tbuckley/cabot-search huggingface dataset:
Long-term survival with metastatic breast cancer (MBC): Results of a retrospective, single-centre analysis from 2000–2005
Authors: J. A. Cnossen, V. Heinemann, D. Laessig, H. J. Stemmler
Journal: Journal of Clinical Oncology (2008)

1128 Background: Recent epidemiological studies suggest that chemotherapy has not contributed to a marked improvement of patient outcome during the last decades. In most randomized trials who investigated the efficacy of a 1st-line schedule for MBC the median survival ranged between 18 and 24 months. The goal of the present analysis was to analyse the survival of patients with MBC treated in a single university outpatient clinic. Methods: Patients who had received their complete anti-cancer treatment for MBC in our outpatient clinic between 2000 and 2005 were analyzed for treatment and survival. Results: 232 patients [median age 53, range 25–84 yrs; ER and/or PgR positive (HR+) n=181 (78%); HER2 over-expression (HER2+) n=79 (34%)] were included into the analysis. Following antihormone treatment in HR+ patients (median 2 regimens), patients received up to 3 chemotherapies in palliative intent (41.1%), 4–6 regimens were applied in 22.0% and 12.5% received more than 6 subsequent regimens during the course of the disease. The median overall survival was 44 months. HR+ patients survived 44 months, whereas the survival of those with HR- tumors was 33 months (p=0.07). HER2+ patients who received trastuzumab survived for a median of 46 months. Visceral involvement was associated with a shorter survival when compared to nonvisceral disease (34 vs 57 months, p< 0.05). 44 pts underwent local-regional procedures as metastasectomy (n=32, 13.8%) or radiofrequency ablation (n=12, 5.2%). Conclusions: These data support the hypothesis that continuous and sequential treatment of MBC patients may result in a prolonged survival. While these data appear to be in contrast to some epidemiological analyses, they may provide the basis for benchmark comparisons in the future. No significant financial relationships to disclose.
The effects of systemic granulocyte-macrophage colony stimulating factor (GM-CSF) and Interleukin-2 (IL-2) on peripheral blood dendritic cell (DC) counts in patients with stage IIB-IV melanoma
Authors: J. L. Zapas, J. H. Hasskamp, S. L. Beam, S. D. Brown, K. A. Jablonski, E. G. Elias
Journal: Journal of Clinical Oncology (2004)

2611 Background: In an attempt to provide more effective adjuvant systemic therapy in Stages IIB-IV melanoma, we chose to study a sequential regimen of GM-CSF, 125 μg/m2 for 14 days, followed by IL-2, 9 million IU/m2 for 4 days followed by a 10 day rest (28 day cycle). While leukocytosis is common after GM-CSF therapy, it is unknown whether this translates to increases in circulating DC. Theoretical anti-tumor mechanisms of action might include a cumulative gain in peripheral DC counts. Methods: Ten patients with stage IIB-IV melanoma were treated with GM-CSF/IL-2 as adjuvant therapy after complete surgical resection. White blood cell counts (WBC) were determined using an automated method (Sysmex) and DC counts were determined using four-color flow cytometry. Assays of the peripheral blood were performed at baseline, the start of each cycle and after the completion of 6 cycles. Counts were compared to those of 29 normal volunteers (NL), 30 patients with no evidence of disease (NED), and 14 patients with tumor burden (TB). Results: Normal (NL) DC counts were determined to be 25 (±6) per μL. Melanoma patients with TB had DC counts of 18 (± 9) per μL. While DC counts were statistically different between in NL patients and TB patients (p<0.01), there were no differences between NL and NED 24 (± 7) per μL. Patients receiving GM-CSF/IL-2 had DC counts similar to patients with TB, 18 (± 8). After cycle 2, there was a significant increase in WBC from the baseline value of 6.4 x103 per μL to 8.2 x103 per μL to a maximum value of 9.0 x103 per μL after cycle 4 (p<0.01). While the WBC remained high after cycle 6 (8.2 x103 per μL), there was no significant elevation in %DC (mean range 0.20–0.27 %) or DC counts (mean range 14–19 per μL) during therapy. WBC fractions showing a significant gain after Cycle 2 were lymphocytes and eosinophils . Conclusions: Although the sample size was small in this study, there was a significant increase in peripheral WBC after two cycles of GM-CSF/IL-2, while no detectable cumulative effect on peripheral DC counts could be demonstrated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron
Innate Lymphoid Cells and Acute Respiratory Distress Syndrome
Authors: Kong Chen, Jay K. Kolls
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

