tbuckley/cabot-search huggingface dataset:
Tolerability and anti-tumor activity of recombinant human IL-18 (rhIL-18) administered as five daily intravenous infusions in patients with solid tumors
Authors: M. J. Robertson, J. Mier, T. Logan, H. Koon, J. Weisenbach, S. Roberts, C. Oei, L. Kirby, S. Kathman, L. Pandite
Journal: Journal of Clinical Oncology (2004)

2553 Background: rhIL-18, a member of the Th-1 inducing family of cytokines, has demonstrated anti-tumor activity in a variety of preclinical tumor models. Methods: In an ongoing phase I dose-escalation study, rhIL-18 (SB485232) was administered as a 2 hour infusion daily for 5 consecutive days to patients (pts) with solid tumors. Doses ranging from 3–1000 μg/kg/day were planned. The objectives were to determine tolerability, define a biologically effective dose, and assess pharmacokinetics, immunogenicity, immunomodulatory and anti-tumor activity of rhIL-18. Pts with detectable anti-SB-485232 antibodies at screening were excluded. Results: Twenty-six pts {metastatic renal cell carcinoma (21), advanced melanoma (4), Hodgkin's lymphoma (1)}were treated at dose levels up to1000 μg/kg/day . Two pts were withdrawn from the study: 1 pt at 10 μg/kg/day due to rapidly progressive disease and 1 pt at 100 μg/kg/day due to hypotension with bradycardia, a dose-limiting toxicity. This cohort was expanded to 6 pts with no further dose-limiting toxicities. Drug-related adverse event data are available for 25 pts: Grade (G) 1–2 fever (n=19), chills (n=14), rash (n=3) nausea/vomiting (n=8); G1 myalgia (n=3); G1–2 neutropenia (n=11), G1–3 lymphopenia (n=16), G1–2 thrombocytopenia (n=4), G1 elevated AST (n=4), G1–2 elevated ALT (n=5), G1 hypocalcemia (n=3), G1–2 hypoalbuminemia (n=12). Five pts developed antibodies to SB-485232. Increases in neopterin (24/25 pts), GM-CSF (25/25 pts), IL-18 BP (25/25 pts), sFas/L(22/25 pts), and INFγ (15/25 pts) were observed. Upregulation of FasL on NK, CD8+, and CD4+ cells as well as of CD69 on CD8+ cells was observed. Evidence of clinical activity was observed in two patients (metastatic melanoma and renal cell carcinoma) treated at 100 μg/kg/day. Conclusions: rhIL-18 administered as a single cycle was well tolerated. Preliminary data demonstrate evidence of immunomodulatory and clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Case 47-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, David C. Christiani, Eugene J. Mark
Journal: New England Journal of Medicine (1988)

Presentation of CaseAn 86-year-old man was admitted to the hospital because of nodular pulmonary densities.He was in excellent health until seven months earlier, when glaucoma was found. Timolol ophthalmic drops were prescribed; marked lethargy and wheezing developed. Betaxolol hydrochloride ophthalmic drops were substituted, but the patient began to experience increasing exertional dyspnea, especially on climbing hills, although he remained capable of mowing his lawn. Five months before admission a daily cough appeared and was occasionally productive of white-to-yellow sputum. Three months later examination at this hospital showed mild, diffuse wheezing in both lungs. Pulmonary-function studies revealed that the . . .
Ascorbic acid plus gemcitabine (gem) and erlotinib (erl) in patients with metastatic pancreatic cancer (mPanc): Preliminary safety results.
Authors: E. P. Mitchell, J. Edman, A. Bazzan, S. J. Littman, A. Mahipal, A. K. Kandra, H. Hargrove, E. P. Kennedy, M. Levine, D. Monti
Journal: Journal of Clinical Oncology (2010)

