tbuckley/cabot-search huggingface dataset:
Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.
Authors: M G De Sain-Van Der Velden, D J Reijngoud, G A Kaysen, M M Gadellaa, H Voorbij, F Stellaard, H A Koomans, T J Rabelink
Journal: Journal of the American Society of Nephrology (1998)

In patients with the nephrotic syndrome, markedly increased levels of lipoprotein(a) (Lp(a)) concentration have been frequently reported, and it has been suggested that this may contribute to the increased cardiovascular risk in these patients. The mechanism, however, is not clear. In the present study, in vivo fractional synthesis rate of Lp(a) was measured using incorporation of the stable isotope 13C valine. Under steady-state conditions, fractional synthesis rate equals fractional catabolic rate (FCR). FCR of Lp(a) was estimated in five patients with the nephrotic syndrome and compared with five control subjects. The mean plasma Lp(a) concentration in the patients (1749+/-612 mg/L) was higher than in control subjects (553+/-96 mg/L). Two patients were heterozygous for apolipoprotein(a) (range, 19 to 30 kringle IV domains), whereas all control subjects were each homozygous with regard to apolipoprotein(a) phenotype (range, 18 to 28 kringle IV domains). The FCR of Lp(a) was comparable between control subjects (0.072+/-0.032 pools/d) and patients (0.064+/-0.029 pools/d) despite the wide variance in plasma concentration. This suggests that differences in Lp(a) levels are caused by differences in synthesis rate. Indeed, the absolute synthetic rate of Lp(a) correlated directly with plasma Lp(a) concentration (P < 0.0001) in all subjects. The present results demonstrate that increased synthesis, rather than decreased catabolism, causes elevated plasma Lp(a) concentrations in the nephrotic syndrome.
Prolonged administration of oral etoposide in non-small-cell lung cancer: a phase II trial.
Authors: T M Waits, D H Johnson, J D Hainsworth, K R Hande, M Thomas, F A Greco
Journal: Journal of Clinical Oncology (1992)

PURPOSE The trial was undertaken to investigate the activity and toxicity of a prolonged schedule of oral etoposide in the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Between March 1989 and August 1990, 25 patients with advanced NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days, repeated every 28 to 35 days. The median patient age was 60 years (range, 38 to 84 years); male:female ratio was 12:13. Eight patients had stage IIIB disease; 17 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy with standard agents; nine patients had received previous or concurrent radiation therapy. Plasma etoposide concentrations were measured to estimate etoposide bioavailability and kinetics. RESULTS Five of 22 patients (23%; 95% confidence interval [CI], 10% to 43%) had partial responses. Median response duration was 5 months (range, 2 to 6 months). Four of five responders were female. Besides alopecia, which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir during course 1 was 3,200/microL; only four of 69 courses produced a leukocyte nadir less than 1,000/microL. Severe thrombocythemia (less than 75,000/microL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 micrograms/mL. A mean serum etoposide concentration greater than 1 microgram/L was maintained for more than 13 hours; the plasma concentration-time curve (AUC) was estimated to be 90% of that predicted after an identical dose of etoposide given intravenously. CONCLUSIONS Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patients, chronic oral etoposide is well tolerated, and incorporation into combination regimens should be feasible. Etoposide bioavailability may be increased at lower oral doses.
Technical criteria of “clinical readiness” to qualify validated pharmacodynamic (PD) assays for clinical trial use
Authors: R. E. Parchment, R. J. Kinders, M. Hollingshead, J. E. Dancey, J. E. Tomaszewski, J. H. Doroshow
Journal: Journal of Clinical Oncology (2007)