There are dramatic demographic shifts occurring in the United States: For the first time, racial/ethnic minorities make up more than half of all the children born in the United States, of which Latinos are the largest and fastest growing group.These facts have significant medical, public health, economic, and political implications.However, the biomedical community has largely adopted the classification and study of Latinos as a single homogenous racial/ethnic group.The results from HCHS/SOL, along with previous studies, provide strong support that environmental and genetic factors for asthma differ by race/ ethnicity.The changing U.S. demographics further underscore the significant disease burden asthma carries for the nation, as well as the need to investigate the etiology of the disease in patient cohorts that are more representative of the current, and future, U.S. population.President Obama made history by announcing the Precision Medicine Initiative during his State of the Union address (12).He proposed a revolutionary shift in patient care that highlighted the necessity of promoting research considering social, environmental, and genetic factors to ensure that all individuals receive the right diagnoses and treatments at the right time.The recognition that many patterns of disease risk are population-specific, and in the case of U.S. Latinos, ethnic-specific, presents a significant gain in our knowledge of complex disease.This recognition is likely to be mirrored by an increase in targeted therapies as the growing biotech industry recognizes the "untapped" market potential of tailored therapies.Applied correctly, the Precision Medicine Initiative edict encourages the application of medical care and research efforts in a socially just manner, such that the rising tide of precision medicine lifts all boats, including groups disproportionately affected by disease.The study by Barr and colleagues is a step in the right direction.
Formation of Methylnitrosocyanamide From Methylguanidine and Sodium Nitrite in Simulated Gastric Juice and in Stomachs of Rats: Quantitative Estimation by a Mutagenicity Assay&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: M Ishizawa, T Utsunomiya, N Kinoshita, H Endo
Journal: JNCI Journal of the National Cancer Institute (1979)

The formation of methylnitrosocyanamide (MNC), a carcionogenic N-nitroso compound, from methylguanidine (MG) and NaNO2 in simulated gastric juice (SGJ) and in the stomachs of rats was quantitatively investigated. With a reverse mutation assay in which a tester strain of Salmonella typhimurium was used, MNC formation was shown to increase linearly for about 40--60 minutes after the incubation of MG with NaNO2 in SGJ. However, it decreased rapidly thereafter. The initial rate of MNC formation was directly proportional to the initial molar ratio of MG to NaNO2, but the yields of MNC depended only on the amount of MG added and were fairly constant (0.3--0.5% of the initial MG). MNC did not form at a pH above 2.5 or in the presence of 2% casein in SGJ at pH 1.2. It decomposed rapidly in SGJ at pH 1.2 with a half-life of approximately 2 minutes, whereas it was stable in phosphate buffer at pH 7.0. Following concurrent administration of MG and NaNO2 via stomach tube, MNC formation was detected in the pylorus-ligated stomachs of rats preconditioned with a casein-free dextrin diet but not in those of rats preconditioned with a casein-containing or synthetic diet. The yields of MNC observed 40--60 minutes after administration of reactants ranged from 0.02 to 0.05% of the initial MG. The possible environment significance of MNC formation in vivo was considered.
Sudden death in cancer patients receiving lithium.
Authors: G H Lyman, C C Williams, W R Dinwoodie, D D Schocken
Journal: Journal of Clinical Oncology (1984)

