tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors
Authors: S. Gail Eckhardt, Jinee Rizzo, Kevin R. Sweeney, Gillian Cropp, Sharyn D. Baker, Maura A. Kraynak,†, John G. Kuhn, Miguel A. Villalona-Calero, Lisa Hammond, Geoffrey Weiss, Allison Thurman, Lon Smith, Ronald Drengler, John R. Eckardt, Judy Moczygemba, Alison L. Hannah, Daniel D. Von Hoff, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m 2 as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-α and -β receptors was performed on malignant tumor specimens obtained at diagnosis. RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m 2 dose levels. Dose escalation of SU101 above 443 mg/m 2 /wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 ± 12 days. At the 443 mg/m 2 /wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 μmol/L. Immunohistochemical studies revealed PDGF-α and -β receptor staining in the majority (15 of 19) of malignant neoplasms. CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m 2 /wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.
Reduction of BCR-ABL Transcript Levels at 6, 12, and 18 Months (mo) Correlates with Long-Term Outcomes on Imatinib (IM) at 72 Mo: An Analysis from the International Randomized Study of Interferon versus STI571 (IRIS) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP)
Authors: Timothy P Hughes, Andreas Hochhaus, Susan Branford, Martin C Müller, Letizia Foroni, Brian J. Druker, François Guilhot, Richard A. Larson, Stephen G O’Brien, Roger J. Waltzman, Manisha Mone, Elisabeth Wehrle, Jerald P. Radich, John M. Goldman
Journal: Blood (2008)
The analysis of NBS-1 gene mutation [657del(5)] in exon 6 in the population of 472 sporadic breast cancer patients in the Czech Republic
Authors: J. Melter, G. Pazdrova, F. Janku, Z. Kleibl, J. Novotny, L. Petruzelka
Journal: Journal of Clinical Oncology (2006)

20087 Background: Nijmegen breakage syndrome (NBS) caused by mutation [657del(5)] in exon 6 of NBS-1 is an autosomal recessive disorder with microcephaly, immunodeficiency, radiosensitivity, and predisposition to lymphoid malignancies. Recently, high frequency of NBS-1 mutation was found in some Slavic populations. Because NBS-1 heterozygotes may have high incidence of neoplastic changes, there is an urgent need to clarify the role of NBS-1 mutation in breast cancer carcinogenesis. Methods: We analyzed the NBS-1 status in 472 sporadic breast cancer patients treated in the Department of Oncology, Charles University Prague. DNA was extracted from peripheral blood monocytes. Subsequently two PCRs for each sample were carried out. Reaction was visualized using electrophoresis on agarose gel. Agarose gel wells with both the NBS-1 gene-specific band and internal control band were interpreted as positive. Wells with internal control only were interpreted as negative. PCR from samples giving neither an internal control band nor specific band were repeated. DNA samples obtained from a previously typed NBS family were used as a positive control. Results: Based on previously published data we expect to find at least 5 mutation carriers. Surprisingly, in our population of 472 subjects there was no mutation identified. Conclusions: Based on results of this study there is no relationship between NBS-1 mutation and breast cancer incidence. Acknowledgment: The study was supported in part by the RASO grant from Czech Society of Oncology, and MSM0021620808. No significant financial relationships to disclose.
Pemetrexed/gemcitabine/cisplatin: Phase I trial in patients with solid tumors
Authors: C. Bolling, C. Lubbing, T. Graefe, S. Mack, J. Von Scheel, S. Muller-Hagen, J. Blatter, H. Depenbrock, U. Ohnmacht, A. R. Hanauske
Journal: Journal of Clinical Oncology (2004)

