tbuckley/cabot-search huggingface dataset:
New Statistical Criteria Detect Phylogenetic Bias Caused by Compositional Heterogeneity
Authors: David A. Duchêne, Sebastian Duchêne, Simon Y.W. Ho
Journal: Molecular Biology and Evolution (2017)

In statistical phylogenetic analyses of DNA sequences, models of evolutionary change commonly assume that base composition is stationary through time and across lineages. This assumption is violated by many data sets, but it is unclear whether the magnitude of these violations is sufficient to mislead phylogenetic inference. We investigated the impacts of compositional heterogeneity on phylogenetic estimates using a method for assessing model adequacy. Based on a detailed simulation study, we found that common frequentist criteria are highly conservative, such that the model is often rejected when the phylogenetic estimates do not show clear signs of bias. We propose new criteria and provide guidelines for their usage. We apply these criteria to genome-scale data from 40 birds and find that loci with severely non-homogeneous base composition are uncommon. Our results show the importance of using well-informed diagnostic statistics when testing model adequacy for phylogenomic analyses.
Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.
Authors: H. I. Scher, C. Logothetis, A. Molina, O. B. Goodman, C. N. Sternberg, K. N. Chi, T. S. Kheoh, C. M. Haqq, K. Fizazi, J. S. De Bono
Journal: Journal of Clinical Oncology (2011)

4 Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or &gt; 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P &lt; 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population. [Table: see text] [Table: see text]
Randomized phase IV trial comparing efficacy and tolerability of temsirolimus with and without an elevated starting dose in patients with relapsed, refractory mantle cell lymphoma.
Authors: A. Bair, G. Hess, J. Boni, F. Offner
Journal: Journal of Clinical Oncology (2011)

TPS222 Background: In a randomized phase III study (Hess et al. J Clin Oncol 2009;27:3822-9), patients with relapsed, refractory mantle cell lymphoma (MCL) who were treated with intravenous temsirolimus 175 mg for the first 3 weeks followed by 75 mg weekly (175/75) had significantly longer progression-free survival (PFS) compared with those receiving investigator’s choice of therapy (HR=0.44; P=.0009). The starting dose of 175 mg was, however, associated with a higher incidence of adverse events relative to investigator’s choice and to that observed with temsirolimus at lower doses. The aim of this study is to evaluate whether efficacy similar to that demonstrated in the phase III study can be achieved with better safety and tolerability in the absence of the 175-mg starting dose. A secondary objective is to assess the potential inhibitory effect of these doses of temsirolimus on cytochrome P450 2D6 substrate metabolism. Methods: Patients with relapsed, refractory MCL who received 2 to 7 prior therapies are eligible for this global multicenter, randomized, open-label study of temsirolimus. The trial opened enrollment in January 2011. Patients are randomized (1:1) to receive temsirolimus 175/75 or 75 mg weekly and are stratified by histologic subtype (blastoid vs nonblastoid vs unknown histology). The primary end point is PFS based on independent tumor assessments; the hazard ratio comparing PFS for the 2 dosages will be estimated using an unstratified Cox regression model. Planned sample size is 100 patients. As the 2 treatment regimens differ only in the 3 initial temsirolimus doses (175 mg vs 75 mg), safety analyses and extent of exposure are assessed separately for this period and from the fourth dose forward. The pharmacokinetic drug interaction component uses a nonrandomized 1-sequence, 2-treatment design wherein the first period is a lead-in to the randomized study. All patients receive 50 mg desipramine (P450 2D6 probe substrate) orally 1 week prior to treatment and concomitantly with the first dose of temsirolimus.
Phase II trial of pazopanib and weekly paclitaxel in metastatic urothelial cancer (UC).
Authors: Sandy Srinivas, Sujata Narayanan, Lauren Christine Harshman, Anthony P. Lam, Ulka N. Vaishampayan, Denise Haas, Shermeen Poushnejad, Russell Pachynski
Journal: Journal of Clinical Oncology (2014)

