tbuckley/cabot-search huggingface dataset:
Major dispersion in etoposide systemic exposure in malignant lymphoma patients receiving BEAM high dose chemotherapy followed by ABMT: A multicentre study of the Groupe d’Etudes des Lymphomes de l’Adulte (GELA)
Authors: B. You, A. Michallet, G. Salles, O. Casasnovas, H. Tilly, V. Ribrag, C. Sebban, C. Falandry, B. Tranchand, G. Freyer
Journal: Journal of Clinical Oncology (2008)

8537 Background: To analyze the pharmacokinetic (PK) parameters of etoposide in patients with malignant lymphomas receiving high dose chemotherapy (BEAM: carmustine, cytarabine, etoposide and melphalan) followed by ABMT. Methods: 91 patients were included in this open multicentre prospective study at first treatment line or at relapse. BEAM comprised etoposide 100 mg/m² twice daily for 4 days. We used a limited blood sampling strategy, allowing to estimate the patients’ PK parameters with acceptable precision. Individual etoposide concentrations versus time curves as well as individual etoposide clearance (etoCL) and Area Under the Curve (etoAUC) were modelized using the NONMEM program. The distribution of total etoAUC (over the 4-day treatment) was investigated according to population quartiles. Results: The inter-individual variability in etoCL was 26.3% (95% CI=20.6–30.9%). The median etoAUC was 906.5 mg/L.h for all patients (range: 547.5–2,271.6 mg/L.h) and was not influenced by treatment line. The total etoAUC upper bounds of 1st, 2nd and 3rd quartiles were 737.5, 906.5 and 1,096.2 mg/L.h respectively. No correlations were observed between body surface area and etoCL. Conclusions: Although all patients received the same etoposide dose calculated using body surface area, we observed a major inter-individual variability in AUC. Some patients had a more than 4 fold higher systemic exposure than other patients, which may have important consequences on treatment tolerance and efficacy. Data on clinical consequences of PK variability will be presented. Distribution of total etoAUC All patients 1st quartile (Q1) 2nd quartile(Q2) 3rd quartile(Q3) 4th quartile(Q4) Number of patients 91 23 23 22 23 Total etoAUC range [547,5–2271,6] [547.5–737.5] [737.5–906.5] [906.5–1096.2] [1096.2–2271.6] Ratio: Q25 etoAUC/Q75 etoAUC=0.67 No significant financial relationships to disclose.
Phase I open-labeled trial of gemcitabine and dasatinib in advanced solid tumors
Authors: S. Vemulapalli, R. Kurzrock, H. Fritsche, J. J. Wheler, S. L. Moulder, M. Cristofanilli, M. Gonzalez-De Luna, R. Khan, Y. Xu, D. S. Hong
Journal: Journal of Clinical Oncology (2008)

14626 Background: The Src family of kinases plays a key role in cell cycle control, adhesion,motility,survival and angiogenesis. Deregulation of Src kinases has been shown to cause malignant transformation and contribute to tumorigenic growth and progression. Moreover increased Src phosphorylation in pancreatic cell lines is associated with gemcitabine resistance. Dasatinib is a potent orally active inhibitor of the BCR-ABL, c-KITand the Src family of kinases. Therefore the combination of gemcitabine and dasatinib is a rational approach in overcoming gemcitabine resistance. Methods: Pts with advanced solid tumors refractory to standard therapy were eligible including pts with previous exposure to gemcitabine. The trial is a conventional phase I 3+3 dose-escalation design.MTD has yet to be reached. Dasatinib is administered orally continuously qd with a 7 day run in prior to first gemcitabine dose. Gemcitabine was given weekly for 7 weeks (cycle1) and 3 weeks on and 1 week off for all other cycles. Correlative studies including PKs at MTD,PBMCs,circulating tumor cells (CTCs) samples pre, prior to starting gemcitabine, and post cycle 1. PD analysis included CTC levels, western blots analysis of total and phosphorylated Src&VEGF levels in pt's PBMCs/serum. Results: A total of 12 pts have been treated. MTD has yet to be determined. Dose escalation continues with dasatinib (100mg qd) and gemcitabine (600mg/m2). The most common drug related toxicities include anemia (58%), leukopenia (58%), &thrombocytopenia (58%). Pleural effusion was observed in 17% of pts. Currently,of the 5 evaluable pts by RECIST 3 pts had SD for 4 months or longer with a thymoma pt on study for 11 months. One confirmed PR was noted in an inflammatory breast cancer pt (54% decrease (RECIST). CTCs levels were low and showed no significant changes after dasatinib and dasatinib+gemcitabine from predose levels or correlation to response. PK and western blot analysis of PBMCS/serum is pending. Conclusions: Combination of dasatinib+gemcitabine is well tolerated and dose escalation continues. CTCs levels showed no significant change from predose levels and no correlation to response but clinical activity was observed in triple negative inflammatory breast ca and prolonged SD in thymoma ca. No significant financial relationships to disclose.
Variation in use of advanced imaging at the time of breast cancer diagnosis in a statewide registry.
Authors: Norah Lynn Henry, Thomas Braun, Elizabeth Lusk, Khan Munir, Jennifer J. Griggs, David H. Gorski, Samuel M. Silver, Tara M. Breslin, Haythem Y. Ali
Journal: Journal of Clinical Oncology (2016)