Lithium carbonate may attenuate the incidence and severity of infection associated with cancer chemotherapy but does not appear to improve patient survival. Of 100 patients with small-cell lung cancer receiving an identical regimen of cyclophosphamide, doxorubicin, and vincristine, 40 were assigned to treatment with lithium concurrently. To date, 60 patients have died, including 14 who died suddenly of apparent cardiovascular causes without evident progression of neoplastic disease or concurrent illness. Thirteen of the 14 sudden deaths were among 50 patients with clinical or electrocardiographic evidence of cardiovascular abnormalities before study entry. Among patients with pretreatment cardiovascular abnormalities, lithium administration was associated with a greater risk of sudden death and shorter survival. A strong interaction for risk of death was evident between lithium treatment and the use of bronchodilators. In multivariate analysis, the major predictors of patient survival were the quality of tumor response and treatment with lithium with or without bronchodilators. Lithium treatment is a major risk factor for sudden death in cancer patients with pretreatment cardiovascular changes receiving combination chemotherapy including an anthracycline antibiotic.
Gefitinib/Chemotherapy Vs Chemotherapy in Epidermal Growth Factor Receptor (Egfr) Mutation-Positive Non-Small-Cell Lung Cancer (Nsclc) After Progression on First-Line Gefitinib: the Phase Iii, Randomised Impress Study
Authors: T.S.K. Mok, Y. Wu, K. Nakagawa, S. Kim, J. Yang, M. Ahn, J. Wang, J.C. Yang, Y. Lu, S. Atagi, S. Ponce, X. Shi, A. Webster, H. Jiang, J-C. Soria
Journal: Annals of Oncology (2014)
The use of extracorporeal membrane oxygenation (ECMO) in severe delayed graft dysfunction after lung transplant
Authors: Karthikan Srikanthan, Martin Carby, Andre Simon, Penny Wilton, Allison Bashford, Heike Krueger
Journal: European Respiratory Journal (2011)

Introduction: Delayed graft dysfunction is an uncommon but serious complication in the first few days following successful lung transplantation and is associated with significant mortality. ECMO has been used in initial graft dysfunction with some success, but there have been few studies on its use in delayed graft failure.

Objectives: To review the experience of using veno-venous (V-V) ECMO in patients with delayed graft dysfunction at Harefield Hospital from January 2010 to January 2011.

Methods: A retrospective review of five cases of severe delayed graft failure requiring V-V ECMO was carried out.

Results: Indications for lung transplant were COPD (2 patients), hypersensitivity pneumonitis (2 patients), pulmonary fibrosis and alpha-1 antitrypsin deficiency.

Four patients (80%) were eventually discharged from hospital and are currently well with stable lung function and good functional status. One patient (20%) died 112 days after ECMO explantation.

Mean transplant to implantation date was 11±9.1 days. Mean PaO2/FiO2 ratio was 9.9±3.8 kPa on mechanical ventilation. All patients had initial extensive bilateral pulmonary infiltrates on chest radiograph or HRCT scan. Three patients had abnormal radiological changes that persisted after discharge. Mean duration of ECMO support was 9.2±2.7 days. Only one patient had positive microbiology – rhinovirus on viral PCR. Mean length of stay in ITU was 56.2±30.0 days. Mean length of stay in hospital was 90.8±25.3 days.

