tbuckley/cabot-search huggingface dataset:
Monitoring plasma voriconazole levels may prevent subtheraputic dosing in pediatric stem cell transplant (SCT) patients
Authors: J. D. Morris, D. Voskoboynik, W. C. Brown, S. Czarnecki, C. L. Morris
Journal: Journal of Clinical Oncology (2007)

7105 Background: Voriconazole is frequently used for prophylaxis and treatment of fungal infections during hematopoeitic stem cell transplant (SCT). Clinical studies demonstrate a poorer outcome when voriconazole concentrations are ≤0.5mcg/ml. Pediatric dosing schedules to achieve trough concentrations &gt;0.5mcg/ml are not established. Methods: Retrospective analysis of voriconazole levels in 16 pediatric allogeneic SCT patients recieving fungal prophylaxis with oral or iv voriconazole. Ages ranged from 0.5 to 16 years, median 8 years. Serum levels were measured by high-performance liquid chromatography. Samples were obtained 5 to 7 days after start or change of voriconazole therapy. Ninety-eight total levels were evaluated. Results: Eight patients (50%) achieved a trough level &gt; 0.5mcg/ml on the majority of samples tested at doses ranging from 3.5 to 10 mg/kg po q 12 hours. At constant dose there was a significant intra-patient variability in trough levels over time. Most patients failing to achieve adequate trough levels were below the median age (see table ). Changing to iv therapy in 3 patients with low trough levels after oral therapy did not improve the trough levels. Multi-time point measurements were &gt; 0.5mcg/ml at 2 to 6 hours after oral dose, but fell to &lt; 0.2mcg/ml by 12 hours in 3 patients tested. Of 98 voriconazole levels, 52 were ≤ 0.5mcg/ml and 74 were &lt; 1.0 mcg/ml. Conclusions: Unlike reports in adult patients, we found that frequent monitoring of voriconazole levels was necessary in pediatric SCT patients due to intra-patient variability. Younger pediatric SCT patients may require more frequent dosing schedules to achieve trough levels. No significant financial relationships to disclose. [Table: see text]
Identification of Four Genes in Endothelial Cells Whose Expression Is Affected by Tumor Cells and Host Immune Status—A Study in Ex Vivo–Isolated Endothelial Cells
Authors: Birgit Liliensiek, Marian Rocha, Victor Umansky, Axel Benner, Jie Lin, Reinhard Ziegler, Peter P. Nawroth, Volker Schirrmacher
Journal: Blood (1998)
Serial alpha-feto protein in predicting radiological response and overall survival of patient with inoperable hepatocellular carcinoma (HCC) during chemotherapy
Authors: S. L. Chan, F. K. Mo, T. S. Mok, E. P. Hui, B. B. Ma, W. M. Ho, T. W. Leung, T. G. Liem, A. T. Chan, W. Yeo
Journal: Journal of Clinical Oncology (2008)

4602 Background: Although alpha-feto protein (AFP) is frequently measured during treatment of hepatocellular carcinoma (HCC), the trend of AFP in predicting response and survival of HCC patients is not clear. Methods: We retrospectively reviewed the serial AFP value in HCC patients who were entered to a phase III randomized clinical trial of doxorubicin versus cisplatin/interferon-α/doxorubicin/fluorouracil (Yeo et al. J Natl Cancer Inst. 2005 19;97) for histologically unresectable HCC. Patients with baseline AFP >100 ng/ml had their serial AFP correlated with response and survival. A significant drop of AFP is defined as a decrease of AFP >20% after the second or third cycle of chemotherapy. The relationship between the trend of AFP and response was examined. Overall survival analysis was performed by using Cox-regression in univariate and multivariate analysis. Results: Total 129 out of 188 patients were eligible for analysis. The Male and Female ratio was 117:12; the median age was 49; 88.8% belonged to ECOG 0. During chemotherapy, 44 patients had significant drop of AFP while 85 did not have. The response rates were 20/44 (45.5%) vs. 4/85 (4.7%) respectively (p<0.0001). Patients with significant drop of AFP had much batter overall survival than those who did not achieve this endpoint (OS: 12.1 vs. 3.8 ms; p <0.0001). Multivariate analysis revealed that post chemo drop of AFP >20% (p<0.0001; hazard ratio=0.36; 95% CI 0.24–0.55) after adjusting the bilirubin and ALT level affected survival significantly. Conclusions: Serial measurement of AFP during chemotherapy is important in monitoring response and outcome for advanced HCC. Dropping of AFP is predictive of radiological response and overall survival. Patients who do not achieve the target drop of AFP >20% after second or third cycle of chemotherapy have poor prognosis. No significant financial relationships to disclose.
