tbuckley/cabot-search huggingface dataset:
Lipoplatin plus gemcitabine versus cisplatin plus gemcitabine in NSCLC: Preliminary results of a phase III trial
Authors: T. Boulikas, N. Mylonakis, G. Sarikos, J. Angel, A. Athanasiou, G. Politis, A. Rapti, A. Rassidakis, M. Karabatzaki, N. Anyfantis
Journal: Journal of Clinical Oncology (2007)

18028 Background: Lipoplatin is a liposomal formulation of cisplatin, designed to reduce its adverse reactions without reducing efficacy. Its nanoparticles evade immune surveillance and extravasate preferentially into tumors inducing tumor cell apoptosis; lipoplatin may also act as antiangiogenesis factor. This is the initial report of a randomized, multicenter, phase III trial comparing the two drugs. Methods: Eligibility criteria included confirmed diagnosis of inoperable/metastatic NSCLC, no previous chemotherapy, WHO PS 0–1, adequate end-organ function. Patients received Lipoplatin 120 mg/m 2 D1,8,15 or cisplatin 100 mg/m 2 D1, combined with gemcitabine 1,000 mg/m 2 D1,8, in 3-week cycles, with disease evaluation after 3 and 6 cycles. Primary endpoints are overall survival and toxicity, with Response Rates, PFS and QOL also being evaluated. Results: 59 patients have been treated, 33 with lipoplatin and 26 with cisplatin; 17 have completed treatment. 2 lipoplatin patients had a hypersensitivity reaction during the first infusion. There were no grade 4 toxicities. Grade 3 toxicities were observed in &lt;5% of the patients and were comparable for the two groups, except neutropenia (3% for lipoplatin, 15% for cisplatin). Main grade 1–2 toxicities were anemia (93% vs 88%), leucopenia (51% vs 38%), neutropenia (45% vs 30%), thrombocytopenia (58% vs 31%), hepatotoxicity (38% vs 46%), nausea/vomiting (13% vs 35%), asthenia (31% vs 30%) and anorexia (32% vs 34%). Concerning nephrotoxicity, grade 2 was reported in only 6% of lipoplatin patients vs 19% in cisplatin, although lipoplatin was administered without pre-hydration as a 6-hour infusion. Neurotoxicity was also markedly less in lipoplatin. So far, 32 patients have been assessed for response, 16 in each group; 4 partial responses have been reported in each group. However, difference has been observed in stable disease (23% in lipoplatin vs 12% in cisplatin) as well as progressive disease (16% vs 35%). Conclusions: Preliminary results show that lipoplatin may have a better safety and therapeutic profile than cisplatin, when combined with gemcitabine, in advanced NSCLC. Particularly important might be its significantly lower neuro- and nephro-toxicity and its administration on an outpatients basis. No significant financial relationships to disclose.
The CMS Innovation Center — A Five-Year Self-Assessment
Authors: Rahul Rajkumar, Matthew J. Press, Patrick H. Conway
Journal: New England Journal of Medicine (2015)

Since 2010, the Center for Medicare and Medicaid Innovation has launched 26 new payment and service-delivery models. Results have been mostly positive to date, though the Center has also faced challenges — beginning with the difficulty of measuring quality in health care.
The potential mechanism of Th17/Treg imbalance in the microenvironments of chronic inflammation and allergic asthma
Authors: Linlin Wang
Journal: European Respiratory Journal (2012)

