomes for the Aalst Technique (ECaRemA Study)
Authors: Christian Gratzke, Zach Dovey, Giacomo Novara, Nicolas Geurts, Ruben De Groote, Peter Schatteman, Geert de Naeyer, Giorgio Gandaglia, Alexandre Mottrie
Journal: European Urology (2015)
Possible hepatosplenic candidiasis treated with liposomal amphotericin B and caspofungin combination
Authors: Bilgin Arda, Nur Soyer, Oguz Resat Sipahi, Ozcan Hüdaverdi, Meltem Isikgoz Tasbakan, Guray Saydam, Murat Tombuloglu
Journal: Journal of Infection (2005)
Cardiac Auscultation
Authors: Morton E. Tavel
Journal: Circulation (2006)

Cardiac auscultation remains an important part of clinical medicine. The standard acoustic stethoscope, which has been useful for more than a century, cannot process, store, and play back sounds or provide visual display, and teaching is hindered because there is no means to distribute the same sounds simultaneously to more than one listener. Modern portable and inexpensive tools are now available to provide, through digital electronic means, better sound quality with visual display and the ability to replay sounds of interest at either full or half speed with no loss of frequency representation or sound quality. Visual display is possible in both standard waveform and spectral formats. The latter format is readily available and provides certain advantages over the time-honored waveform (phonocardiographic) method. Both methods, however, can and should be used simultaneously. Sound signals obtained electronically may then be subjected to objective visual and numerical analysis, transmitted to distant sites, and stored in medical records. Signal analysis shows early promise for clinical application, such as in the assessment of severity of aortic stenosis and in the separation of innocent from organic murmurs. In addition to their clinical value, these methods provide a critical vehicle for the teaching of cardiac auscultation, a method that can and should be preserved for future generations.