Conclusion: In severe delayed graft dysfunction refractory to mechanical ventilation, a short period of V-V ECMO can be highly effective in supporting patients during recovery of acute lung injury.
Progress Toward Strengthening National Blood Transfusion Services — 14 Countries, 2011–2014
Authors: Michelle S. Chevalier, Matthew Kuehnert, Sridhar V. Basavaraju, Adam Bjork, John P. Pitman
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Blood transfusion is a life-saving medical intervention; however, challenges to the recruitment of voluntary, unpaid or otherwise nonremunerated whole blood donors and insufficient funding of national blood services and programs have created obstacles to collecting adequate supplies of safe blood in developing countries (1). Since 2004, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) has provided approximately $437 million in bilateral financial support to strengthen national blood transfusion services in 14 countries in sub-Saharan Africa and the Caribbean* that have high prevalence rates of human immunodeficiency virus (HIV) infections. CDC analyzed routinely collected surveillance data on annual blood collections and HIV prevalence among donated blood units for 2011-2014. This report updates previous CDC reports (2,3) on progress made by these 14 PEPFAR-supported countries in blood safety, summarizes challenges facing countries as they strive to meet World Health Organization (WHO) targets, and documents progress toward achieving the WHO target of 100% voluntary, nonremunerated blood donors by 2020 (4). During 2011-2014, overall blood collections among the 14 countries increased by 19%; countries with 100% voluntary, nonremunerated blood donations remained stable at eight, and, despite high national HIV prevalence rates, 12 of 14 countries reported an overall decrease in donated blood units that tested positive for HIV. Achieving safe and adequate national blood supplies remains a public health priority for WHO and countries worldwide. Continued success in improving blood safety and achieving WHO targets for blood quality and adequacy will depend on national government commitments to national blood transfusion services or blood programs through increased public financing and diversified funding mechanisms for transfusion-related activities.
Progress in the treatment of plasma cell myeloma?
Authors: D Bergsagel
Journal: Journal of Clinical Oncology (1983)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1983.1.8.510 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 6668513 Progress in the treatment of plasma cell myeloma? D BergsagelxD BergsagelSearch for articles by this author https://doi.org/10.1200/JCO.1983.1.8.510 First Page PDF © 1983 by American Society of Clinical Oncology
The Prevalence and Risk Factors of Atopic Dermatitis from Nationwide Study: Korean Environmental Health Survey in Children and Adolescents (KorEHS-C)
Authors: sung-Hee Lee, Ju-Hee Seo, Hyun-Ju Cho, Eun Lee, Mina Ha, Eunae Burm, Kee-Jae Lee, Hwan-Cheol Kim, Sinye Lim, Hee-Tae Kang, Hee-Tae Kang, Mia Son, Soo-Young Kim, Hae-Kwan Cheong, Yu-Mi Kim, Gyung-Jae Oh, Joon Sakong, Chul-Gab Lee, Sue Jin Kim, Yong-Wook Baek, Soo-Jong Hong
Journal: Journal of Allergy and Clinical Immunology (2016)
Activation of both transcription factors STAT5 and IRF-1 is insensitive to corticosteroids in asthmatic bronchial smooth muscle cells exposed to TNFα/IFNγ
Authors: Adelina Gavrila, Latifa Chachi, Omar Tliba, Christopher Brightling, Yassine Amrani
Journal: European Respiratory Journal (2012)

We have previously developed a cellular model in healthy airway smooth muscle (ASM) cells where corticosteroids (CS) lose their anti-inflammatory action when cells are exposed to TNFα in combination with IFNγ. The molecular mechanisms by which TNFα/IFNγ promote CS insensitivity has not been completely investigated although an increased activation of transcription factors such as STAT5 has been implicated in other cell types. It is also not known whether TNFα/IFNγ also interfere with CS in ASM cells derived from asthmatic patients. In the present study, we found that TNFα/IFNγ-induced the expression of different steroid-resistant chemokines CX3Cl1, CCl5 and CCl11 in asthmatic ASM cells (n=3). We also found that TNFα/IFNγ (0-6hr)-increased phosphorylation of STAT5 in a time-dependent fashion reaching a maximum at 30 min followed by a lower activated state that was sustained up to 6 hr. Prior treatment with fluticasone (0.1-100 nM) did not affect cytokine-induced STAT5 activation but dose-dependently increased STAT5 phsophorylation. Similarly, the sustained activation of the transcription factor IRF-1 by TNFα/IFNγ (up to 6 hr) was also unaffected by fluticasone (01-100 nM). Together, these data show for the first time that TNFα/IFNγ induced a sustained activation of corticosteroid-resistant STAT5 and IRF-1 in asthmatic ASM cells (n=3). Because STAT5 and IRF-1 have been associated with reduced CS action in other cell types, our findings suggest the possible of involvement of these transcription factors in driving CS insensitivity in asthmatic airway smooth muscle cells.
Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation
Authors: Nirav Dhanesha, Ajmal Ahmad, Prem Prakash, Prakash Doddapattar, Steven R. Lentz, Anil K. Chauhan
Journal: Circulation (2015)