Phase I and Pharmacokinetic Study of Exatecan Mesylate (DX-8951f): A Novel Camptothecin Analog
Authors: Melanie E. Royce, Paulo M. Hoff, Pamela Dumas, Yvonne Lassere, J. Jack Lee, John Coyle, Murray P. Ducharme, Robert De Jager, Richard Pazdur
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors. PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status ≤ 2, were entered. The starting dose of DX-8951f was 0.15 mg/m 2 ; the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred. RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m 2 and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m 2 , grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m 2 , three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m 2 , DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively. CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m 2 . DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m 2 for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.
Streamlining federally mandated quality metric reporting in cancer care.
Authors: Lisa M. Kidin, Ronald Stewart Walters, Doug Browning, Sarah H Taylor, Victoria S. Jordan
Journal: Journal of Clinical Oncology (2013)

68 Background: Public reporting has been an established process for non-PPS exempt hospitals since the inception of the Core Measures in 2001; however, Cancer Centers were not subject to public reporting and had no standardized established formal mechanism to collect, analyze and report clinical quality data until the Affordable Care Act (ACA) of 2010. The first three Clinical Process/Oncology Care Measures must be submitted through the American College of Surgeons Rapid Quality Reporting (RQRS) system. Since registries are designed to provide a retrospective snapshot of the patient population during the first four months of the disease process, the change to longitudinal data collection, while critical for intervention in time to improve concordance, is extremely difficult for cancer centers with large volumes and complex cases. Our institution created a collaborative interdisciplinary model utilizing quality management nurses to support and enhance the submission process by utilizing an early identification and intervention process. Methods: Prior to implementation, the average submission time for the initial three oncology specific metrics was eight months due to the significant effort to determine the analytic population based on our volume of patients. In addition, many patients receive treatments outside the facility with little or no documentation that often resulted in the inability to determine metric concordance. Results: The new process identified patients at two months and created a robust follow up and validation process utilizing a model to ensure evidence based care is provided across the continuum. This enabled monthly submission to RQRS at the end of three months and leveraged the system to ensure that patients had the appropriate therapy documented in the system. This process shortened the submission time to less than half and initial projections indicate increased overall compliance. Conclusions: We enhanced the process of submission for federally mandated measures to RQRS by initiating early identification and follow up. This significantly impacted our ability to accurately represent the high quality care provided at our institution and provide documented concordance with national quality measures.