Objective  Recent studies have shown that Tregs can differentiate into IL-17+Foxp3+T cells in the colitic microenvironment and allergic rhinitis. However, the biology of CD39+Treg cells, IL-17+Foxp3+T cells and Th17 cells, and the relationship among these three kinds of cells remain poorly understood in allergic asthma.  Methods  We investigated the proportions of Th17, CD39+Treg cells and IL-17+Foxp3+T cells in peripheral blood from allergic asthmatics and healthy controls by flow cytometry. All patients were allergic to house dust mites. Dermatophagoides pteronyssinus specific IgE levels, pulmonary function and Asthma Control Questionnaire were assessed. Moreover, the associations among all these kinds of index and disease severity were analyzed.  Result  There was a deficiency in the frequency of total Tregs in asthmatics, whereas the frequency of Th17 cells, IL-17+Foxp3+T cells, CD39+Treg cells and plasma IL-17 levels were increased in moderate to severe asthma. FEV1 (% predicted) was negatively correlated with the frequency of Th17 cells, IL-17+Foxp3+ T cells, CD39+Treg cells and plasma IL-17 levels, and positively correlated with the frequency of total Tregs. Moreover, the frequency of Th17 cells and IL-17+Foxp3+T cells were positively correlated with the frequency of CD39+Treg cells.  Conclusion  Our findings suggest that the increased expression of CD39 on Tregs in asthma can offset the other decreased immunosuppressive functions of Tregs. And Tregs in the microenvironment of asthma also have plasticity of differentiate into IL-17+Foxp3+T cells. CD39+Treg cells play an important role in constraining pathogenic Th17 cells and IL-17+Foxp3+T cells.
Effect of Dietary Protein on &lt;italic&gt;N&lt;/italic&gt;-Nitrosobis(2-oxopropyl)amine-Induced Carcinogenesis and on Spontaneous Diseases in Syrian Golden Hamsters&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: P M Pour, D F Birt
Journal: JNCI Journal of the National Cancer Institute (1986)

For assessment of the effect of dietary protein on spontaneous diseases and on the carcinogenicity of N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4], Syrian golden hamsters were fed either low protein (LP; 9% casein), medium protein (MP; 18% casein), or high protein (HP; 36% casein) in a diet containing a medium fat (corn oil) level. The experimental design permitted distinguishing between the effects of protein levels on initiation and development of various lesions in hamsters, in comparison with a control group that was given MP diet for life. When fed after BOP treatment, HP diet inhibited, among induced tumors, pulmonary adenomas in males. Among spontaneous diseases, LP diet fed before 8 weeks of age enhanced colitis in both males and females, renal and adrenal gland amyloidosis in males, and gastric vascular calcinosis in males but inhibited liver abscesses and liver cysts in both males and females. When fed after 8 weeks of age, LP diet enhanced gastric and renal vascular calcification and parathyroid gland adenomas in both sexes but inhibited hepatic, renal, and adrenal gland amyloidosis in females and liver abscesses and liver cysts in both males and females. The feeding of HP diet before 8 weeks of age enhanced the development of colitis and adrenal gland lipomatosis in both males and females but inhibited the development of adrenal gland amyloidois and adrenal cortical cell hyperplasia in males. When fed to hamsters after 8 weeks of age, HP diet increased the incidence of adrenal gland amyloidosis in females and colitis in both males and females but reduced the frequency of liver cysts in both males and females and of adrenal cortical cell hyperplasia in males. The overall data and literature review indicate that the effect of dietary protein on tumorigenesis is tissue, sex, species, and strain related.
Intratumoral and plasma concentrations of gefitinib in breast cancer patients: Preliminary results from a presurgical investigatory study (BCIRG 103)
Authors: D. McKillop, G. Raab, H. Eidtmann, A. Furnival, A. Riva, J. Forbes, J. Mackey, M. P. Spence, M. Koehler, D. Slamon
Journal: Journal of Clinical Oncology (2004)