3096 Background: Pemetrexed (P), a novel multitargeted antifolate, has activity in a variety of solid tumors. P inhibits pivotal enzymes of purine and pyrimidine synthesis. Combining P with gemcitabine (G) and cisplatin (C) may improve the clinically established activity of GC by introducing an independent molecular mechanism of tumor growth inhibition. The aim of this study was to determine the maximum tolerated dose (MTD) of the PGC combination. Secondary aims included determining dose-limiting toxicities (DLTs), recommended doses for subsequent studies, and collecting anecdotal antitumor activity data. Methods: : DLT was defined as CTC grade (g) 4 neutropenia >7 days (d), febrile neutropenia, g4 thrombocytopenia (plts), g3 non-hematologic toxicities (except alopecia/nausea/vomiting), or toxicities causing delay on d22. MTD was defined as identical DLTs in ≥2 out of ≤6 patients (pts) at a given dose during cycle 1. P was administered (IV 10 min d1) prior to G (IV 30 min d1 and d8), and C (IV 2 hours d1) q 3 weeks. Results: : 12pts (9 male), median age 58 (range 39–77) were enrolled. Tumor types included head/neck (4), unknown primary (2), thymoma (1), bile duct (1), nasopharynx (1), prostate (1), renal (1), and parotid gland (1). A total of 41 courses of PGC were administered. Dose levels were: 1: P 400 mg/m2, G 800 mg/m2, C 40 mg/m2; 2: P 500 mg/m2, G 800 mg/m2, C 40 mg/m2. At each dose level, DLTs were observed without fulfilling criteria for MTD. Toxicities included g3 skin rash, syncope, mucositis, fatigue, diarrhea, and g4 febrile neutropenia, plts. Five cycles were delayed due to treatment-related toxicities, 5 omitted, and 4 reduced. Three patients discontinued due to g4 plts, g3 fatigue, and g3 syncope. One partial response was observed (head and neck) and 8 pts had stable disease (6+ weeks). Conclusions: The PGC regimen demonstrated clinical antitumor activity. Modified administration schedules are under investigation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.
Abstract 16339: Independent Relevance of Cytokines for Risk of Coronary Heart Disease
Authors: Robert Clarke, Jemma C Hopewell, Michael Hill, Martin Farrall, Hugh Watkins
Journal: Circulation (2012)

Aims: Genetic studies have refuted a causal role for C-reactive protein (CRP) in the etiology of coronary heart disease (CHD), but prompted increased interest in susceptibility variants affecting the IL-5 and IL-6 pathways and their impact on CHD risk. This study compared the independent relevance of plasma levels of several cytokines for prediction of CHD. Methods: The PROCARDIS case-control study compared the associations of five cytokines with CHD risk in 980 CHD cases and 985 controls. Plasma levels of cytokines (IL-6, IFN-γ, IL-5, IL-1β and TNF-α) were measured using a Meso Scale Discovery assay platform. Spearman correlation coefficients were used to examine associations with CRP in controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for CHD risk for extreme thirds of cytokines after adjustment for age, sex and country, and additionally for established risk factors (smoking, diabetes mellitus, hypertension, blood lipids and cystatin C). Results: Amon...
Abstract 19795: S-glutathionylation of eNOS occurs in Clinical Obstructive Sleep Apnea (OSA)
Authors: Saradhadevi Varadharaj, Jacob Wannemacher, Brian Patt, Hemalatha Rao, Levy Reyes, Rami Khayat, Jay L Zweier
Journal: Circulation (2012)

Obstructive sleep Apnea (OSA) is a risk factor for cardiovascular disease and causes vascular endothelial dysfunction (VED); however, the basis of this VED is unknown. Increased oxidant production is observed in the endothelium of OSA patients. We have recently demonstrated that under oxidant stress eNOS uncoupling is triggered by S-glutathionylation of specific cysteines including C689 of the reductase domain. Since OSA is associated with oxidant stress, we hypothesized that S-glutathionylation of eNOS may occur in OSA and trigger eNOS uncoupling. Methods: 13 patients with recently diagnosed OSA and 10 healthy individuals with low cardiovascular risk were studied. OSA patients underwent subcutaneous forearm biopsy and Doppler measurements of endothelial function by flow mediated dilation (FMD) prior to, and 12 weeks after initiation of treatment. Non-OSA control patients also provided FMD measurements and biopsies. eNOS S-glutathionylation was studied using specific anti-eNOS C689 S-glutathionylation antibody. Superoxide ·( O 2 _ ) levels in the microcirculation were determined using fluorescent probe DHE in the absence or presence of the SOD mimetic, MnTBAP. Results: OSA patients had impaired FMD, compared to non-OSA controls, which decreased after 12 weeks of treatment with CPAP. Immunohistochemical analysis of frozen sections from OSA patients using anti-eNOS C689 glutathionylation antibody revealed that prominent eNOS S-glutathionylation was present in the endothelium of OSA patients that was abolished by treatment with the reducing agent DTT, and was attenuated following CPAP treatment and absent in healthy control subjects. In association with these findings, · O 2 _ production from the endothelium was also decreased with CPAP treatment in OSA patients. Conclusions: These findings demonstrate that eNOS S-glutathionylation occurs in OSA and is associated with endothelial dysfunction with increased superoxide and decreased NO availability.
Abstract P074: Restless Legs Syndrome and Carotid Intima-Media Thickness in Women
Authors: Karen Jacobo, Adriana Monge, Eduardo Ortiz-Panozo, Elsa Yunes, Andres Catzin-Khulmann, Carlos Cantu-Brito, Ruy Lopez-Ridaura, Martin Lajous
Journal: Circulation (2015)