287 Background: Advanced imaging for diagnosis of metastatic disease at the time of diagnosis of stage 0-II breast cancer is not recommended according to national guidelines. The purpose of this study was to examine the variation in ordering of CT chest, abdomen, and pelvis, PET, and bone scans across the state of Michigan, and to investigate clinical and non-clinical factors associated with test ordering. Methods: We prospectively collected data from all patients diagnosed with stage 0-II breast cancer from 2008-2014 in 25 health systems in the Michigan Breast Oncology Quality Initiative (MiBOQI), a Blue Cross Blue Shield of Michigan/Blue Care Network-sponsored quality initiative. Demographic, imaging, and pathologic data were abstracted from the medical record. The primary endpoint was the percentage of patients with at least one advanced imaging test performed within 90 days after diagnosis of breast cancer. Analyses were performed using the chi-squared test of association. Results: Of the 27,011 patients, 4799 (17.8%) had at least one staging exam performed within 90 days of diagnosis. Imaging tests were primarily performed post-operatively. The average percentage of patients who had at least one staging exam performed varied by stage and by site (Table). The rate of testing decreased over time for stage 0-IIA cancers but not for stage IIB. On multivariate analysis, younger age, black race, hormone receptor negativity, HER2 positivity, and higher grade were associated with increased likelihood of undergoing imaging. Conclusions: There is considerable variability in ordering of staging scans at the time of diagnosis of early stage breast cancer across Michigan. Factors underlying use of imaging in stage IIB disease should be examined in order to develop interventions for rate reduction. [Table: see text]
Building success in quality improvement: An analysis of what barriers hinder and what catalysts promote the widespread adoption of quality improvement initiatives.
Authors: William T. Sause, John C. Ruckdeschel, Thomas W. Belnap, Cory Jones, Braden D. Rowley
Journal: Journal of Clinical Oncology (2012)

122 Background: Quality improvement initiatives and outcomes research activities at Intermountain Healthcare are regularly conducted across 9 clinical domains, including oncology. The purpose of this abstract is to define some of the projects initiated in the primary management of breast cancer and critically analyze the barriers and catalysts allowing for adoption of quality improvement processes. Methods: Between 2003 and 2010 we initiated approximately 15 projects designed to measure and improve quality of care delivery in the treatment of breast cancer. These projects included increasing the use of breast conservation for primary surgical management, reducing axillary dissections for patients with ductal carcinoma in situ and the adaptation of sentinel node biopsy rather than axillary dissection for primary breast cancer. Quality improvement projects involving diagnostic imaging included evaluation of the time from abnormal mammogram to biopsy and the utility of follow-up mammography following breast conservation. Results: Measured variability among practicing clinicians in many instances was substantially reduced or eliminated. Adoption of clinical improvements was most often rapid and noticeable across the entire health care system, however, in some instances quality processes were not completely adopted. The adoption of quality improvement initiatives occurred where obvious clinical benefit could be documented, technical expertise was enhanced and peer supervision existed. Adoption occurred less frequently when financial barriers to adoption existed, clinical benefit was less well defined and peer encouragement was less vigorous. Conclusions: Quality improvement processes across a large healthcare system can be instituted and adopted by a variety of facilities and practicing clinicians. Barriers and catalysts to adoption do exist and this presentation will attempt to document and outline opportunities for success using quality improvement in a large healthcare system.
Comprehensive genomic profiling of renal cell carcinoma with sarcomatoid dedifferentiation to pinpoint recurrent genomic alterations.
Authors: Gabriel G. Malouf, Siraj Mahamed Ali, Kai Wang, Sohail Balasubramanian, Jeffrey S. Ross, Vincent A. Miller, Philip J. Stephens, David Khayat, Roger Mouawad, Sumanta K. Pal, Xiaoping Su, Kanishka Sircar, Pheroze Tamboli, Eric Jonasch, Nizar M. Tannir, Christopher G. Wood, Jose A. Karam
Journal: Journal of Clinical Oncology (2016)