Pooled safety analysis of oblimersen alone or with fludarabine and cyclophosphamide in patients with advanced chronic lymphocytic leukemia
Authors: B. Koziner, S. O’Brien, T. Boyd, L. Larratt, J. Moore, A. Chanan-Khan
Journal: Journal of Clinical Oncology (2006)

6611 Background: Bcl-2 is an antiapoptotic protein linked to chemotherapy resistance and poor prognosis in chronic lymphocytic leukemia (CLL) patients (pts). Oblimersen (Obl), an anti-Bcl-2 oligonucleotide, has been shown to enhance apoptosis induced by fludarabine (Flu) + cyclophosphamide (Cy) in pts with relapsed CLL. We combined safety results from 2 CLL clinical trials to determine the relative effect of Obl on treatment-emergent adverse events (TEAEs) in Obl+Flu+Cy therapy. Methods: This analysis included 30 pts who received Obl 3mg/kg/d alone by continuous IV on days 5–7 and 230 pts who received Flu 25mg/m 2 /d + Cy 250mg/m 2 /d on days 5–7, every 28th day, either with (n=115) or without (n=115) Obl 3mg/kg/d on days 1–7. Mean number of cycles initiated were 3.3, 3.6, and 4.0 for Obl, Obl+Flu+Cy, and Flu+Cy, respectively. Results: The most frequent (&gt;2% patients) grade 4 TEAEs were mainly hematologic: neutropenia (Obl alone, 0.0%; Flu+Cy, 11.3%; Obl+Flu+Cy 7.0%), thrombocytopenia (3.3%, 1.7%, 4.3%), anemia (0.0%, 5.2%, 3.5%), febrile neutropenia (0.0%, 0.9%, 2.6%), hypotension (0.0%, 0.0%, 2.6%), and leukopenia (0.0%, 2.6%, 0.0%). Thrombocytopenic events with Obl-Flu-Cy were reversible and were not associated with clinically significant bleeding events. The most frequent non-hematologic grade 3–4 TEAEs (&gt;5%) were nausea (0.0%, 1.7%, 7.8%), vomiting (0.0%, 0.9%, 6.1%), fatigue (3.3%, 4.3%, 6.1%), and dyspnea (3.3%, 1.7%, 5.2%). Serious TEAEs occurred at a rate of 23.3%, 32.2%, and 57.4%, respectively. TEAEs resulting in death occurred in 2 pts (Obl alone), 5 pts (Flu+Cy), and 9 pts (Obl+Flu+Cy). One Obl+Flu+Cy death was due to cytokine release reaction and one to tumor lysis syndrome. Discontinuation due to TEAEs occurred in 20.0% of pts who received Obl alone, in 34.8% of Flu+Cy pts, and in 34.8% of Obl+Flu+Cy pts. Conclusions: The addition of Obl to Flu+Cy was well tolerated, with similar low frequencies of grade 3+4 TEAEs, primarily the same type observed with Flu+Cy alone. Despite an increased incidence of serious TEAEs observed with Obl+Flu+Cy, the percentage of patients who discontinued protocol therapy due to a TEAE was the same in each group. First cycle reactions mandate close observation when initiating combination therapy. [Table: see text]
High DNA Sequence Variability at the α1 Na/K-ATPase Locus of Artemia franciscana (Brine Shrimp): Polymorphism in a Gene for Salt-Resistance in a Salt-Resistant Organism
Authors: A G Sáez, R Escalante, L Sastre
Journal: Molecular Biology and Evolution (2000)

We previously reported that the Na/K-ATPase α1 subunit coding gene showed signs of being a very polymorphic locus in Artemia franciscana. This species is adapted to highly saline waters, and the Na/K-ATPase α1 isoform presumably plays a key role in this adaptation. Therefore, we were interested in further study of the α1 Na/K-ATPase polymorphisms to examine whether they might be due to an adaptation to salt resistance driven by natural selection. Using coding sequences from 10 genomic clones and 3 cDNAs, we observed that most substitutions are in synonymous positions (88.8%). The 12 nonsynonymous substitutions code for conservative amino acid replacements with an apparent scattered distribution across functional domains of the protein. Interspecific comparison between these sequences and two genomic clones from Artemia parthenogenetica containing 1,122 bp of the α1 Na/K-ATPase locus coding sequence showed independence of the synonymous/nonsynonymous ratio in the comparison within A. franciscana and between A. franciscana and A. parthenogenetica, which fits the neutral model of evolution. Since there were no previous studies on DNA polymorphism for other A. franciscana genes, we also studied variability at the Actin 302 locus for comparison. Both loci were amplified by reverse transcription–polymerase chain reaction, and 20 sequences were obtained for each. This study shows that the amplified region of the α1 Na/K-ATPase gene is 3.5 times as polymorphic as the Actin 302 gene and 2.9 times as heterozygotic. Interestingly, under a model of neutral evolution, the data observed would be expected with a probability of approximately 0.05, suggesting an excess of intraspecific variation of α1 Na/K-ATPase with respect to Actin 302. Restriction fragment length polymorphism studies show similar patterns of polymorphism along the ∼41-kb span of the α1 Na/K-ATPase locus. Most of the nucleotide differences are linked in a few haplotypes, although recombination events are also inferred from the data. We propose a possible explanation for the high polymorphic levels at the α1 Na/K-ATPase locus which invokes positive selection acting tightly to the locus in transiently isolated or semi-isolated subpopulations.