299 Background: Currently, there are no standard treatments for relapsed or refractory urothelial carcinoma (UC). Discouraging results have been achieved in trials evaluating drugs as single agents or in combination regimens. Paclitaxel has activity when used alone and in combination in urothelial cancer, and pazopanib is active in solid tumors secondary to its potent anti-angiogenic effect. We report the results of an ongoing multicenter phase II study evaluating the combination of paclitaxel with pazopanib in refractory UC. Methods: Patients (pts) eligible for the study have histologically confirmed UC, with relapse after receiving up to 2 chemotherapeutic regimens. Pazopanib (800 mg) is administered daily, with weekly paclitaxel (80mg/m2) for 3 weeks in a 28 day cycle. Treatment is continued until disease progression or unacceptable toxicity. Primary endpoint of the study is the response-rate (RR) based on RECIST criteria. Secondary endpoints include safety, and progression free-survival (PFS). For designing the study, Simon’s two-stage method was applied, and 9 pts were recruited in the first stage. After having ≥1 response in the first group, a full enrollment of 32 pts has been initiated. Results: 25 pts were enrolled from April 2010 to September 2013. Their median age was 67 years (47-89), with a median ECOG performance status of 1 (0-2). 10 pts (40%) had UC of the upper urinary tract and 15 had primary bladder/ureter tumors. All pts had multiple metastatic sites, including 11 (44%) with liver metastases. Median number of prior cytotoxic regimens was 2, and 50% were considered cisplatin responsive. Based on RECIST (v1.1) criteria,13 pts (52%) had partial response (PR), 5 (20%) had stable disease (SD), and 2 (8%) had complete response (CR) (80% clinical benefit). The side effects included grade 3 hypertension (n=2), grade 3 fatigue (n=4), grade 3 thrombosis (n=2) and grade 4 neutropenia (n=2). 14 pts required growth factor support. Conclusions: Our phase II study combining paclitaxel and pazopanib demonstratedsignificant anti-tumor activity of combining paclitaxel in relapsed/refractory UC. This combination is safe, and is worthy of evaluation in larger studies. Clinical trial information: 1108055.
Time-driven activity-based costing and the impact on cost measurement in the face of health reform.
Authors: Heidi Wied Albright, James Incalcaterra, Thomas W. Feeley
Journal: Journal of Clinical Oncology (2013)

262 Background: In 2010, the Institute for Cancer Care Innovation (ICCI) began measuring the true cost of cancer care delivery by following the patient treatment cycle from initial referral to survivorship or supportive care. The project was prompted by both internal and external concerns about the rising costs of health care, the ability to demonstrate value for services provided, and potential changes in reimbursement. Hospital cost accounting systems are historically charge-based and are inherently skewed to shift costs towards procedures or encounters that are higher volume and well-reimbursed. However, these systems do not accurately reflect the actual acquisition costs of the resources providing care. Methods: In order to more accurately and transparently capture costs, the ICCI piloted the use of the time-driven activity-based costing (TDABC) methodology. This methodology allowed the team to map the entire patient experience of care while also capturing costs and capacity associated with each activity in the care delivery cycle. Results: To date, the team has created over 150 maps made up of over 6,500 unique activities with associated cost and capacity rates, which make up various costing equations. Actual clinical volumes are then run through the model to produce cost and capacity results. Initial results provided an unexpected view of the costs of various processes occurring within the care delivery cycle with the ability to rank the processes from most to least costly. This provided a unique opportunity to target specific areas for improvement. Additionally, transparency of the costing equations allows for precise modeling of episode-based bundles of care for different diseases and treatments. Conclusions: TDABC provides a more accurate and transparent approach to developing cost and capacity rates for cancer care delivery to aid in identifying the greatest opportunities for improvement, as well as providing a mechanism for creating episode-based bundles of care that are reflective of actual treatment being provided.
Imaging of Body Iron Stores in Transfusion-Dependent Patients By Liver Dual- Energy CT
Authors: Hironori Kobayashi, Norihiko Yoshimura, Takashi Ushiki, Yasuhiko Shibasaki, Masato Moriyama, Jun Takizawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko
Journal: Blood (2014)
Everolimus as second-line therapy for metastatic renal cell carcinoma (mRCC) after one previous VEGF-targeted therapy: Final results of the noninterventional change study.
Authors: Peter J. Goebell, Ulrich Kube, Michael Staehler, Christian Doehn, Thomas Steiner, Manfred Kindler, Edwin Herrmann, Jan Janssen, Steffen Weikert, Michael Thomas Scheffler, Joerg Schmitz, Friedrich Overkamp, Gernot Guderian, Michael Albrecht, Lothar Bergmann
Journal: Journal of Clinical Oncology (2014)

