tbuckley/cabot-search huggingface dataset:
IMPS-41IMMUNE MODULATORY NANOPARTICLE THERAPEUTICS
Authors: Nasser Yaghi, Jun Wei, Yuuri Hashimoto, Ling-Yuan Kong, Konrad Gabrusiewicz, Edjah Nduom, Xiaoyang Ling, Neal Huang, Shouhao Zhou, Jonathan Levine, Virginia Fajt, Gwendolyn Levine, Brian Porter, Kiyoshi Tachikawa, Padmanabh Chivukula, David Webb, Joseph Payne, Amy Heimberger
Journal: Neuro-Oncology (2015)

BACKGROUND: Tumors establish an immunosuppressive environment acting like an invisibility cloak, allowing the tumor to grow while the immune system remains “blind” to the threat; however, microRNAs (miRs) can reverse this. Previously showing robust efficacy in glioblastoma murine models, we were one of the first groups to deliver therapeutic miRs intravenously. A hurdle to clinical translation remains a scalable formulation affording protection against RNases. Nanoparticles encapsulate and protect miRs from degradation, enhancing immune cell compartment delivery and facilitating antitumor effects – thus, overcoming need for direct tumor delivery. METHODS: Lipid nanoparticles, designated LUNAR, were devised to deliver miRs to peripheral blood mononuclear cells (PBMCs) and verified by in vivo pharmacokinetics and immune monitoring. Nanoparticles contain active immune modulatory agent, miR-124, which inhibits the signal transducer and activator of transcript 3 (STAT3). Formulations were tested in multiple murine models of malignancy, and evaluated for safety and immune modulation in a canine model. RESULTS: In mice dosed with LUNAR, miR-124 was delivered to PBMCs with reversal of immune suppression and enhancement of immune effector responses. The delivery of miR-124 was found to be highest in the monocyte/macrophage population, with the second highest population being the B cells. Median survival for mice with intracerebral GL261 treated with LUNAR exceeded 70 days, compared to 32.5 days for mice treated with previous gold-standard, miR-124 + lipofectamine. The cure rate difference between LUNAR and miR-124 + lipofectamine (4 out of 16 mice) was 35% (P = 0.0532). In a subcutaneous murine model of melanoma, tumor growth rate was expected to increase 44% daily, but reduced to 26.1% with LUNAR treatment (P = 0.007). Canines treated with LUNAR had no significant clinical toxicities and measurable increases in immune effector functions. CONCLUSIONS: LUNAR has favorable safety and efficacy profiles to justify implementation in client-owned canines or human clinical trials for glioma treatment.
Cost Effectiveness of Simvastatin Treatment to Lower Cholesterol Levels in Patients with Coronary Heart Disease
Authors: Magnus Johannesson, Bengt Jönsson, John Kjekshus, Anders G. Olsson, Terje R. Pedersen, Hans Wedel
Journal: New England Journal of Medicine (1997)

The Scandinavian Simvastatin Survival Study (4S) showed that lowering cholesterol levels with simvastatin reduces mortality and morbidity in patients with angina pectoris or previous acute myocardial infarction. Before the widespread use of cholesterol-lowering drugs in such patients is recommended, its cost effectiveness should be demonstrated. We estimated the cost effectiveness of simvastatin treatment to lower cholesterol levels in relation to the age, sex, and cholesterol level before treatment of patients with coronary heart disease.
P82 Lung clearance index (LCI) and genotype-phenotype correlations in Primary Ciliary Dyskinesia (PCD)
Authors: S Irving, M Dixon, S Ollosson, C Hogg, A Shoemark, A Bush
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Mutation type may affect clinical phenotype in PCD, as shown by differences in forced expiratory volume in 1 s (FEV<sub>1</sub>) (AJRCCM 2015;191:316–324). LCI, measured using multi-breath washout (MBW) is raised in PCD (AJRCCM 2013;188:545–549) but the relative sensitivities of the two physiological measurements is disputed (Thorax 2015;70:339–345, and 305–306). We hypothesised that LCI would be more sensitive to genotype-phenotype differences in PCD. <h3>Methods</h3> MBW (using sulphur hexafluoride MBW with a photoacoustic gas analyser) and spirometry were performed in 77 PCD patients (mean age 16.4 years (range 4–62.2), 33 males, mean FEV<sub>1</sub> z score -2.09 (range <sup>-</sup>5.33–1.59)). 44 had outer dynein arms (ODA) defects, or both inner (IDA) and ODA, 18 had microtubular defects (either transposition or microtubule disorganisation with absent IDA), 15 had normal ultrastructure (diagnosis made on either genetics (n = 10), low nasal NO, clinical phenotype and consistent dyskinesia on light microscopy (n = 1), or low nasal NO, clinical phenotype and an affected sibling (n = 3)). There was no significant difference in age or gender composition between the 3 groups. <h3>Results</h3> Patients with normal ultrastructure had significantly higher FEV<sub>1</sub> and lower LCI, indicating milder disease. Those with ODA +/- IDA had a more normal LCI than those with microtubular defects (Figure 1), but similar FEV<sub>1</sub>. <h3>Conclusions</h3> PCD patients with normal ultrastructure have the milder disease, and those with microtubular defects more severe. Differences were more apparent on LCI than FEV<sub>1</sub>, suggesting LCI may be more sensitive to worse distal small airway disease in PCD.
The Doctors' Dilemma
Authors: Robert G. Petersdorf
Journal: New England Journal of Medicine (1978)