Introduction: Restless legs syndrome (RLS) is a common chronic disorder characterized by an irresistible need to move the lower limbs that is usually worse in the evening and is associated with sleep disturbances. RLS has been associated with hypertension and has been proposed as a marker for increased cardiovascular risk. Hypothesis: Individuals with RLS have an increased common carotid intima-media thickness (cIMT) relative to individuals without RLS. Methods: We evaluated cross-sectional relation of RLS and cIMT in 1,147 disease-free Mexican women of the Mexican Teachers’ Cohort. In 2011, participants responded to a follow-up questionnaire that included standardized questions addressing the four minimal diagnostic criteria of the International Restless Legs Study Group. Participants were asked: “Do you have unpleasant leg sensations (like crawling, loss of sensation or pain) combined with restlessness and an urge to move your legs?”, “Do these symptoms occur only at rest?”, “Does moving improve these symptoms?”, “Are these symptoms worse in the evening or at night compared with the morning?” Women who answered yes to all the four questions were defined as having RLS. Between 2012 and 2013, a subsample of participants were invited for a clinical visit where neurologists assessed cIMT with an ultrasound. cIMT measurements were found to be reproducible in a substudy in 52 participants (intra-class correlation=0.89). We defined subclinical atherosclerosis as a cIMT ≥0.8 mm or the presence of plaque. Results: Among women with a mean age of 48.2 (SD±4.3), the prevalence of RLS was 14.2% (cases, 163). The age-adjusted mean difference of cIMT comparing participants with RLS to those without RLS was 0.009mm (95%CI -0.004 to 0.023). After further adjustment for diabetes, hypercholesterolemia, migraine, oral contraceptive use, menopause, smoking, body mass index, physical activity and alcohol, the mean difference of cIMT comparing participants with and without RLS was not statistically different (0.007mm; 95%CI -0.007 to 0.021). The prevalence of subclinical atherosclerosis was 27% (n=44) in those with RLS and 21.9% (n=215) in those without RLS. The age-adjusted OR comparing women with RLS to those without RLS was 1.23 (95%CI 0.83-1.82). In the multivariable model the OR remained non-significant (1.16, 95%CI 0.77-1.74). Conclusions: In this cross-sectional study in middle-aged women, RLS was not associated to cIMT. Our results do not support the observation that individuals with RLS are at an increased risk for cardiovascular disease.
Gefitinib for advanced cutaneous squamous cell carcinoma of head and neck: Phase II trial
Authors: R. S. Weber, R. A. Lustig, A. K. El-Naggar, D. I. Rosenthal, E. S. Kim, I. I. Wistuba, X. M. Tang, F. F. Wan, S. A. Taylor, B. S. Glisson
Journal: Journal of Clinical Oncology (2009)