469 Background: The mTOR inhibitor everolimus is approved for the treatment of mRCC following failure of VEGF-targeted therapy. To evaluate the effectiveness and tolerability of everolimus following the first VEGF-targeted therapy in routine clinical practice, we conducted the prospective, noninterventional CHANGE study in Germany. Methods: Patients (pts) with mRCC (any histology) were registered at the time of everolimus initiation, or within 90 days thereof, following treatment with either VEGFR-TKI or bevacizumab. Other previous systemic therapies (e.g., cytokines) were permitted. Pts received everolimus 10 mg/d according to the summary product characteristics until disease progression or intolerable toxicity. Study objectives included assessing treatment duration, time to progression (TTP), progression-free survival (PFS), Karnofsky performance status (KPS), and safety. Results: 334 pts were documented at 116 German sites between August 2009 and January 2012 (median age, 68 years; 75% male; median KPS, 80%; 88% clear cell histology). At the start of first-line therapy, MSKCC risk status was favorable in 35%, intermediate in 56%, and poor in 9%. Effectiveness results are shown in the table. In the safety population (n=318), median time to ≥10% deterioration in KPS was 8.4 months (95% CI, 6.1-10.1 months); the most common AEs (any grade) were dyspnea (17%), anemia (14%), and fatigue (12%). Treatment adherence was high, with &lt;2% of patients per visit showing &lt;50% intake of the expected doses. Conclusions: The CHANGE study demonstrates favorable effectiveness and tolerability for everolimus when given in routine clinical practice to pts with mRCC. Our data confirm the use of everolimus as a standard second-line therapy following VEGF-targeted treatment. [Table: see text]
PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition
Authors: Deepti Mathur, Elias Stratikopoulos, Sait Ozturk, Nicole Steinbach, Sarah Pegno, Sarah Schoenfeld, Raymund Yong, Vundavalli V. Murty, John M. Asara, Lewis C. Cantley, Ramon Parsons
Journal: Cancer Discovery (2017)

Abstract Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN-mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase PTEN-mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN-mutant cancers. Significance: We have found a prospective targeted therapy for PTEN-deficient tumors, with efficacy in vitro and in vivo in tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation of PTEN. Cancer Discov; 7(4); 380–90. ©2017 AACR. See related article by Brown et al., p. 391. This article is highlighted in the In This Issue feature, p. 339
Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology.
Authors: S. Niraula, U. Emmeneger, L. Adams, I. Tannock, S. S. Sridhar, J. J. Knox, J. R. Day, J. Manthe, J. Groskopf, A. M. Joshua
Journal: Journal of Clinical Oncology (2011)

59 Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase II clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis. Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m 2 -0.25 g/m 2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4. Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion). Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour cells. [Table: see text]
Is the change of serum nitric oxide level indicator of the survival during cervix cancer treatment?
Authors: H. Ozyurt, S. Ozden, Z. Ozgen, D. Gul, O. Gümüstekin Bülbül, S. Bilsel, M. Eren, A. Mayadagli
Journal: Journal of Clinical Oncology (2008)

16600 Background: Nitric oxide (NO) by having inhibitory and activating roles in the carcinogenesis can influence the outcome of cancer treatment. In this study we aimed to investigate the existence of a correlation between the serum NO levels and survival in the cervix cancer patients treated with chemoradiotherapy. Methods: 20 patients with FIGO stage 2B-3B invasive cancer of cervix treated with chemoradiotherapy in 2005 were included into the study. 50.4 external-beam pelvic radiotherapy and 14–20 Gy intracavitary boost dose were delivered. Patients received cisplatin (50 mg/m2) weekly with concurrent pelvic radiotherapy. On the first day (for basal level determination) and the 6th, 11th, 16th, 21st, 26th days of the treatment, 15 minutes before the irradiation blood samples were collected. Cisplatin administrated within two hours after the completion of radiotherapy. Serum NO levels were determined indirectly with the measurement of serum nitrite/nitrate levels. Results: Serum levels of NO which were obtained in the 26th day of the treatment were significantly higher than the basal levels (p < 0.01, one way ANOVA) It was showed that the patients whose serum NO levels were lower than the basal level in the 26th of the treatment had longer survival than the patients whose NO levels increased in that measurement (30 versus 27 months). The decreased NO serum levels were significantly associated with a longer survival (Pearson correlation r=0.04). Conclusions: The changes in the level of serum NO during chemoradiotherapy may be an indicator of survival. No significant financial relationships to disclose.
Coordinating cancer care: Measurement and intervention approaches across the cancer continuum.
Authors: Sherri Sheinfeld Gorin, David Haggstrom, Kathryn McDonald, Paul Han, Kathleen Fairfield, Patricia A. Ganz, Winson Y. Cheung, Steven Clauser
Journal: Journal of Clinical Oncology (2013)