581 Background: Gefitinib (‘Iressa’, ZD1839) has a high volume of distribution in animals and humans, with a volume of 1400 L in cancer patients. Consistent with these pharmacokinetic data, gefitinib is extensively distributed into the tissues of rats and mice, with tissue:blood ratios of >10 in a number of organs. Concentrations of gefitinib in mouse subcutaneous tumour xenografts (LoVo: colorectal; A549: non-small-cell lung cancer) are considerably higher (10–15-fold) than plasma. Concentrations of gefitinib have been determined in plasma and breast cancer tissue as a secondary endpoint in a study designed primarily to identify molecular alterations in human breast cancer tissue after short-term exposure of patients to gefitinib. Preliminary concentration data are reported here. Methods: BCIRG 103 is a multicentre, open-label, noncomparative, presurgical study in women with invasive adenocarcinoma of the breast. Patients receive gefitinib (250 mg) once daily for at least 14 days and up to a maximum of 45 days prior to definitive surgery. Blood samples are taken immediately before and 24 h after the final dose of gefitinib. A sample of tumour tissue (100 mg) is taken and immediately snap-frozen during definitive surgery. Plasma and tumour samples were assayed for gefitinib and its major metabolites by high-performance liquid chromatography (HPLC) with mass spectrometric detection. Results: So far, 16 out of 40 patients have been enrolled and samples from 9 patients have been examined. Concentrations of gefitinib in tumour (2.3–25.8 μg/g) were much higher than plasma (0.10–0.42 μg/ml). There was no apparent correlation between tumour and plasma concentrations. Conclusions: The pronounced tumour:plasma ratio (mean 54-fold) was much higher than that from the mouse xenograft model. Gefitinib tumour concentrations will also be compared with the biomarker data as they become available. Data on a larger sample size will be presented. ‘Iressa’ is a trademark of the AstraZeneca group of companies Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1
Authors: Yuhong Luo, Juan Feng, Qingbo Xu, Wengong Wang, Xian Wang
Journal: Circulation Research (2016)

Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown.To investigate the mechanisms on the regulation of ICAM-1 by NOP2/Sun domain family, member 2 (NSun2)-mediated mRNA methylation and the impact of NSun2-ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis.By using in vitro, in cells, and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. Tumor necrosis factor-α or homocysteine activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with homocysteine treatment in wild-type rats were markedly decreased in NSun2(-/-) rats. In a rat model of aortic allograft, the lack of donor NSun2 impaired the formation of allograft arteriosclerosis.NSun2 upregulates the expression of ICAM-1 by methylating ICAM-1 mRNA. This regulatory process impacts on vascular inflammation and allograft arteriosclerosis.
Antibiotic Therapy for Adults Hospitalized With Community-Acquired Pneumonia
Authors: Jonathan S. Lee, Daniel L. Giesler, Walid F. Gellad, Michael J. Fine
Journal: JAMA (2016)

<h3>Importance</h3> Antibiotic therapy is the cornerstone of medical management for community-acquired pneumonia. <h3>Objective</h3> To assess the associations between 3 key aspects of antibiotic therapy (optimal time to antibiotic initiation, initial antibiotic selection, and criteria for the transition from intravenous to oral therapy) and short-term mortality in adults hospitalized with community-acquired pneumonia. <h3>Evidence Review</h3> Bibliographic databases of MEDLINE, EMBASE, and the Cochrane Collaboration were searched for studies of adults hospitalized with radiographically confirmed community-acquired pneumonia published from January 1, 1995, until November 5, 2015. <h3>Findings</h3> Twenty studies (17 observational and 3 randomized trials) met eligibility criteria. Among 8 observational studies identified, the 4 largest (study populations of 2878 to 1 170 022) found that antibiotic initiation within 4 to 8 hours of hospital arrival was associated with relative reductions of 5% to 43% in mortality; the 4 smallest studies (study populations of 451 to 2076) found no associations between the timing of antibiotic initiation and mortality. One cluster randomized trial (n = 1737) demonstrated noninferiority of β-lactam monotherapy (n = 506) vs β-lactam plus macrolide combination therapy (n = 566), with an absolute adjusted difference of 2.5% (90% CI, −0.6% to 5.2%) in 90-day mortality favoring β-lactam monotherapy. A second randomized trial (n = 580) failed to demonstrate noninferiority of β-lactam monotherapy vs β-lactam plus macrolide combination therapy, with an absolute difference of 7.6% (1-sided 90% CI upper limit, 13.0%) in attainment of clinical stability on hospital day 7 favoring β-lactam plus macrolide combination therapy. Six of 8 observational studies (study populations of 1188 to 24 780) found that β-lactam plus macrolide combination therapy was associated with relative reductions of 26% to 68% in short-term mortality and all 3 observational studies (study populations of 2068 to 24 780) reported that fluoroquinolone monotherapy was associated with relative reductions of 30% to 43% in mortality compared with β-lactam monotherapy. One randomized trial (n = 302) reported significantly reduced hospital length of stay (absolute difference, 1.9 days; 95% CI, 0.6 to 3.2 days), but no differences in treatment failure when objective clinical criteria were used to decide when to transition patients from intravenous to oral therapy. <h3>Conclusions and Relevance</h3> In adults hospitalized with community-acquired pneumonia, antibiotic therapy consisting of β-lactam plus macrolide combination therapy or fluoroquinolone monotherapy initiated within 4 to 8 hours of hospital arrival was associated with lower adjusted short-term mortality, supported predominantly by low-quality observational studies. One randomized trial supports the use of objective clinical criteria to guide the transition from intravenous to oral antibiotic therapy.
Phase II study of RAD001 in previously treated patients with metastatic pancreatic cancer
Authors: B. M. Wolpin, A. F. Hezel, D. P. Ryan, T. A. Abrams, J. A. Meyerhardt, L. S. Blaszkowsky, J. W. Clark, B. Allen, E. M. Regan, C. S. Fuchs
Journal: Journal of Clinical Oncology (2008)