A phase I study of MK-5108, an oral aurora A kinase inhibitor, in both monotherapy and in combination with docetaxel in patients with advanced solid tumors.
Authors: S. E. Minton, P. LoRusso, A. C. Lockhart, M. Saif, S. S. Krishnamurthi, C. A. Pickett-Gies, Y. Wang, S. Guan, E. Roben, M. N. Stein
Journal: Journal of Clinical Oncology (2010)

e13026 Background: MK-5108 is a potent, highly selective Aurora A kinase inhibitor. Aurora A is a serine/threonine kinase that plays a critical role in mitotic spindle formation and centrosome maturation. Preclinical studies of MK-5108 have demonstrated robust sensitization of tumor cells to taxanes, induction of biomarkers of Aurora A inhibition, and efficacy in rat xenograft models as monotherapy and in combination with taxanes. Methods: Objectives of this multicenter first in human study were to evaluate 1) the safety and tolerability profile, 2) PK, 3) PD effects, and 4) antitumor activity of MK-5108 as monotherapy (MT - Panel 1) and in combination (CT - Panel 2) with docetaxel. MT patients receive oral MK-5108 q 12 hr for 2 days every 14-21 days. CT patients receive docetaxel IV at 60 mg/m2 followed by oral MK-5108 q 12 hr for 2 days every 21 days. A 3+3 dose escalation scheme of MK-5108 is employed with a fixed dose of docetaxel. MK-5108 PK and pre- and post- skin and hair follicle biopsies for PD markers are obtained in Cycle 1. Results: 34 patients have been treated with MK-5108; 17 patients in Panel 1 (MT) with doses ranging from 200 to 1800 mg q 12 hr and 17 patients in Panel 2 (CT) with doses ranging from 100-225 mg q 12 hr. No DLTs were identified in Panel 1 and an MTD has not been established in MT. CT patients experienced a DLT of febrile neutropenia (3). Other Gr 3/4 AEs in CT included neutropenia, leucopenia, lymphopenia, sinus bradycardia (1), and angioedema (1). Plasma AUC0-12hr and Cmax appeared to increase dose proportionally following the 1st dose but less than dose proportionally following the 4th dose. The apparent terminal half-life ranged from 8.3 to 13.5 hrs. All patients reached a 2 μM preclinical target efficacious concentration following the 4th 1200-mg dose. Stable disease was observed in 7 patients in MT, 4 in CT, and partial response (2) was noted in CT. Conclusions: MK-5108 is well tolerated in MT at doses up to 1,800 mg q 12 hours for 2 days every 14-21 days at plasma levels reaching the preclinical target. MT will now enroll to obtain pre- and post-tumor biopsies to examine with PD markers. Preliminary results suggest that MK-5108 may have clinical activity even when used as a single agent. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, sanofi-aventis Bayer, Enzon, Genentech, ImClone Systems, Lilly, Merck, Novartis, Pfizer, PhytoCeutica, Roche, sanofi-aventis, Taiho Pharmaceutical, Taxolog, Wyeth
Abstract 16401: Systematic Approach to Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Family Screening in a Large Transatlantic Cohort
Authors: Anneline S te Riele, Cynthia A James, Abhishek C Sawant, Judith A Groeneweg, Kai Kammers, Brittney Murray, Crystal Tichnell, Jeroen F van der Heijden, Daniel P Judge, J. Peter van Tintelen, Richard N Hauer, Hugh Calkins, Harikrishna Tandri
Journal: Circulation (2014)

Background:  Relatives of patients with Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C) are at increased risk of sudden death, but heterogeneous disease expression complicates their risk assessment. We sought to 1) determine predictors of manifest ARVD/C; and 2) optimize arrhythmic risk stratification in at-risk relatives.   Methods:  Detailed phenotypic and outcome data of 345 relatives (46% male; 35.5 ± 18.9 years) from 140 families enrolled in the US and Dutch ARVD/C registries was obtained. Diagnosis of relatives was ascertained as per 2010 Task Force Criteria (conventional TFC), and according to the 2010 TFC independent of family history (TFC independent of family history). The primary outcome was development of sustained ventricular arrhythmia or appropriate ICD discharge in follow-up.   Results:  One hundred sixteen (34%) relatives were diagnosed with ARVD/C according to conventional TFC. Multivariate analysis identified symptoms (OR 8.50 [95% CI 4.01-18.02] p   Conclusions:  One-third of at-risk relatives has overt ARVD/C. Siblings are at highest risk of disease. A combination of symptoms, being a sibling, pathogenic mutation in the family, and female gender allows for accurate prediction of overt ARVD/C. Fulfillment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of at-risk relatives.