IN the preface to the Doctor's Dilemma, George Bernard Shaw says:Make up your mind how many doctors the community needs to keep it well. Do not register more or less than this number; and let registration constitute the doctor a civil servant with a dignified living wage paid out of public funds.Although this statement was made in 1911, it has a remarkably contemporary ring and could as easily be made in 1978 by a consumer advocate or by a government official. It also constitutes the major dilemma of American medicine today — that is, how to deploy the . . .
SAT0627 Association Between Power Doppler Ultrasound (PDUS) and Disease Activity in Early Rheumatoid Arthritis (RA) Patients: Results from the Idea Study
Authors: R.B. Dumitru, E.M. Hensor, J. Nam, R.J. Wakefield, P. Emery, M.H. Buch
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> DAS is a validated composite measure of disease activity yet it has limitations in accurately reflecting synovitis; with in particular, the effect of subjective components tender joint counts and patient VAS<sup>1</sup>. Ultrasound imaging is more sensitive than clinical examination at detecting synovitis and power Doppler (PD) has been shown to correlate with markers of joint inflammation<sup>2.</sup> <h3>Objectives</h3> The aim of this study was to assess the association between PDUS and 28-joint disease activity score (DAS28) in early RA patients receiving treat-to-target (TT) regimen. <h3>Methods</h3> Data were obtained from the IDEA study<sup>3</sup>, a 78-week multicentre controlled trial, double-blinded to week 26. Patients with early RA were randomized to methotrexate (MTX) and infliximab (IFX) or MTX and intravenous methylprednisolone (iv MP), followed by TT regimen. Patients had US assessment at weeks 0, 50 and 78. Sum PDUS score of 18 joints (bilateral metacarpophalangeal 1-5, proximal interphalangeal 2, 3 bilateral, wrists, knees) and 3-variable DAS28 (CRP) were calculated at baseline, weeks 50 and 78. PDUS scores were transformed using ln (PDUS+1). Pearson9s product moment correlations between DAS28 and PDUS were determined. Linear regression models were constructed to adjust for DAS28 and PDUS values at baseline, treatment (MTX and iv MP/MTX vs IFX/MTX), age and disease duration. <h3>Results</h3> Of the 89 patients scanned, full data were available for 64; 34 (53%) received IFX and MTX and 30 (47%) received MTX and iv MP. Mean baseline DAS28 was 5.5 (SD=1.3). Median (IQR) PDUS at baseline was 10 (5, 17); median (IQR) improvement in PDUS at 50 and 78 weeks was 8 (3, 14) and 9 (4, 16) respectively. PDUS poorly correlated with DAS28 at baseline (r=0.24, p=0.053) but associations were stronger at weeks 50 (r=0.34, p=0.006) and 78 (r=0.616, p&lt;0.001). Associations between changes in DAS28 and in PDUS were moderate at weeks 50 (r=0.41, p=0.001) and 78 (r=0.50, p&lt;0.001). In adjusted models, change in DAS28 was associated with change in ln-transformed PDUS at weeks 50 [coefficient 0.20 (0.01, 0.39), p=0.039; adjusted r-squared=0.42] and week 78 [0.32 (0.20, 0.44), p&lt;0.001; adjusted r-squared=0.74] <h3>Conclusions</h3> In an early, DMARD-naive cohort, DAS28 and PDUS did not correlate at baseline but showed improved association with lower levels of inflammation at weeks 50 and 78. Interval change in clinical and ultrasound measures showed moderate correlation, indicating in early RA, DAS28 is reasonably sensitive to change. The relationship in established disease is not as clear. <h3>References</h3> Ranzolin A, et al. Arthitis Care Res 2009 Saleem B, et al. Ann Rheum Dis 2011 Nam JL, et al. Ann Rheum Dis 2014 <h3>Disclosure of Interest</h3> None declared
Age-Related Increase in Mortality among Patients with First Myocardial Infarctions Treated with Thrombolysis
Authors: Aldo A. Maggioni, Attilio Maseri, Claudio Fresco, Maria G. Franzosi, Francesco Mauri, Eugenio Santoro, Gianni Tognoni
Journal: New England Journal of Medicine (1993)