14068 Background: Pharmacodynamics may inform drug development decisions by providing evidence of drug action on molecular target and additional data supporting dose/schedule. While a bad decision when selecting the most appropriate PD assay to use is not fatal to completing Phase 1–2 trials, assays that cannot produce meaningful scientific results create an ethical dilemma if patients are being subjected to invasive procedures, and weaken decision making. In some exploratory IND trials, the primary endpoint is demonstrating a PD effect of investigational drug on molecular target, so selection of a PD assay becomes a critical decision. Methods: SAIC-Frederick’s applied research program developed, validated and implemented a PD assay to quantify drug-induced PARP inhibition as the primary endpoint of a Phase 0 trial of ABT-888 at the NIH Clinical Center (see Kinders et al, Kummar et al). This project has been analyzed to identify technical requirements critical for establishing the clinical readiness of a PD assay. Results: Many more technical requirements arose than were originally expected, but the requirements fell into three conceptual categories: assay validation, clinical feasibility and therapeutic relevance. Assay validation requires formal assessment of analytical performance on a set of standards and specimens relevant to the trial, including storage stability of the analyte. Clinical feasibility requires the PD assay to yield analytically valid results in preclinical models when using clinically relevant tissue acquisition, handling procedures and biopsy scheduling, including significant drug effect in needle biopsies when confounded by stress, previous biopsy, biopsy method, and co-medications. Therapeutic relevance requires a relationship between dose/exposure, target modulation quantified with the PD assay, and a disease outcome of interest. Conclusions: “Clinical readiness” sets a very high standard for accepting PD assays into clinical trials, and a highly integrated team is required to meet it. However, the use of such rigorous assay development criteria holds much promise for the clinical development of molecularly targeted agents. Funded by NCI Contract N01-CO-12400. No significant financial relationships to disclose.
Impact of response to chemotherapy and treating institution on survival in primary CNS lymphoma (PCNSL): Long-term results of the multicenter BMPD study
Authors: A. Korfel, P. Martus, M. Nowrousian, D. Hossfeld, W. Weber, J. Bruecher, W. Berdel, J. Birkmann, C. Peschel, E. Thiel
Journal: Journal of Clinical Oncology (2004)

1522 Background: The role of adjuvant whole-brain irradiation (WBI) in PCNSL remains to be defined. Eliminating WBI from the initial treatment could reduce neurotoxicity but also adversly affect disease control and survival. Methods: Fifty-six patients were included in this prospective multicenter trial to evaluate the role of adjuvant WBI in PCNSL:. All received chemotherapy (CHX) composed of carmustine, high-dose methotrexate (HD-MTX) 1.5 g/m2, procarbazine, and dexamethasone (only in course 1). Patients without complete response (CR) received salvage chemotherapy with idarubicine and ifosfamide or high-dose cytarabine. Patients with CR after CHX were randomized to either WBI or one additional CHX course. Results: The CR rate after CHX was 61% (34/56), but only 23 patients were randomized to the two study arms. With a median follow-up of 40 months median overall survival (OAS) of all 24 patients without adjuvant WBI was 28.5 months (95% CI 7.7–49.2 months), that of all 10 responders with adjuvant WBI 12.8 months (95% CI 0–40.4 months; P=0.97). Responders to CHX had significantly longer survival than non-responders (18.2 versus 9.9 months, P=0.02). Median OAS was significantly longer at institutions accruing at least 4 patients than at those with fewer patients (31.5 versus 9.5 months, P=0.03). Late neurotoxicity developed in 5/24 (21%) patients younger than 60 years as compared to 6/32 (19%) older patients (P=0.84) and in 6/28 patients after WBI as compared to 5/22 without WBI treatment (P=0.91). Conclusions: Response to CHX and treating institution were predictive of survival. The neurotoxicity rate was independent of age and WBI. The high drop-out and low randomization experience of this study led to a similar ongoing multicenter trial with HD-MTX monotherapy and upfront randomization. No significant financial relationships to disclose.
Quality of life in long-term survivors of muscle-invasive bladder cancer.
Authors: Kimberley S. Mak, Angela Smith, Alec Eidelman, Rebecca Helen Clayman, Jed-Sian Cheng, Jonathan Matthews, Andrzej Niemierko, Matthew Edward Nielsen, Adam S. Feldman, Richard J. Lee, Anthony L. Zietman, William U. Shipley, Ronald C. Chen, Matthew I. Milowsky, Jason Alexander Efstathiou
Journal: Journal of Clinical Oncology (2015)