4614 Background: Traditional cytotoxic agents have limited activity in metastatic pancreatic ductal adenocarcinoma (PDAC) and median survival for patients is less than 6 months. The majority of PDAC have activation of the PI3K/AKT/mTOR pathway and inhibition of this pathway reduces pancreatic cancer cell proliferation in preclinical studies. We performed a phase II study of RAD001, an oral inhibitor of mTOR (mammalian target of rapamycin), in patients with metastatic PDAC whose tumors progressed on gemcitabine. Methods: Eligible patients had histologically confirmed, measurable, metastatic PDAC with prior disease progression on gemcitabine. Patients were treated continuously with 10 mg of RAD001, once daily, on 28-day cycles. A single-stage, non-randomized, phase II study was designed to evaluate progression-free survival at 2 months with target enrollment of 35 patients. Secondary objectives included safety, response rate, and CA19–9 response. Disease response by RECIST criteria was assessed by independent radiologic review. Results: 31 patients were enrolled between Jan and Dec 2007. Baseline characteristics include median age, 62 (range, 40–79); male/female,16/15; ECOG PS 0/1, 8/23. Four patients received prior 5-fluorouracil postoperatively or for locally-advanced disease; all patients received prior gemcitabine. Among the 27 patients with available data, no responses were seen at 2 months; 5 of 27 patients had stable disease (SD). All 5 patients had progressive disease by the second restaging scan (4 months). Median progression-free survival was 1.9 months (range, 0.5–4.5 months). Two patients had >30% reduction in CA19–9, as best biochemical response, and both had SD on 2-month scan. Grade 3/4 toxicities seen in >5% of patients include hyperglycemia, 5/27 (19%); neutropenia 3/27 (11%); fatigue, 3/27 (11%); thrombocytopenia, 2/27 (7%); lymphopenia, 2/27 (7%). No patients were removed from study due to drug toxicity. Conclusions: Single-agent RAD001 is well tolerated in patients with metastatic, previously treated PDAC; yet, no patients experienced a disease response. A limited number of patients had stable disease for 2 or more months and reductions in CA19–9. No significant financial relationships to disclose.
LP09 : High efficacy of retreatment with ledipasvir and sofosbuvir in HCV patients who failed initial short course therapy with combination DAA regimens (nih synergy trial)
Authors: E.M.P. Wilson, S. Kattakuzhy, Z. Sims, L Tang, M. McLaughlin, A. Price, R. Silk, C. Gross, E. Akoth, A. Osinusi, H. Masur, A. Kohli, S. Kottilil
Journal: Journal of Hepatology (2015)
Abstract 261: Intermittently Encouraging Laypersons to Practice CPR Does Not Improve CPR Quality, Whereas Actual Practice Does Improve CPR Quality, 6 Months Post Training
Authors: Audrey L Blewer, David G Buckler, Jiaqi Li, Marion Leary, Lance B Becker, Peter W Groeneveld, Mary E Putt, Vinay M Nadkarni, Benjamin S Abella
Journal: Circulation (2014)