The overall rate of mortality due to ischemic heart disease is known to increase progressively with age. We evaluated the relation between the mortality rate and age in patients with first myocardial infarctions treated with thrombolytic therapy.
Study of Total and Allergen Specific IgE and Salivary IgA, As Well As Leukocyte Populations in Atopic and Non-Atopic Children with Asthma and / or Rhinitis
Authors: Julio cesar Orellana, Maria ofelia Miño, Estela Pautasso, Ana Romero Boni, Stefania c Santo, Maria ines Pereira, Adriana Cassinerio, Telma Varela, Pablo Romero, Omar Romero, Horacio marcelo Serra
Journal: Journal of Allergy and Clinical Immunology (2016)
Failure of Prolonged Treatment of Chronic Urinary-Tract Infections with Antibiotics
Authors: Marvin Turck, Ann A. Browder, Robert I. Lindemeyer, Norman K. Brown, Kenneth N. Anderson, Robert G. Petersdorf
Journal: New England Journal of Medicine (1962)

CHRONIC urinary-tract infections are often refractory to antimicrobial therapy or recur after cessation of treatment. The paucity of cures in these patients after antibacterial therapy may not be solely due to inability of the drug to eradicate foci of infection within the renal parenchyma, but may involve other factors known to predispose to sepsis of the urinary tract, such as structural abnormalities, renal stones, diabetes mellitus, pregnancy, repeated instrumentation and surgical manipulations of the urethra, bladder or ureters.1 , 2 Frequently, however, none of these factors are present, or, if recognized, they cannot be remedied. Furthermore, it has been postulated that chronic . . .
Results of a randomized phase III trial (MPACT) of weekly <i>nab</i>-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates.
Authors: Daniel D. Von Hoff, Thomas J. Ervin, Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus Frederic Renschler
Journal: Journal of Clinical Oncology (2013)

4005^ Background: nab-paclitaxel (nab-P; 130 nm albumin-bound paclitaxel) has demonstrated both single-agent activity and synergy with gemcitabine (G) in preclinical models of pancreatic cancer (PC). nab-P + G also demonstrated promising efficacy in a phase I/II study in metastatic PC (J Clin Oncol. 2011:4548-4554), warranting a phase III study of nab-P + G vs G for metastatic PC. Methods: 861 patients (pts) with metastatic PC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m 2 + G 1000 mg/m 2 days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m 2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥ 2). The primary endpoint was OS; secondary endpoints were PFS and ORR by independent review. Results: The median age was 63 years (range 27 - 88). KPS was 100 (16%), 90 (44%), 80 (32%), and 70 (7%). Pts had advanced disease with liver metastases (84%), ≥ 3 metastatic sites (46%), and CA19-9 ≥ 59 × ULN (46%). nab-P + G was superior to G for all efficacy endpoints: median OS was 8.5 vs. 6.7 mo (HR 0.72; 95% CI, 0.617 - 0.835; P = 0.000015); median PFS was 5.5 vs. 3.7 mo (HR 0.69; 95% CI, 0.581 - 0.821; P = 0.000024), and ORR was 23% vs. 7% (P = 1.1 × 10 −10 ) by RECIST v1.0. Metabolic response by PET in 257 patients was 63% for nab-P + G vs 38% for G (P = 0.000051). CA19-9 response (≥ 90% decrease) was 31% for nab-P + G vs. 14% for G (P &lt; 0.0001). Grade ≥ 3 AEs with nab-P + G vs. G included neutropenia (38% vs. 27%), fatigue (17 % vs. 7%), diarrhea (6% vs 1%), and febrile neutropenia (3% vs. 1%). Grade ≥ 3 peripheral neuropathy (PN) occurred in 17% vs. 1% of pts who received nab-P + G vs. G, respectively; for nab-P + G, PN improved to grade ≤ 1 in a median 29 days, and 44% of patients resumed nab-P treatment. The median duration of treatment was 3.9 mo for nab-P + G and 2.8 mo for G. Conclusions: MPACT was a large, international study performed at community and academic centers. nab-P + G was superior to G across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens. Clinical trial information: NCT00844649.
Using the Skindex-16 and CTCAE to assess rash symptoms: Results of a pooled-analysis (N0993).
Authors: P. J. Atherton, K. N. Burger, C. L. Loprinzi, R. C. Miller, A. Jatoi, J. A. Sloan
Journal: Journal of Clinical Oncology (2010)