319 Background: Health-related quality of life (QOL) is not well-studied in survivors of muscle-invasive bladder cancer (MIBC). This cross-sectional multi-institutional study compared long-term QOL in MIBC patients treated with bladder-sparing trimodality therapy (TMT) vs. radical cystectomy (RC). Methods: Patients with non-metastatic cT2-T4 MIBC, diagnosed in 1990-2011 and disease-free for ≥2 years were identified. A questionnaire using validated general and disease-specific QOL instruments was administered (score ranges: 0-100). Results: Of 226 eligible patients, 173 returned the questionnaire for a response rate of 77%. Sixty-four received TMT and 109 RC (89 with ileal conduit and 18 with neobladder diversions). The median time from diagnosis to questionnaire was 9 vs. 6 years, respectively (p=0.009). Comparing TMT to RC, there was no significant difference in age at diagnosis or questionnaire, gender, smoking, clinical stage or comorbidities. On univariable analysis (UVA), patients who received TMT had significantly better general QOL than patients who received RC by 4.8 points on the EQ-5D 3L and 7.4 points on the EORTC QLQ-C30 (Table). On multivariable analysis (MVA), adjusting for age, time from diagnosis, year of treatment, gender and comorbidities, patients who received TMT had significantly better general QOL by an average 6-7 points. On MVA, TMT was associated with significantly better bowel function by an average 4.5 points on the EPIC bowel function subscale, but with no difference in bowel bother. Urinary QOL was equivalent between groups, as measured by the EORTC QLQ-BLM30. Conclusions: While both TMT and RC provide good long-term outcomes, TMT appears to be associated with higher general QOL and bowel function compared to RC. [Table: see text]
Percutaneous tissue debulking and cement augmentation for advanced malignant vertebral compression fractures
Authors: B. Georgy, W. Wong
Journal: Journal of Clinical Oncology (2006)

9535 Background: Percutaneous cement injection procedures (eg vertebroplasty, kyphoplasty) are used successfully to palliate patients with painful osteoporotic vertebral compression fractures (VCFs). When VCFs occur because of malignant lesions however, treatment can be challenging; often by the time symptoms occur, the tumor has extended into the epidural tissue and is associated with posterior cortical disruption. As a result, patients have a higher likelihood of cement extravasation outside the vertebral body, thought to be associated with increased complication risk. This study was to investigate clinical viability and effectiveness of a technique designed to improve control of bone cement placement over standard methods when treating patients with symptomatic VCFs caused by malignancy. Methods: All patients had intractable pain determined to be associated with VCFs caused by metastasized malignancy. The procedure involved using a plasma-mediated radiofrequency-based device to debulk tissue and etch a void within the affected vertebral body and then filling the void and adjacent interstices with bone cement to stabilize the vertebral body and relieve pain. Results: 28 patients (36 vertebral bodies) with various types of metastatic lesions were treated. No evidence of cement extravasation outside the vertebral boundary was detected in 34/36 (94%) cases, even in cases with severe posterior cortical compromise and prominent epidural involvement pre-operatively. In the 2 observed cases, cement extravasation was clinically inconsequential. All treated patients reported marked pain relief. No patients were prevented from continuing other oncologic treatments. Conclusions: Tissue removal to create a void before injecting bone cement into a vertebral body compromised by malignancy may reduce the complication rate observed when injecting cement. This technique may redirect cement away from the spinal canal, notably in cases with posterior cortical defect and epidural extension, while also improving interdigitation of cement and decreasing risk of metastatic embolization. The resulting palliation potentially improves functionality and quality of life during and does not appear to affect the effectiveness of continued oncologic treatment. [Table: see text]
Trajectories of specific IgE in the PASTURE birth cohort study
Authors: Alexander Hose, Martin Depner, Charlotte Braun-Fahrländer, Juha Pekkanen, Josef Riedler, Jean-Charles Dalphin, Jon Genuneit, Roger Lauener, Petra Ina Pfefferle, Erika Von Mutius, Markus Ege
Journal: European Respiratory Journal (2014)