103 Background: According to a landmark study by the Institute of Medicine, patients with cancer often receive poorly coordinated care in multiple settings from many providers. Lack of coordination is associated with poor symptom control, medical errors, and higher costs. The aims of this presentation are to: (1) describe the state-of-the science on cancer care coordination measures and intervention outcomes from a systematic review and meta-analysis of empirical papers published between 1980-2013; (2) explore the implications of these findings from the patient, provider, healthcare system, and national policy perspectives. No similar review has yet been published. Methods: Of 1,241 abstracts collected from a systematic search of PubMed, MeEMBASE, Medline, CINAHL, and Cochrane Library, 50 studies met the inclusion criteria. Each study had US or Canadian participants; comparison or control groups, measures, times, samples, and/or interventions. Two raters independently applied a standardized search strategy and coding scheme. Eight studies (14 outcomes) met the additional criteria for the meta-analysis. We used the Care Coordination Atlas (McDonald, 2010) definition of care coordination. Results: Overall, coordination improved cancer care across 83% (44) of the measured outcomes. Interventions led to more appropriate healthcare use (g = 0.37 [95% CI = 0.29 – 0.46]; I 2 = 0.00) across screening (patient navigation), treatment (home telehealth, nurse case management and education), and end-of-life care (early palliation). Measures varied considerably in psychometric quality and were limited in focus. They included; rates of guideline compliance (screening), timeliness of care (diagnosis), health-related quality of life (treatment), cancer-related distress (survivorship), and home death (end-of-life). Conclusions: The findings revealed effective interventions across the cancer continuum from screening to end-of-life. More, and better measures are needed across the cancer continuum. We discuss the implications of these findings for more and better measures, approaches to implement effective interventions in clinical settings, and to develop supportive policy (and reimbursement) contexts.
The association of epidermal growth factor receptor (EGFR) mutation and survival in N2(+) non-small cell lung cancer patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy.
Authors: H. K. Ahn, Y. L. Choi, J. Sun, Y. C. Ahn, K. Kim, J. Kim, Y. M. Shim, J. S. Ahn, K. Park, M. Ahn
Journal: Journal of Clinical Oncology (2011)

7034 Background: Epidermal growth factor receptor (EGFR) mutation is reported to be associated with radiosensitivity of non-small cell lung cancer (NSCLC) in vitro. The aim of this study is to analyze the association of clinical outcome to neoadjuvant concurrent chemoradiotherapy (CCRT) with EGFR mutation status in N2(+) NSCLC patients. Methods: We retrospectively identified 161 patients with mediastinoscopy-proven N2(+) NSCLC who were treated with platinum-based neoadjuvant concurrent chemoradiotherapy at Samsung Medical Center between 1998 and 2006. In 98 patients with remaining tumor tissue, EGFR mutation was assessed by both peptide nucleic acid (PNA)-mediated PCR clamping method and sequencing simultaneously. 88 patients were finally included in analysis, excluding 4 patients with indeterminate EGFR mutation results and 6 patients who didn’t proceed to operation by reason of other than disease progression. Results: Among 88 patients, EGFR mutation (exon 19 deletions or L858R) was detected in 13 patients (14.8%), and KRAS mutation in 2 patients (2.3%). After neoadjuvant concurrent chemotherapy, 5 patients showed progressive disease, pathologic downstaging of lymph nodes (LN) to N0 or N1 was achieved in 44 patients (50%), and pathologic CR in 13 patients (14.8%). Achievement of pathologic CR or pathologic downstaging of LNs were not associated with EGFR mutation status. With a median follow-up of 73.8 months, there were no significant difference in overall survival or progession free survival between EGFR mutation and negative patients (28.2 months vs 33.6 months, p=0.125; 15.2 months vs. 18.0 months, p=0.631), respectively. Conclusions: In N2-positive NSCLC patient, EGFR mutation didn’t show any significant clinical benefit to neoadjuvant CCRT in terms of response rate, PFS or OS. Further study should be needed to confirm and elucidate the association between EGFR mutation status and radiosensitivity in NSCLC patients.