Final results of the efficacy and safety of rasburicase (recombinant urate oxydase) for the prevention and treatment of hyperuricemia in patients with aggressive lymphoma (GRAAL 1 study).
Authors: B. Coiffier, N. Mounier, S. Bologna, C Ferme, R. Herbrecht, H. Tilly, Anne Sonet, B. Christian, O. Casasnovas, E Jourdan, K Belhadj
Journal: Blood (2002)
Translational proof of mechanism (PoM) for sorafenib with bevacizumab: Endpoint analysis and clinical activity
Authors: N. S. Azad, R. Henning, M. Yu, B. Davidson, W. D. Figg, K. Calvo, A. Venkatasen, C. Annunziata, P. Meltzer, E. Kohn
Journal: Journal of Clinical Oncology (2009)

3574 Background: We hypothesized that molecular targeting of tumor and its microenvironment with rational combination therapy would yield improved outcome. Bevacizumab (B) is a monocolonal antibody to vascular endothelial growth factor (VEGFF) and sorafenib (S) is a small molecule inhibitor of the VEGF receptor-2 and RAF-kinase.We have previously reported that S 200mg bid with B 5mg/kg q2wk resulted in partial responses and prolonged disease stabilization (ovarian cancers, renal cell cancer, leiomyosarcoma). Serial tumor biopsies were obtained for translational proof of mechanism analysis. Methods: Percutaneous core biopsies of metastatic sites were obtained at baseline, after 2wk of S (group A) or B (group B), and at 6wks (2 wk into S+B combination therapy). Tissue was used for: lysate array (TLA) proteomic analysis of signaling proteins, IHC for CD31, VEGF, and Ki67, Raf/Ras mutation, and SNP analysis. Results: 18 sets of 3 biopsies were obtained, assessed for morphologic response (MR; decrease to &lt;60% viable tumor seen), and processed for TLA and IHC. 11 pts had morphologic response including all 4 PR and 6/12 SD pts. Greater reduction in change in phospho(p)-ERK was seen at 2wk in group A pts (starting with sorafenib only) (p = 0.003). 9/11 MR pts had inhibition of ERK or AKT activation (p &lt; 0.03). OvCa pts were more likely to have reduction in bRaf (p = 0.02). Pts in group B (starting with bevacizumab only) had lower microvessel density as measured by CD31 IHC (p = 0.05) at 2 wks; there was also a trend to lower VEGF expression by IHC in that group.These effects were muted at time 3, after combination treatment. No relationships to clinical outcomes were found, every pt had at least 1SNP in &gt;1 tested gene; there were no Ras mutations and 1 V600KRaf mutation . Conclusions: These exploratory results demonstrate proof of mechanism in the tumor and its microenvironment for the combination of S and B. Randomization of initial exposure for the first 4 wks allowed interrogation of the role of the independent agents; the Raf/ERK axis was inhibited by S treatment first and there was reduction in tissue angiogenesis markers with B first. The molecularly targeted combination of sorafenib and bevacizumab is biologically active and on target. Phase II studies in multiple tumor types are ongoing. No significant financial relationships to disclose.