Background   IgE sensitisation patterns have been shown to change within the first 12 months of life and to be determined by maternal and environmental influences (Depner et al., JACI 2013; 131:781-8).   Objective   To explore the course of atopic sensitisation between birth and 6 years of age in the context of a farming environment.   Methods   Specific IgE levels for 6 food and 13 common inhalant allergens were assessed in cord blood and in peripheral blood at age 1, 4, and 6 years in the PASTURE (Protection against Allergy–Study in Rural Environments) birth cohort (n=1133) from rural regions of 5 European countries.   Results   Using a cut-off of 0.35 kU/L (RAST class 1), the prevalence of sensitisation to any allergen was 28% at year 1, 58% at year 4, and 54% at year 6. The steep increase between year 1 and 4 was also accompanied by a switch from RAST class 1 to 3 in about 20% of sensitised children.  Figure 1 illustrates diverse sensitisation patterns for farm and non-farm children with respect to seasonal and food allergens. Food sensitisation was more common in farm children only at lower levels, whereas seasonal sensitisation was more common in non-farm children at any level. Prevalence of sensitisation to perennial allergens did not differ between farm and reference children and peaked at 4 years at 30%.   Conclusion   Growing up on a farm might alter sensitisation patterns possibly revealing a modified immune response with a limited production of specific IgE.
Abstract 21: Mobile Extracorporeal Life Support for Patients With Refractory Cardiogenic Shock or Reanimation - The Concept of a Regional Supply Network
Authors: Alexander Albert, Frank Born, Hiro Kamiya, Diyar Saeed, Payam Akhyari, Detlef Kindgen-Milles, Artur Lichtenberg
Journal: Circulation (2012)

Objectives: To prove the concept of a regional supply network for mobile extracorporeal life support (ECLS), provided by an university heart centre, specialised on mechanical support. Methods: We established a mobile ECLS service for regional catheter laboratories (cath-lab). We included patients with severe refractory cardiogenic shock and/or resuscitation if locally available therapies failed and a safe transport to a heart centre was not possible. Without immediate mechanical support the patients are considered to die. Logistic optimization was achieved by 1) use of a miniaturized ECLS device (Life Box, Sorin), which is 24-hours instantly ready for use, 2) provision of a passenger car with flash lights for going, 3) placement of stickers with the 24 hours emergency numbers on prominent places, 4) training of cardiologists in insertion of femoral ECLS cannulae. Results: Seven cath-labs joined the supply network. From 08/2011 until 05/2012 mobile ECLS was used in 39 cases (age: 3 to 86 years; mean 58). Distance: 0.5 to 224 km. Resuscitation time: 5 -240 min. All patients received on-site femoral veno-arterial ECLS. Duration of support: 1 to 28 days (mean:8.3). Further treatment include: implantation of a ventricular assist device, cardiac transplantation, coronary artery bypass grafting, left ventricular thrombectomie, PTCA, mitral- and aortic valve replacement. 30-day survival without significant neurological deficits was 44% for men, 50% for women. Conclusion: Mobile ECLS therapy, using recent technology, offers new options for patients, who are otherwise likely to die. The concept of a regional ECLS supply network ensures an optimized logistic and minimization of loss of time
Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children's Cancer Study Group.
Authors: G Reaman, P Zeltzer, W A Bleyer, B Amendola, C Level, H Sather, D Hammond
Journal: Journal of Clinical Oncology (1985)