537 Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is found in five percent of all renal cell carcinoma (RCC) cases, and has a significantly worse prognosis relative to matched highgrade RCC with only epithelial elements. The genomic features underpinning sRCC are not well understood, and at present, there are no specific or effective therapies for sRCC. Methods: We conducted comprehensive genomic profiling (CGP) on paired epithelial and sarcomatoid areas of 3 sRCC cases. In the course of routine clinical care, CGP was performed on another 23 sRCC harboring diverse epithelial components. CGP was conducted using a hybrid capture next generation DNA sequencing assay(NGS) of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC devoid of sarcomatoid component, and with clear cell TCGA. Results: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Conclusions: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations.
MicroRNA expression profiles associated with pancreatic cancer.
Authors: N. A. Schultz, J. Werner, H. Willenbrock, A. Roslind, T. Horn, M. Wøjdemann, J. S. Johansen
Journal: Journal of Clinical Oncology (2011)

153 Background: The aim was: 1) to define the global microRNA (miRNA) expression pattern in pancreatic cancer (PC) and compare it with normal pancreas (NP) and chronic pancreatitis (CP); 2) to validate reported diagnostic miR profiles in PC; 3) to discover new diagnostic miRs in pancreas samples without micro-dissection of cancer cells. Methods: MiR expression patterns in FFPE tissue blocks from patients operated for pancreatic ductal adenocarcinoma (PDAC, n=170) and ampullary adenocarcinomas (A-AC, n=107) were determined using TaqMan Human miR microarrray (Applied Biosystem; 754 miRs were determined) and compared to profiles of CP (n=23) and NP (n=28). Raw Ct-values were normalized using quantile-normalisation. Results: 83miRs were differentially expressed in PDAC and NP (42 higher expression; 41 reduced expression in PDAC). 32 miRs were differentially expressed in PDAC and CP. The most differentially expressed miRs were miR-614, miR-492, miR-622, miR-135b* and miR-196. The miR signatures of PDAC and A-AC were highly correlated (0.99; only 5 miRs were significantly differentially expressed). An earlier reported diagnostic miR profile for PDAC was validated (mirR196b - miR217), and 3 other significant profiles were identified (Table). A more complex Lasso classifier using 19 miRs could separate PDAC from NP and CP (accuracy = 98%). Conclusions: We identified systematic differences in patterns of miR expressions between tumor tissue including both cancer cells and surrounding desmoplasia obtained from patients with PDAC and A-AC compared to tissue from patients with CP and NP. We validated the diagnostic miR expression profile (miR-196b, miR-217) described by Szafranska et al. (Clin Chem 2008;54:1716-24). Furthermore, we identified 5 miRs which were better to discriminate PDAC and A-AC from CP and NP. Prospective studies are needed to evaluate if this panel of miRs is useful for early diagnosis of patients with PDAC. [Table: see text] No significant financial relationships to disclose.
Are patients with Gleason 6 pathology safe from developing metastatic castration-resistant prostate cancer (mCRPC)?
Authors: Christoph A. J. von Klot, Alena Boeker, Thomas R. W. Herrmann, Mario W. Kramer, Markus A. Kuczyk, Axel S. Merseburger
Journal: Journal of Clinical Oncology (2015)