The fibronectin-splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts in the plasma of healthy humans but markedly elevated in patients with comorbid conditions, including diabetes mellitus and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes in such conditions. We determined the role of Fn-EDA in stroke outcome in a model of hypercholesterolemia, the apolipoprotein E-deficient (Apoe(-/-)) mouse.In a transient cerebral ischemia/reperfusion injury model, Apoe(-/-) mice expressing fibronectin deficient in EDA (Fn-EDA(-/-)Apoe(-/-) mice) exhibited smaller infarcts and improved neurological outcomes at days 1 and 8 (P<0.05 versus Apoe(-/-) mice). Concomitantly, intracerebral thrombosis [assessed by fibrin(ogen) deposition] and postischemic inflammation (phospho-nuclear factor-κB p65, phospho-IκB kinase α/β, interleukin 1β, and tumor necrosis factor-α) within lesions of Fn-EDA(-/-)Apoe(-/-) mice were markedly decreased (P<0.05 versus Apoe(-/-) mice). In an FeCl3 injury-induced carotid artery thrombosis model, thrombus growth rate and the time to occlusion were prolonged in Fn-EDA(-/-)Apoe(-/-) mice (P<0.05 versus Apoe(-/-) mice). Genetic ablation of TLR4 improved stroke outcome in Apoe(-/-) mice (P<0.05) but had no effect on stroke outcome in Fn-EDA(-/-)Apoe(-/-) mice. Bone marrow transplantation experiments revealed that nonhematopoietic cell-derived Fn-EDA exacerbates stroke through Toll-like receptor-4 expressed on hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA into Apoe(-/-) mouse 15 minutes after reperfusion significantly improved stroke outcome.Hypercholesterolemic mice deficient in Fn-EDA exhibit reduced cerebral thrombosis and less inflammatory response after ischemia/reperfusion injury. These findings suggest that targeting Fn-EDA could be an effective therapeutic strategy in stroke associated with hypercholesterolemia.
First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors.
Authors: J. Delord, N. Houede, A. Awada, A. Taamma, S. J. Faivre, T. Besse-Hammer, A. Italiano, C. Vignaud, M. Donica, E. Raymond
Journal: Journal of Clinical Oncology (2010)

2504 Background: AS703026 is a highly selective and potent noncompetitive inhibitor of MEK1/2. AS703026 exhibited strong antiproliferative activity in tumor cell lines with activated mitogen-activated protein kinase (MAPK) signalling, and antitumor efficacy in numerous human tumor xenograft models. This phase I trial was initiated to determine the maximum tolerated dose (MTD) of two AS703026 R. Methods: Pts with solid tumors received oral, fixed doses of AS703026 once a day, on days 1–5, 8–12, and 15–19 (R1) or days 1–15 (R2), of 21-day cycles. Accelerated then modified Fibonacci dose-escalation processes were applied for each R. PK samples and pre- and post-dose peripheral blood mononuclear cells (PBMC) for the measurement of phosphorylated extracellular signal-regulated kinase (pERK) were collected for all pts. Results: As of November 1, 2009, 68 pts (36 pts R1, 32 pts R2) received AS703026 across 10 dose levels [range 1–94 mg/day]. Pt characteristics were median age [range] 60 yrs [34–75] R1, 62 yrs [43–77] R2; males 56% R1, 55% R2; ECOG PS (0/1) 56%/44% R1, 55%/46% R2. Most frequent tumors were colorectal (42% R1, 36% R2) and melanoma (14% R1, 12% R2). Pts received a median of 2 cycles [range] in both R [1–6, R1, 1–11, R2]. Most common adverse events (all grades): asthenia (49% R1, 50% R2), diarrhea (40% R1, 28% R2), acne-like skin reactions (37% R1, 41% R2), nausea (34% R1, 25% R2), constipation (26% R1, 16% R2), vomiting (23% R1, 25% R2). At 28 mg/day, 1/6 pts experienced a DLT (grade 3 liver function test elevation). Visual disturbances were reported at 94 mg/day (66% R1, 33% R2). Plasma concentrations and exposures increased proportionally with dose, with a median tmax of 1.5 hours [range 0.5–4.0] after intake. Complete pERK inhibition was observed in PBMC 2 hours post-intake at doses ≥28 mg/day. Two confirmed partial responses (at 68 and 94 mg/day) were reported in previously-treated melanoma pts. Conclusions: AS703026 showed a good safety and PK profile with complete target inhibition in PBMCs at doses ≥28 mg/day. MTD has not been reached; dose escalation is ongoing. Interestingly, antitumor activity has been observed prior to reaching the MTD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono Amgen Bayer, Merck Serono, Pfizer EMD Serono, Merck Serono