9018 Background: Historically, symptoms of rash have been measured in prospective clinical trials using the clinician- reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The patient-reported Skindex-16 measures symptoms and patient perceptions of the skin toxicity. This study was designed to compare and contrast the information provided by these two methods. Methods: Data were compiled from 3 North Central Cancer Treatment Group studies (N06C4, N03CB, N05C4) where patients received medication for rash prevention during cancer treatment. All used the Skindex-16 and CTCAE at baseline, weekly during treatment, and weekly during a minimum 2 week follow-up period. Procedures, including the Pearson correlation as primary, were utilized to determine relationships between AE grades and Skindex-16 scores. Results: 412 unique patients provided data (median age 61, 134 male). Patients' Skindex-16 total score results show an overall mean of 0.9 (range 0-6 with 6 being worse symptoms), baseline mean of 0.4 (range 0-4.3) and end of treatment mean of 1.3 (range 0-5.9). 93, 142 and 177 patients experienced a grade 0, 1 and 2+ skin toxicity, respectively, as measured by the CTCAE. Baseline Skindex-16 scores had very low Pearson correlation with CTCAE grades. Overall, the correlation of rash grade with the Skindex-16 scores ranged from r = 0.49, with the function subscale, to r = 0.63, with the symptom subscale. The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r = 0.48, for the total Skindex-16 score, and r = 0.55, for the symptom subscale. Conclusions: The Skindex-16 and the CTCAE measure different aspects of skin toxicity and/or morbidity. This supports the inclusion of both measures in a clinical trial to assess the patient clinical trial experience. No significant financial relationships to disclose.
Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: A multicenter randomized, controlled trial
Authors: Àngels Escorsell, Oana Pavel, Andrés Cárdenas, Rosa Morillas, Elba Llop, Càndid Villanueva, Juan C. Garcia‐Pagán, Jaime Bosch
Journal: Hepatology (2015)

Balloon tamponade is recommended only as a "bridge" to definitive therapy in patients with cirrhosis and massive or refractory esophageal variceal bleeding (EVB), but is frequently associated with rebleeding and severe complications. Preliminary, noncontrolled data suggest that a self-expandable, esophageal covered metal stent (SX-ELLA Danis; Ella-CS, Hradec Kralove, Czech Republic) may be an effective and safer alternative to balloon tamponade. We conducted a randomized, controlled trial aimed at comparing esophageal stent versus balloon tamponade in patients with cirrhosis and EVB refractory to medical and endoscopic treatment. Primary endpoint was success of therapy, defined as survival at day 15 with control of bleeding and without serious adverse events (SAEs). Twenty-eight patients were randomized to Sengstaken-Blakemore tube (n = 15) or SX-ELLA Danis stent (n = 13). Patients were comparable in severity of liver failure, active bleeding at endoscopy, and initial therapy. Success of therapy was more frequent in the esophageal stent than in balloon tamponade group (66% vs. 20%; P = 0.025). Moreover, control of bleeding was higher (85% vs. 47%; P = 0.037) and transfusional requirements (2 vs 6 PRBC; P = 0.08) and SAEs lower (15% vs. 47%; P = 0.077) in the esophageal stent group. TIPS was used more frequently in the tamponade group (4 vs. 10; P = 0.12). There were no significant differences in 6-week survival (54% vs. 40%; P = 0.46).Esophageal stents have greater efficacy with less SAEs than balloon tamponade in the control of EVB in treatment failures. Our findings favor the use of esophageal stents in patients with EVB uncontrolled with medical and endoscopic treatment. (Hepatology 2016;63:1957-1967).
Hemophilus Influenzae Type B Disease in Children Vaccinated with Type B Polysaccharide Vaccine
Authors: Dan M. Granoff, Penelope G. Shackelford, Brian K. Suarez, Moon H. Nahm, K. Lynn Cates, Trudy V. Murphy, Raymond Karasic, Michael T. Osterholm, Janardan P. Pandey, Robert S. Daum
Journal: New England Journal of Medicine (1986)