Background: CPR quality varies considerably and skills deteriorate over time from initial training. Investigations suggest that frequent training may improve CPR skills. Few studies have tested methods to encourage laypersons to practice their skills post-training. Objectives: We hypothesized that trained laypersons who receive intermittent encouragement to practice their CPR skills will perform faster and deeper chest compressions (CC); additionally, we hypothesized that those who actually practiced their skills will have improved CPR quality when tested 6 months post-training. Methods: In a multicenter trial of CPR strategies, cardiac patient caregivers were trained in CPR. All subjects were contacted at 2 and 4 months post-training and randomized to receive encouragement to practice CPR (“prompting”) or no suggestion to practice (“no prompting”) via a self-reported method (telephone, email, etc). At 6 months post-training, CPR skills were assessed through a “surprise” home visit and subjects were asked if they practiced their skills. CPR performance was quantified on a CPR-manikin and analyzed using multivariable regression controlling for confounders. Results: Subjects were enrolled from 02/2012-05/2014. 398 subjects consented to a skills check (180 in the prompting group, 183 in the control group, 35 lost to follow-up). Enrollees’ mean age was 51±14 years, and 73% were female. In an adjusted regression analysis, CC depth was 2.6±3.1 mm deeper among the prompted cohort (p=ns) and CC rate was 0.7±6.3 per min faster among those prompted (p=ns). Of those prompted, 56% reported practicing after prompting, while 44% of those not prompted reported practicing CPR skills after training. CC rate was 1.7 ± 3.2 per min faster among those who practiced their skills (p=ns). CC depth was 5.0 ±1.6 mm (95% CI: 1.8, 8.2) deeper among individuals who practiced their skills compared to those who did not practice (p&lt;0.01). Conclusions: Intermittent encouragement using self-reported preferred contact methods did not improve CPR quality, while CC depth improved among laypersons that actually practiced their skills. This work suggests that practicing improves CC depth and additional efforts are needed to facilitate practicing post-training among laypersons.
Macrocytosis in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKI's)
Authors: M. F. Khasawneh, J. Unnithan, T. Choueiri, B. Rini, R. Dreicer, J. Garcia, L. Wood, P. Elson, R. Bukowski
Journal: Journal of Clinical Oncology (2007)

15583 Background: Sunitinib and sorafenib are TKIs with inhibitory activity against a variety of kinases including VEGFR, PDGFR, and cKIT, as well as significant clinical activity in mRCC. Off target toxicity is frequently seen, and in pts treated with these TKIs the development of anemia ± macrocytosis was noted. Further studies were conducted to clarify the frequency and etiology of these findings. Methods: A retrospective review of mRCC patients treated with sunitinib or sorafenib for = 3 months was undertaken. Complete blood count data including RBC indices was recorded at baseline, 3 months, and at the end of treatment. Thyroid function tests (TFTs) were collected, and in selected patients, bone marrow examination was undertaken. Results: Ninety eight pts were evaluated (61 sunitinib-treated, 37 sorafenib-treated). In sunitinib-treated mRCC patients, median MCV levels increased significantly at 3 months compared to baseline (97.1 fL vs. 90.2 fL; p&lt;0.001) and median Hgb levels decreased from 13.4 to 12.8 (p =0.31). In patients receiving sunitinib &gt;12 months, MCV continued to increase throughout treatment. There was no association between increasing MCV and the development of hypothyroidism. In 10 patients discontinuing sunitinib, MCV returned to baseline within 2 to 4 months. The number of patient receiving sunitinib with an MCV &gt; 100 at the beginning, 3 months, and end of treatment were 2, 14 and 40 respectively. Bone marrow examinations performed during sunitinib therapy (n=3) demonstrated hypocellularity (5–10%) with normal trilineage hematopoiesis and no evidence of dysplastic changes. In contrast, sorafenib- treated mRCC patients showed no effects at 3 months on MCV levels (90.7 fL vs. 90.6 fL) but an increase in hemoglobin level (14.0 g/dL vs. 13.2 g/dL p=0.02) . At the beginning of treatment 2 patients had MCV values more than 100, but at 3 months and 12 months none of the patients had MCV values more than 100. Conclusions: Macrocytosis commonly develops in sunitinib-treated, but not sorafenib- treated mRCC pts. The etiology of this finding is unclear, but studies suggest direct effects on bone marrow precursors. Sunitinib-induced macrocytosis appears reversible with drug discontinuation. [Table: see text]