e14659 Background: Intravenous ascorbic acid in pharmacologic concentrations, via production of extracellular hydrogen peroxide and reactive oxygen species, has selective cytotoxicity to cancer cells but not normal cells and tissues in vitro and in vivo. In this study we have evaluated safety and tolerability of ascorbic acid combined with gem/erl in patients with mPanc, and we now report preliminary safety results. Methods: This is the phase I, open label portion of a phase I/II trial. The primary objective is to determine safety and tolerability of intravenous ascorbic acid at three dosage levels with gem/erl. The secondary objective is to evaluate tumor free progression. Eligible patients were >18 yrs of age, life expectancy > 3 months, histologically confirmed mPanc and ECOG PS 0/1. All patients received intravenous ascorbic acid at three times weekly combined with gem 1,000 mg/m2 weekly for 7 weeks and erl 100 mg oral daily. After a week of rest and reevaluation, subsequent cycles consisted of gem 1,000 mg/m2 weekly times 3 with 1 week of rest. The study used a 3+3+3 design with three different ascorbic acid doses: 50 gm, 75 gm, and 100 gm infused over 90-minute duration. Safety and tolerability is based on dose-limiting toxicities (DLTs), and grade 3/4 combination chemotherapy related adverse events (AEs) deemed clinically significant by the investigator. Plasma levels of ascorbic acid, gem, and erl will be determined. The primary endpoint was incidence of DLTs. Results: No DLT has been reported for the first 5 DLT evaluable subjects. Accrual to part 1 continues. Five patients have enrolled in part 1; 4 patients were female. Mean age was 69 years (60-82); ECOG 0/1 = 4/1. No grade 4 or 5 treatment related DLTs were seen. Serious possible AEs included diarrhea (grade 3) in one pt and jaundice (grade 3) in 1 pt. One pt had partial response, 2 pts had stable disease, and 2 pts had disease progression. Conclusions: Ascorbic acid combined with gem/erl has been well tolerated and may in the future offer potential in pts with mPanc. The MTD has not yet been reached. Treatment-related AEs Number of pts Grade of toxicity Nausea/vomiting 1 1 Infection 0 Diarrhea 2 1, 3 Erythema 1 1 Thrombocytopenia 2 1, 2 Rash 1 1 Jaundice 1 3 No significant financial relationships to disclose.
Phase I trial of vinorelbine and sorafenib in metastatic breast cancer (MBC).
Authors: T. H. Luu, P. H. Frankel, C. T. Chung, J. E. Mortimer, A. Hurria, M. McNamra, S. Koehler, G. Somlo
Journal: Journal of Clinical Oncology (2010)

e13576 Background: Vinorelbine, a semisynthetic vinca alkaloid, at 20–25 mg/m2 has a response rate of 15–30% for second line therapy of MBC. Sorafenib is an oral multi-kinase inhibitor against the tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Flt-3 and c-Kit receptors. In preclinical studies, sorafenib demonstrated antitumor activity by inducing complete tumor stasis in a variety of tumor types through the Raf/MEK/ERK pathway. In the NCI H460 cell line for NSCLC tumor xenograft, synergy between vinorelbine and sorafenib were observed. Methods: Eligibility include: MBC with adequate end-organ function and performance status (<2) with up to two lines of prior chemotherapy regimens. Intravenous vinorelbine on days 1, 8, 15 and oral sorafenib twice daily each 28-day cycle were given. Dose escalation using 3+3 design was determined based on course 1 toxicities. Vinorelbine was started at 20 mg/m2 and sorafenib at 200 mg. Tumor response was evaluated every two cycles by RECIST. Results: 11 patients were enrolled from 1/09 to 6/09 with a median age of 59 years (range 39–70). Prior chemotherapy regimens were 1/6/4 patients with 0/1/2 prior regimens. Dose limiting toxicities (DLT) on the second dose level, vinorelbine 25 mg/m2 and sorafenib 200 mg twice daily, were grade 3 hand-foot skin reactions in 1 and grade 3 febrile neutropenia in 2 out of 5 patients, establishing the maximum tolerated dose (MTD) as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. At the MTD, 6 patients were treated with 1 patient having grade 3 treatment-related toxicities (low sodium, neutropenia) during course 1. Additional grade 3 or 4 toxicities noted (in subsequent cycles) at the MTD include hypertension (2), neutropenia (1), and fatigue (1). The median number of cycles delivered at the MTD was 7 (range 2- 12+). We observed 1 partial response (PR) and 3 stable diseases (>4 months) at the MTD, with 1 additional stable disease at the DLT level. Conclusions: We established the phase II MTD as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. With acceptable toxicity and encouraging initial response, a phase II trial is now on-going. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx
Myocardial T2 Mapping Increases Noninvasive Diagnostic Accuracy for Biopsy-Proven Myocarditis
Authors: Florian Bönner, Maximilian Spieker, Sebastian Haberkorn, Christoph Jacoby, Ulrich Flögel, Bernhard Schnackenburg, Patrick Horn, Petra Reinecke, Mirja Neizel-Wittke, Malte Kelm, Ralf Westenfeld
Journal: JACC. Cardiovascular imaging (2016)
Severe Aortic Regurgitation in Young People
Authors: Edward F. Bland, Edwin O. Wheeler
Journal: New England Journal of Medicine (1957)