110 Background: Prostate cancer may remain clinical unapparent for decades, however at the stage of metastatic castration resistant prostate cancer (mCRPC), patients have only limited survival even with new therapeutic options. Recent evidence from histology studies regarding random prostate biopsies hint toward a relationship between higher biopsy Gleason score and the development of mCRPC. A few patients with initial low risk prostate cancer also seem to develop mCRPC. However, prostate biopsy underestimates final pathology in about one third of patients. We therefore evaluated the final whole gland pathology from radical prostatectomy to better assess the risk of progressing to mCRPC for patients with Gleason 6 prostate cancer in particular. Methods: Clinical data was assessed for patients with confirmed mCRPC between 3/2007 and 10/2014. Whole gland pathology workup was not available for patients with either metastatic disease on diagnosis, external radiation therapy or no curatively intended initial therapy. Results: Out of 605 screened patients we identified a total of 77 patients with confirmed mCRPC. Mean PSA at initial diagnosis was 29.5 ng/mL (range 1 - 58 ng/mL ). Mean PSA at the end of follow up was 34.1 ng/mL (range 1 - 71 ng/mL ). A total of 30 patients died during follow up. Distribution of Gleason scores for gleason 6, 7, 8, 9 and 10 were 2, 24, 28, 18, 5 patients respectively. Pathological evaluation obtained from laparoscopic or retropubic radical prostatectomy was available in 43 of 77 cases. cases. Interestingly, out of the only two patients with a documented gleason score of 6, one had radiation/I125 brachytherapy while the other had primary anti hormonal therapy. Therefore an understaging may be possible. Out of the confirmed final pathologies, non of the patients had a Gleason score below 7. Conclusions: Our observations suggest a non significant occurrence of mCRPC during the development of prostate cancer for patients with Gleason pathology of less than 7. Our results may potentially help better counseling for patients and need further validation in a larger series.
Bevacizumab changes in patients with naïve, stage II-III breast cancer assessed by 18F-fluoromisonidazole and 18F-fluorotymidine PET-CT.
Authors: V. Boni, I. Dominguez, M. J. Garcia Velloso, J. M. Lopez-Vega, P. Martinez, A. Plazaola, B. Hernando, A. Llombart Cussac, J. Lao, R. M. S. Gomez, I. Alvarez, J. J. Illarramendi, E. G. Calvo, S. Morales Murillo, T. Puertolas, L. J. Pina, E. Bernedo, G. Palacios, S. J. Scherer, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2011)

2529 Background: PET offers a non invasive tool to assess cancer biology, staging tumors and potentially monitoring treatment response, anti-angiogenic therapy included. The aim of this study was to evaluate the effects of bevacizumab in breast cancer (BC) patients (pts) by fluoromisonidazole (MISO) and Fluorotymidine (FLT) PET imaging as indicators of hypoxia and proliferation rate. Methods: 73 pts (49 yr, range 29-70) with biopsy-proven BC were prospectively enrolled. Pts received one infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of chemotherapy consisting in 4 cycles of docetaxel (60 mg/mq), adriamicine (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5). All pts had MISO and FLT studies and paired tumor-biopsies pre and post C1. MISO and FLT uptakes were correlated with immunohystochemic (IHC) biomarkers. Association between SUVmax values and clinic-pathological characteristics was analyzed using Kruskal-Wallis and Mann-Whitney tests. To compare paired SUVmax values and to test correlation with IHC expression Wilcoxon and Spearman rank test were used. Results: Median baseline MISO and FLT values in tumors were 1.2 (range 0.69-2.39) and 2.89 (range 0.97-7.18). FLT and MISO uptakes were significantly higher in IIIA stage versus IIA-IIB (3.9 vs 2.6) and (1.45 vs 1.19) and in estrogen (ER) negative versus positive tumors (3.7 vs 2.6) and (1.09 vs 1.59). Significant change after one bevacizumab administration was observed in FLT (2.7 vs 1.8, p<0.001) but no in MISO uptake. FLT was correlated with Ki67 index and MISO with VEGFR2-IHC expression (r2=0.336 and r2=0.314, p<0.01). Conclusions: Bevacizumab determines a marked decrease in tumor proliferation rate. Hypoxic status in BC was high, associated with VEGFR2 overexpression, but, interestingly, no change after bevacizumab. These findings have direct implications in understanding bevacizumab effects in breast cancer biology. PET studies seem to be novel pharmacodynamic biomarkers able to distinguish antivascular from antitumor effects of antiangiogenic agents. In the future, their role as potential predictive biomarkers will be investigated.
Comorbidity and androgen deprivation therapy use in men undergoing high-dose radiation for unfavorable intermediate- and high-risk prostate cancer.
Authors: Michael A Dyer, Ming-Hui Chen, Michelle H. Braccioforte, Brian Joseph Moran, Anthony V. D'Amico
Journal: Journal of Clinical Oncology (2016)