6054 Background: Advanced head and neck cutaneous squamous cell carcinoma (HN cSCC) carries a 30–40% risk of death by 2 years with standard therapies. Small molecular inhibitors of the epidermal growth factor receptor (EGFR) may have an impact. We evaluated gefitinib as an induction therapy in a high-risk patient (pt) group prior to definitive therapy to determine efficacy, toxicity and feasibility. Correlative studies of EGFR expression, gene mutation, and ploidy may serve as predictors of response. Methods: Eligible pts must have HN cSCC &gt;2cm, regional nodal metastases, peri-neural invasion, or deep invasion and must be candidates for definitive locoregional therapy with surgery and/or radiation. Two 30-day induction cycles of gefitinib (250mg po qd). Pts are assessed clinically after 15 days. If a response is noted, gefitinib is continued. For pts with stable disease, the dose is escalated to 500mg qd. Pts with progressive disease go off study. Total and phosphorylated (p) EGFR protein expression was analyzed by immunohistochemistry and gene copy number by fluorescent in-situ hybridization (FISH). Results: To date, 23 pts are enrolled and 22 are evaluable for responses and toxicities. Complete responses (CR) were noted in 3 pts, partial response (PR) 7, stable disease (SD) 5, and progressive disease (PD) 7 (68.1% response per RECIST criteria). Minimal side effects are associated with gefitinib (cutaneous and GI related). EGFR and p-EGFR protein overexpression were observed in 5 of 11 (45.5%) pts tested thus far. Eight of the pts were FISH negative with respect to EGFR gene expression: 7 had low trisomy and 1 had low polysomy. Two were FISH positive and expressed high polysomy. No gene amplification was detected. No statistically significant correlations between EGFR gene or protein expression and responses to administration of gefitinib were found at this point in the analysis. Protein and gene expression analyses are ongoing. Conclusions: The preliminary results from our study are encouraging and suggest that anti-EGFR therapy may have a role in the adjuvant treatment of HN cSCC. Correlative studies may help identify pts most likely to respond to anti-EGFR therapy. No significant financial relationships to disclose.
The risk of breast cancer recurrence in the sentinel lymph node era
Authors: L. P. Gold, Z. Cheng, L. Tafra, K. Sawyer, K. Verbanac, M. Rosman
Journal: Journal of Clinical Oncology (2006)

10600 Background: Sentinel lymph node biopsy (SLNB), the preferred method of axillary staging in early breast cancer, is more sensitive and accurate compared to axillary node dissection. However, this data has not been incorporated into current prognostic models estimating the risk of breast cancer recurrence. We hypothesize that prognostic models based on data in the pre-SLN era underestimate survival and exaggerate benefits resulting from adjuvant therapy. In order to evaluate this hypothesis, we examined the disease free survival (DFS) and overall survival (OS) in an IRB approved, prospective, multicenter study of SLNB. Methods: From 1996–2005, 564 patients who had invasive disease in whom a SLN was found were examined from two experienced sites . Data was analyzed with regards to SLN status, tumor size, grade, lymphovascular invasion (LVI), age, estrogen receptor (ER) status and use of chemotherapy with respect to DFS and OS. Results: Median age was 57 years, tumor size was 1.5 (range 0.08–10.5) cm and follow-up was 46.2 (range 1–104.5) months. The SLN was positive in 31.2% of patients. The Kaplan-Meier (K-M) 5 year estimate of OS was 94.5(±1)% and DFS 88(±2)%. Tumor grade and size, LVI, ER- and +SLN significantly correlated with poorer DFS and OS by univariate analysis. By multivariate analysis, however, SLN status was the only statistically significant predictor for DFS (p = 0.004; HR = 3.4; CI = 1.5 - 8.0) and OS (p = 0.0051; HR = 7.3; CI = 1.8–29.4). SLN negative patients showed K-M 5 year DFS and OS estimates of 94(±)% and 97.4(±1)% respectively. There was no significant difference in DFS for SLN- patients treated with or without chemotherapy (p = 0.3). Conclusions: SLN status was the only significant predictor of DFS and OS. In node negative patients, we observed a higher DFS and OS than current statistical models based on historical data would have predicted. In this new era of SLNB, the magnitude of benefit from adjuvant therapy in sentinel node negative patients should be re-evaluated. No significant financial relationships to disclose.
Abstract 14725: Comparative Efficacy of Pre-procedural Statins in Preventing Contrast-induced Nephropathy: A Network Meta-analysis
Authors: Ambarish Pandey, Bhuvnesh Aggarwal, Saurav Chatterjee, Purav Mody, Hani Jneid, Subhash Banerjee, Emmanouil Birlakis, Anthony Bavry, Jay Giri, Sandeep Das, James De Lemos, Dharam Kumbhani
Journal: Circulation (2014)