THE purpose of this report is twofold. It concerns first the characteristic and in some respects unique features of a small but special group of young patients with rheumatic heart disease whose principal lesion is aortic regurgitation of an extreme degree, and second our personal experience with the plastic valve of Hufnagel as a palliative maneuver in these patients when medical measures fail.It has long been recognized that aortic regurgitation of high degree is as a rule badly borne, that even in childhood it may be accompanied by angina pectoris, and that sudden death is a common consequence. It . . .
Diagnosis of Aneurysms of the Hepatic and Splenic Arteries by Intravenous Abdominal Aortography
Authors: Israel Steinberg
Journal: New England Journal of Medicine (1960)

CONTRAST visualization of the hepatic and splenic arteries has become generally recognized as the definitive way to establish the diagnosis of aneurysms of these arteries. Kirklin and his associates,1 in 1955, were apparently the first to make the diagnosis of a hepatic-artery aneurysm after translumbar aortography. In 1953 Owens and Coffey2 discussed the value of translumbar aortography for diagnosis of splenic-artery aneurysms and illustrated a case. Earlier, in 1946, Wagner3 was probably the first to opacity a splenic-artery aneurysm. Subsequently, 3 additional reports of splenic-artery aneurysm diagnosed by translumbar aortography have been presented.3 4 5 6 7 The safe and practical method of intravenous . . .
Case 33-2001
Authors: C. Fordham von Reyn, Eugene J. Mark
Journal: New England Journal of Medicine (2001)

Presentation of CaseA 33-year-old man was admitted to the hospital because of leg numbness and back pain.The patient had been well until six weeks before admission, when pruritus developed on his upper abdomen, accompanied by burning pain when he assumed a recumbent position. An erythematous rash without vesicles or scarring spread across both sides of his upper abdomen to the midaxillary lines and was interpreted by a physician as herpes zoster. Within two weeks, the rash cleared spontaneously. Four days before admission, numbness developed in both legs and ascended to the lumbar region and then to the abdomen . . .
Diagnostic Import of Virus-Like Particles in the Glomerular Endothelium of Patients with Systemic Lupus Erythematosus
Authors: Henry Grausz, Laurence E. Earley, Boyd G. Stephens, John C. Lee, James Hopper
Journal: New England Journal of Medicine (1970)