A retrospective review of all 115 infants less than 1 year of age with acute lymphoblastic leukemia (ALL) entered on a consecutive series of recent Children's Cancer Study Group (CCSG) leukemia protocols was undertaken to examine in detail the outcome and clinical course of a large group of similarly treated infants. In comparison to the 4,392 children older than 1 year, entered on the same studies, infants had a significantly (P = .0001) increased incidence of leukocytosis, hepatosplenomegaly, meningeal leukemia at presentation, hypogammaglobulinemia, and failure to achieve complete remission (CR) status by day 14 of induction therapy. In contrast, lymphadenopathy, non-L1 French-American-British (FAB) morphology, mediastinal mass, and T cell leukemia were not more frequently observed. Ninety percent of these infants successfully completed the induction phase of therapy. With a median follow-up of 35 months, life table estimate of disease-free survival is only 23% at 4 years. Identical disease-free survival rates for infants were observed in each of the individual studies reviewed. Excessive toxicity resulting in limitation of therapy delivered was not a causative factor for the disappointing outcome of these patients. Rather, early disease recurrence, characterized by bone marrow relapse (55%) and CNS (22%) relapse, was the major factor responsible for the extremely poor prognosis of this patient group. Identical CNS relapse rates were observed in those patients who received cranial irradiation as part of CNS prophylaxis (21.8%) and in those patients who did not receive cranial radiotherapy (24%). Results of salvage therapy for patients who experienced systemic or extramedullary relapse were dismal. Debilitating neuropsychologic sequellae, presumably related to CNS irradiation, have been observed in 50% of the small number of long-term survivors. Infants less than 1 year of age with ALL present with a constellation of features which predict a poor outcome and constitute the group of children with ALL at greatest risk for treatment failure.
ALD518, a humanized anti-IL-6 antibody, treats anemia in patients with advanced non-small cell lung cancer (NSCLC): Results of a phase II, randomized, double-blind, placebo-controlled trial.
Authors: M. Schuster, J. R. Rigas, S. V. Orlov, B. Milovanovic, K. Prabhash, J. T. Smith
Journal: Journal of Clinical Oncology (2010)

7631 Background: ALD518 is a humanized anti-IL-6 antibody being developed for the treatment of cancer- related anemia, cachexia, and fatigue. The primary objective of the study was to determine the efficacy and safety of ALD518 in patients with advanced NSCLC. Methods: 124 patients (pts) with NSCLC, ECOG 0-3, weight loss in the preceding 3 months of >5% body weight, hemoglobin (Hb) >7 g/dL, and C-reactive protein (CRP) >10 mg/L were dosed. Pts were randomized to 1 of 4 groups (n∼30/group). Placebo or ALD518 80 mg, 160 mg, or 320 mg was administered intravenously every 8 weeks. Pts were followed up for 24 weeks. Data included hematology, clinical chemistry, CRP, and adverse events (AEs). Results: 29 pts completed the study treatments and evaluations, 38 failed to complete every visit, 52 died of progressive disease, and 5 withdrew because of adverse events. There were no dose-limiting toxicities (DLTs) or infusion reactions. 84 pts had serious AEs of which 1 was deemed to be possibly related to administration of ALD518 (rectal hemorrhage). The mean (±SD) values for Hb, hematocrit (Hct), mean corpuscular Hb (MCH), and albumin are shown in the Table. 38/93 pts treated with ALD518 and 10/31 given placebo had a pre-dose Hb =<11 g/dL. 24 of these pts on ALD518 and 7 of these pts on placebo remained in the study at week 4. 14/24 pts on ALD518 and 0/7 on placebo had raised their Hb from =<11 g/dL to >=12 g/dL. Conclusions: ALD518 increased Hb, Hct, MCH and albumin in NSCLC pts and raised Hb to >=12g/dL in 58% of pts with a Hb =<11 g/dL at baseline. ALD518 may be a novel non-erythropoietic stimulating agent for cancer-related anemia. There were no major safety signals related to the administration of ALD518. n Hb (g/dL) Hct (%) MCH (pg) Albumin (g/L) ALD518 Pre-dose 93 11.5 (±2.1) 37.9 (±6.2) 28.4 (±2.8) 37.3 (±5.3) (pooled) Week 4 69 13.1 (±1.6)a 42.5 (±5.0)a 29.2 (±2.5)a 43.6 (±4.7)a Week 12 39 13.4 (±1.6)a 42.5 (±4.7)b 29.8 (±2.8)a 45.2 (±4.5)a Placebo Pre-dose 31 12.2 (±1.8) 39.0 (±5.9) 29.0 (±2.8) 37.5 (±5.7) Week 4 29 11.8 (±2.0) 39.5 (±6.4) 28.0 (±2.8)c 37.3 (±6.8) Week 12 21 12.0 (±2.5) 39.6 (±7.4) 27.8 (±3.0)c 37.0 (±7.5) a p < 0.0001; b p = 0.0002; c p ≤ 0.001 (paired t-test compared to pre-dose). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alder Biopharmaceuticals Inc. Alder Biopharmaceuticals Inc. Alder Biopharmaceuticals Inc.