41 Background: Despite evidence of prolonged survival when adding androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) in men with unfavorable intermediate- and high-risk prostate cancer (PC), some of these men are not receiving ADT. We explored whether comorbidity can explain this discrepancy given the observation that survival may be shortened in men with moderate to severe comorbidity who receive ADT. Methods: Between 10/1997 and 5/2013, 3,348 men with unfavorable intermediate- (2,380 patients; 70.7%) or high-risk (986 patients; 29.3%) PC were treated at the Prostate Cancer Foundation of Chicago using brachytherapy with or without neoadjuvant EBRT and/or ADT, and formed the study cohort. A multivariable logistic regression analysis was used to evaluate whether comorbidity (history of congestive heart failure [CHF] and/or myocardial infarction [MI]) was associated with decreased odds of ADT use in men with unfavorable intermediate- or high-risk PC, adjusting for age, PC prognostic factors, year of brachytherapy, and EBRT use. Results: Among patients with unfavorable-intermediate-risk PC, 31.2% received ADT, and in the high-risk cohort, 38.3%, 12.3%, and 4.8% received up to 6, &gt;6-18, or &gt;18 months of ADT respectively. In men with high-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use of any duration (all p values &gt;0.71), but the odds of ADT use decreased over time (adjusted odds ratio (AOR) 0.87, 95% confidence interval (CI) [0.83,0.91], p&lt;0.0001; AOR 0.93, 95% CI [0.87,0.99], p=0.023; AOR 0.92, 95% CI [0.83,1.01], p=0.089, for up to 6, &gt;6-18, and &gt;18 months respectively, with no ADT as the reference). Similarly, in men with unfavorable intermediate-risk PC, a history of CHF/MI was not significantly associated with decreased odds of ADT use (p=0.49), whereas the odds of ADT use decreased significantly over time (AOR 0.96, 95% CI [0.94,0.98], p=0.0009). Conclusions: While ADT use has decreased over time in men with unfavorable intermediate- and high-risk PC undergoing brachytherapy with or without supplemental EBRT, this decrease does not appear to be occurring in men with a history of CHF or MI.
Phase I/II study of ISIS 183750 in combination with irinotecan for advanced solid tumors or colorectal cancer: Final results.
Authors: Oxana V. Makarova-Rusher, Austin G. Duffy, Susanna Varkey Ulahannan, Suzanne Fioravanti, Melissa Walker, Mark Raffeld, Kathryn Compton, Sunmin Lee, Yusuke Tomita, Jane B. Trepel, William Douglas Figg, Tim F. Greten
Journal: Journal of Clinical Oncology (2015)

639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.
Ambulatory Management of Anemia: A Retrospective View from an Italian Multidisciplinary Team
Authors: Eleonora Arboscello, Elisa Molinari, Francesco Tolomeo, Lisette Del Corso, Luana Vignolo, Gianluca Ubezio, Paolo Carlier, Paolo Strada, Riccardo Ghio, Francesco Puppo, Paola Mangini, Sabrina Beltramini, Pietro Dulbecco, Paola Anserini, Maria Teresa van Lint, Andrea Bacigalupo, Fabio Guolo, Marino Clavio, Andrea Bellodi
Journal: Blood (2015)