Examination of existing files of electron photomicrographs of renal biopsies showed virus-like intracellular inclusions in glomerular endothelial cytoplasm from 29 of 30 patients with an unequivocal diagnosis of systemic lupus erythematosus and in none of a group of 37 with a variety of nonlupus renal lesions. The virus-like particles were found in the glomerular endothelium of two patients with discoid lupus and histologically normal-appearing glomeruli. In both these patients systemic lupus, including nephritis, subsequently developed. The particles were found also in four of six cases of suspected but not proved systemic lupus. Renal-biopsy material from two patients who had positive L.E.-cell preparations while receiving hydralazine did not contain the virus-like particles. This study does not establish the nature or etiologic import of these particles but indicates that their presence is diagnostically helpful in systemic lupus regardless of the extent of histologic or functional involvement of the kidney.
P124 A randomised, parallel-group study to evaluate the effect of umeclidinium added to inhaled corticosteroid/long-acting beta-agonist combination therapy in subjects with chronic obstructive pulmonary disease: Abstract P124 Table 1
Authors: AR Sousa, JH Riley, A Church, CQ Zhu, YS Punekar, WA Fahy
Journal: Thorax (2015)

<h3>Rationale</h3> To evaluate efficacy and safety of adding umeclidinium (UMEC), a long-acting muscarinic antagonist (LAMA), to inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) for 12-weeks. <h3>Methods</h3> Multicentre, randomised, double-blind, parallel-group study. Inclusion criteria included diagnosis of COPD, modified Medical Research Council Dyspnoea Scale score ≥2 (i.e. patients symptomatic on ICS/LABA), post-salbutamol forced expiratory volume in one second (FEV<sub>1</sub>) ≤70% predicted and FEV<sub>1</sub>/forced vital capacity ratio of 1 at Day 85; other endpoints included 0−6 h weighted mean FEV<sub>1</sub>, rescue medication use, COPD assessment test (CAT) score, and transition dyspnoea index (TDI) score. Adverse events (AEs) were also investigated. <h3>Results</h3> In the UMEC+ICS/LABA and PBO+ICS/LABA groups, 119 and 117 patients were randomised, respectively, receiving fluticasone/salmeterol (40%), budesonide/formoterol (43%), and other ICS/LABA, including generics (17%). Compared with PBO+ICS/LABA, UMEC+ICS/LABA resulted in statistically significant improvements in change from baseline trough FEV<sub>1</sub> at Day 85 and 0−6 h weighted mean FEV<sub>1</sub> at Day 84 (Table 1). UMEC+ICS/LABA resulted in a statistically significant reduction in change from baseline mean puffs/day of rescue salbutamol over Weeks 1–12 versus PBO+ICS/LABA, but not for percentage of rescue-free days. Change from baseline in CAT score at Day 84 was statistically significantly different for UMEC+ICS/LABA versus PBO+ICS/LABA, but TDI score was not significantly different for UMEC+ICS/LABA versus PBO+ICS/LABA; the study was not powered for these endpoints. Incidence of AEs was similar with UMEC+ICS/LABA and PBO+ICS/LABA; n = 45 (38%) and n = 49 (42%), respectively. The most common AEs were nasopharyngitis (13–15%) and headache (3–7%). <h3>Conclusions</h3> UMEC+ICS/LABA improved lung function and reduced rescue medication use (mean puffs/day) and CAT score in patients with COPD versus PBO+ICS/LABA. No additional safety concerns were identified with UMEC+ICS/LABA. Funded by GlaxoSmithKline (NCT02257372). <h3>COI Statement</h3> ARS, JR, AC, WAF, CQZ and YSP are employees of GSK and hold stocks/shares in GSK.