Introduction:  Contrast-induced nephropathy (CIN) is an important adverse outcome of coronary angiography/intervention. The role of pre-procedural statins in preventing CIN is unclear. Furthermore, the relative efficacy of different statins is unknown. Accordingly, we sought to perform a network meta-analysis to address this question.   Methods:  We performed a Bayesian network meta-analysis of randomized controlled trials that evaluated the impact of statin therapy prior to coronary angiography/intervention on post-procedure outcomes. The primary outcome was the incidence of CIN assessed as an increase in serum creatinine >0.5 mg/dl or > 25% from baseline at 48-72 hours; need for hemodialysis (HD) at 30 days was the secondary outcome. Different types and doses of statins were pooled and compared with Bayesian random-effects models, calculating pooled odds ratios (OR) and associated 95% credible intervals (95% CrI) for the Bayesian analysis.   Results:  A total of 14 studies (9 statin vs. placebo; 5 high-dose vs. low dose statin; 9 atorvastatin; 4 rosuvastatin; 2 simvastatin) enrolling a total of 5,927 patients were included in the analysis. High-dose statin therapy was associated with lower risk of CIN compared with placebo/low dose statin (OR = 0.5; 95% CrI 0.4-0.7). Among different statins, high dose atorvastatin was associated with the lowest risk of CIN (Table). High dose statin therapy was associated with a numerically lower incidence of need for HD compared with placebo (OR = 0.25; 95% CrI 0.05-1.20), with minor differences observed among the different statins.   Conclusion:  Pre-procedure statin therapy is associated with a lower risk of CIN following coronary angiography/intervention, with high dose atorvastatin having the highest efficacy. It should be considered in all patients undergoing these procedures, especially in those who are high-risk for post-procedure CIN.
False negative rates of PET scanning in bronchoalveolar lung (BAL) cancer and its implication for diagnosis and staging
Authors: C. W. Seidler, A. Buttar, B. Harrow
Journal: Journal of Clinical Oncology (2007)

18196 Background: Positron Emission Tomography (PET) scanning is extensively used for the diagnosis and staging of NSCLC lung cancer. Studies have shown PET scanning has a higher sensitivity and specificity in NSCLC than conventional diagnostic studies. False negative results in bronchoaveolar (BAL) lung cancer have not been systematically studied. We conducted a retrospective review to report and evaluate the low sensitivity of PET scanning in BAL when compared to other types of NSCLC cancer. Methods: We reviewed records of all patients who were diagnosed with lung cancer at Saint Vincent Hospital from 2000 to 2005. A total of 1361 patient were identified with a pathologically confirmed diagnosed of lung cancer out of which PET scanning was done in 36. All of these 36 cases reported NSCLC cancer: 29 NSCLC (adenocarcinoma 8, squamus cell 4, undifferentiated 6, non-small cell carcinoma 10), 7 bronchoalveolar carcinoma (BAL). Results: Among the cases diagnosed with NSCLC lung cancer at our institution, PET scans were done in 36 cases. Adenocarcinoma was found in 8 cases, all of which had positive PET reports. Squamous cell carcinoma was found in 4 cases, non-small cell carcinoma (not otherwise specified) was found in 10 cases, carcinosarcoma was found in 1 case, and undifferentiated carcinoma was found in 6 cases, all of which had positive PET reports and no false negatives (n=29/29,100%). Surprisingly, in the 7 bronchoalveolar cancer cases, only one PET scan was positive with 6 false negative reports (n= 1/7, 14.2%). A bivariate analysis (chi-square with Yate’s correction for continuity) revealed that the PET scan false negatives are significantly higher (p &lt; 0.0000007) for BAL when compared to other types of NSCLC cancers. Conclusions: PET scanning does not appear to be sensitive in the stagging and detection of BAL lung cancer with sensitivity of 14%. Routine use of PET scans for staging and diagnosis of BAL is not supported by this study. No significant financial relationships to disclose.