We studied 55 cases of invasive Hemophilus influenzae type b disease occurring in children at least three weeks after vaccination with type b polysaccharide vaccine. Their mean age at the time of immunization was 27.8 months (range, 18 to 47). Meningitis developed in 39 patients, of whom 3 died and 6 had neurologic sequelae. We investigated certain host factors that may have contributed to the failure of the vaccine. The geometric mean concentration of antibody to type b polysaccharide in convalescent-phase serum from 31 of the vaccinated patients who had hemophilus disease was significantly lower than that in serum from 25 patients of similar age with the disease who had never been vaccinated (0.59 vs. 3.46 micrograms per milliliter, P less than 0.001). However, only 3 of 46 patients in whom the vaccine failed and who were tested for hypogammaglobulinemia had this finding, and none of 33 children tested for IgG2 had low serum concentrations of this immunoglobulin subclass, which is thought to be important in the immune response to polysaccharide antigens. In addition, all but 1 of the 46 patients in whom the vaccine failed and who were tested for IgG antibody to tetanus toxoid protein, a thymic-dependent antigen, had normal values, and 19 of 20 tested for hemolytic complement activity had normal levels. In white children, the presence of the Gm immunoglobulin phenotype (1,2,3, 17; ;5,13,21) was associated with a sevenfold increase in the relative risk of vaccine failure (P less than 0.003). We conclude that vaccine failure may be related in part to genetic factors, and that most vaccinated children in whom Hemophilus influenzae disease develops have deficient antibody responses to the type b polysaccharide despite normal serum concentrations of immunoglobulin and normal antibody responses to tetanus toxoid.
Serum thrombospondin-1 (TSP-1), vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and basic-fibroblast growth factor (b-FGF) as predictive factors for sorafenib plus interferon-alfa-2a (IFN) in metastatic renal cell carcinoma (MRCC): Biologic results from the randomized phase II RAPSODY trial.
Authors: S. Bracarda, V. Ludovini, C. Porta, C. Boni, A. Santoro, D. Gasparro, E. Cortesi, V. De Angelis, M. Sisani, L. Crinò
Journal: Journal of Clinical Oncology (2010)

4628 Background: Sorafenib is an oral multi-kinase inhibitor with a demonstrated efficacy in MRCC. IFN is a pleiotropic molecule with an antiangiogenic activity probably dose and schedule-dependent. We evaluated the activity and safety of sorafenib combined with IFN in two different schedules and their relationships with potentially predictive serum factors related to angiogenesis and its inhibition (TSP-1). This latter tested, at the best of our knowledge, for the first time. Methods: Eligible patients had untreated MRCC. Patients received oral sorafenib 400mg BID continuously plus sc IFN, 9 MU three times a week (arm-A) or 3 MU five times a week (arm-B). End points of the study were progression free survival (PFS), safety, overall response (intention-to treat analysis), overall survival and their relationship with baseline serum TSP-1, b-FGF, VEGF and VEGFR-2. Biomarker levels were determined, with a commercial ELISA assay, in serum samples collected just before starting treatment and stored at -80°. Results: Final overall response rate (ORR) and PFS results of the study (preliminary reported at ASCO 2007 and ASCO-GU 2008) were: 9/51 partial responses in Arm-A (ORR: 17.6%) and 3 complete plus 14 partial responses out of 50 cases in Arm-B (ORR: 34%) with a median PFS of 7.9 versus 8,6 months (p=0.049), respectively. Biological data refers to 87 out of 101 cases with an available serum sample (median age 63 years, range 39-81). Biomarker levels were well balanced between treatment arms. Baseline median VEGFR-2 level (median overall value 8.108 pg/ml, range 2846-14357) predict for an improved median PFS (p= .013) with a non significant trend for Arm-B versus Arm-A (9.4 versus 8.0 months). Serum TSP-1 does not predict for PFS or ORR but relate only with age (p= .03). No significant data were observed for VEGF and b-FGF. Conclusions: Patients with MRCC and low baseline serum VEGFR-2 could achieve a significantly improved median PFS when treated with sorafenib plus IFN. A non significant trend was observed in Arm-B. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Schering-Plough, Wyeth Novartis, Roche
Relation of Isolated Recurrences of Sydenham's Chorea to Preceding Streptococcal Infections
Authors: Angelo Taranta
Journal: New England Journal of Medicine (1959)

IT is now well established that rheumatic polyarthritis and carditis occur one to five weeks after infections of the throat due to the Group A streptococcus. Although the preceding infections may be asymptomatic, they are almost always detectable, in retrospect, by titration of streptococcal antibodies.1 , 2 On this fact the theory of the streptococcal etiology of rheumatic fever was based. This theory was confirmed by the reduction in the recurrence rate of rheumatic fever achieved through antistreptococcal prophylaxis3 , 4 and, further, by the close relation of the recurrences that do occur to preceding streptococcal infections.5 Contrariwise, in cases of Sydenham's chorea — . . .