OP0220 Intraarticular Micro Channels of MCP Joints Increase During Development of Rheumatoid Arthritis
Authors: D. Werner, D. Simon, J. Rech, J. Haschka, T. Buder, W. Neuhuber, G. Schett, A.J. Hueber, A. Kleyer
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> High Resolution peripheral Quantitative Computed Tomography (HR- pQCT) allows to detect very small cortical breaks, so called “microchannels” in the periarticular bone. These structures resemble an interaction between the bone marrow and synovial compartment potentially allowing communication of inflammation between these two compartments. <h3>Objectives</h3> To quantify micro-channels in healthy individuals, ACPA-positive individuals and early rheumatoid arthritis (RA) patients. <h3>Methods</h3> HR-pQCT (XtremeCT, Scanco, Switzerland) scans of healthy subjects, ACPA positive subjects without RA and ACPA positive early RA patients were assessed. Transversal, sagittal and coronal planes of the 2nd metacarpophalangeal (MCP) head were scored for microchannels. Analysis was performed by two independent and blinded readers. To search for a potential function these cortical microchannels we performed HR-pQCT measurements of cadaveric hands (n=6, Body Donation Program of the Institute of Anatomy, University Erlangen-Nuremberg) with contrast enhancement to display vessels. After defrosting at room temperature for 24h hours, the radial and ulnar artery was dissected and contrast agent (Imeron 350 Iod/ml, Bracco Imaging, Germany) was injected in both arteries followed by HR-pQCT measurement. The study was approved by the local ethics committee. <h3>Results</h3> A total of 61 healthy controls (29 females; 32 males), 21 ACPA positive subjects (17 females; 4 males), 35 ACPA positive RA (25 females; 10 males; disease duration 0.66 yrs) were evaluated. Cortical channels were detected in all subjects with distinct localization (Fig. 1a). Most lesions were located intra-articularly at the palmar and radial side of the MCP 2 head. We found a significant difference (p=0.001) in the numbers of microchannels between the three groups with higher numbers in the early RA group compared to the healthy controls (Fig 1b). Using contrast enhanced HR-pQCT images of human cadaver hands we were able to display intracortical and medullar vessels with a size as low as 0.15 mm diameter (Fig. 2a/b). In addition, vascular trees around the wrist and MCP joints could be visualized after 3D segmentation (Fig. 2c). Despite good vascular visualization no contrast enhancement was observed in the intraarticular region of the above described channels. <h3>Conclusions</h3> Micro-channels in the periarticular bone increase during the development of RA. Until now the function of micro channels is still unclear. If cortical channels reflect breaks, vessels from “inside-out”, cartilage anchors or nutritive channels still needs to be determined. <h3>Disclosure of Interest</h3> None declared
Pituitary-Thyroid Responsiveness to Intramuscular Thyrotropin-Releasing Hormone Based on Analyses of Serum Thyroxine, Tri-Iodothyronine and Thyrotropin Concentrations
Authors: Fereidoun Azizi, Apostolos G. Vagenakis, Gary I. Portnay, Basil Rapoport, Sidney H. Ingbar, Lewis E. Braverman
Journal: New England Journal of Medicine (1975)

Original Article from The New England Journal of Medicine — Pituitary-Thyroid Responsiveness to Intramuscular Thyrotropin-Releasing Hormone Based on Analyses of Serum Thyroxine, Tri-Iodothyronine and Thyrotropin Concentrations
The Clinical Course of Pulmonary Embolism
Authors: Jeffrey L. Carson, Mark A. Kelley, Amy Duff, John G. Weg, William J. Fulkerson, Harold I. Palevsky, J. Sanford Schwartz, B. Taylor Thompson, John Popovich, Thomas E. Hobbins, Margaret A. Spera, Abass Alavi, Michael L. Terrin
Journal: New England Journal of Medicine (1992)

Pulmonary embolism is a potentially fatal disorder. Information about the outcome of clinically recognized pulmonary embolism is sparse, particularly given that new treatments for more seriously ill patients are now available.We prospectively followed 399 patients with pulmonary embolism diagnosed by lung scanning and pulmonary angiography, who were enrolled in a multicenter diagnostic trial. We reviewed all hospitalizations, all new investigations of pulmonary embolism, and all deaths among the patients within one year of diagnosis.Of the 399 patients, 375 (94 percent) received treatment for pulmonary embolism, usually conventional anticoagulation. Only 10 patients (2.5 percent) died of pulmonary embolism; 9 of them had clinically suspected recurrent pulmonary embolism. Clinically apparent pulmonary embolism recurred in 33 patients (8.3 percent), of whom 45 percent died during follow-up. Ninety-five patients with pulmonary embolism (23.8 percent) died within one year. The conditions associated with these deaths were cancer (relative risk, 3.8; 95 percent confidence interval, 2.3 to 6.4), left-sided congestive heart failure (relative risk, 2.7; 95 percent confidence interval, 1.5 to 4.6), and chronic lung disease (relative risk, 2.2; 95 percent confidence interval, 1.2 to 4.0). The most frequent causes of death in patients with pulmonary embolism were cancer (in 34.7 percent), infection (22.1 percent), and cardiac disease (16.8 percent).When properly diagnosed and treated, clinically apparent pulmonary embolism was an uncommon cause of death, and it recurred in only a small minority of patients. Most deaths were due to underlying diseases. Patients with pulmonary embolism who had cancer, congestive heart failure, or chronic lung disease had a higher risk of dying within one year than did other patients with pulmonary embolism.
Case 38-2014
Authors: Christiana A. Iyasere, Leigh H. Simmons, Florian J. Fintelmann, Anand S. Dighe
Journal: New England Journal of Medicine (2014)

An 87-year-old man presented with a sore throat, hoarseness, fatigue, and periorbital and facial swelling. He had a creatine kinase level of 2713 U per liter and an aspartate aminotransferase level of 90 U per liter. A diagnostic test result was received.
Abstract SY02-02: Shared risk factors for diabetes, cardiovascular disease, and cancer in a low-income population
Authors: William J. Blot, Margaret Hargreaves, Wei Zheng
Journal: Cancer Research (2015)

Abstract Diabetes, cardiovascular disease (CVD) and cancer are the three most common chronic disease afflicting Americans today, but few investigations have compared and contrasted disease-specific risk factors, especially among low-income populations where incidence of the conditions is elevated. Herein we examine major lifestyle and social determinants of the illnesses, including cigarette smoking, obesity, physical activity, and socioeconomic status, and how they predict subsequent disease-specific mortality within the Southern Community Cohort Study (SCCS). The SCCS is tracking a population of approximately 85,000 adults age 40-79, two-thirds African American, recruited during 2002-2009 predominantly from community health centers (CHCs) across 12 southeastern states. Since CHCs provide basic health care and preventative services in underserved areas, the cohort comprises many individuals, both black and white, with low income and educational levels. Participants enrolling at CHCs were interviewed using a structured comprehensive questionnaire and then followed for mortality via linkage with the National Death Index. CVD and cancer were the leading causes among the nearly 7,500 deaths observed, and diabetes was reported by nearly 20% of participants at cohort entry. In Cox modeling, mortality hazard ratios (HRs) rose markedly and steadily with increasing cigarette smoking amounts for both CVD and cancer, but more so for cancer. HRs were elevated among the obese, but only mildly and only for CVD and not cancer. Diabetes prevalence, however, was very strongly and linearly related to body mass index (BMI), with 6- and 12-fold higher odds of diabetes among blacks and whites, respectively, with BMI ≥ 40 vs &amp;lt;25 kg/m2. HRs were modestly elevated among the most sedentary (and modestly decreased among the most physically active), more so for CVD than cancer. Low socioeconomic status, especially low income, was a strong (for CVD), modest (for diabetes) and weak (for cancer) risk factor. The findings indicate that these common diseases tend to share many of the same determinants, raising the possibility that mechanisms by which these exposures affect cardiovascular disease and diabetes may also relate to cancer risk and that public health measures aimed at other chronic diseases may have benefits for cancer prevention. Citation Format: William J. Blot, Margaret Hargreaves, Wei Zheng. Shared risk factors for diabetes, cardiovascular disease, and cancer in a low-income population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY02-02. doi:10.1158/1538-7445.AM2015-SY02-02