tbuckley/cabot-search huggingface dataset:
The letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial: A direct comparison of bone biochemical measurements between aromatase inhibitors (AIs) in healthy postmenopausal women
Authors: E. McCloskey, R. Hannon, G. Lakner, G. Clack, A. Miyamoto, R. Eastell
Journal: Journal of Clinical Oncology (2006)

555 Background: The LEAP trial is an open, randomized, multicenter, Phase I pharmacodynamic study comparing the effects of the AIs L, E and A on safety parameters, such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip. Elevated bone biochemical levels indicate high turnover of bone, and correlate with a loss in bone mineral density. It has been suggested that there are differences between the effect of the steroidal AIs (E) and non-steroidal AIs (A and L) on bone turnover, with steroidal AIs having a less negative effect. Methods: Healthy volunteersfrom the UK and Hungarywere randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Changes from baseline in log-transformed bone alkaline phosphatase (ALP), serum C-telopeptide crosslinks (CTX), parathyroid hormone (PTH) and propeptide of type I procollagen (PINP) at 24 weeks on A, were compared with those on L and E by ANCOVA, adjusting for treatment, baseline measurement, BMI, smoking status and baseline estradiol. No adjustments were made for multiple comparisons. Results: A total of 102 healthy volunteers were recruited, with 90 participants evaluable at 24 weeks (29 A, 29 L, 32 E). Participant demographics were similar between the treatment groups in terms of age, years since menopause, and history of hysterectomy and oophorectomy. Bone biochemical measurement changes are presented in the table . With the exception of PTH, where there is a greater decrease in PTH with E than with A (p=0.04), there were no statistically significant differences between the AIs. Conclusions: The steroidal and non-steroidal AIs appear to have similar effects on bone biochemical measurements, and thus bone turnover. All three licensed AIs result in increases in bone turnover. [Table: see text] [Table: see text]
Enhanced detection of EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients using Scorpion primers
Authors: W. Holland, A. M. Davies, N. C. Farneth, O. Gautschi, P. N. Lara, D. R. Gandara, P. C. Mack
Journal: Journal of Clinical Oncology (2007)

7682 Background: Activating epidermal growth factor receptor (EGFR) mutations identified in NSCLC patient tumors are often associated with rapid and profound response to EGFR tyrosine kinase inhibitors (TKIs). Conventional detection methods are cumbersome and may underestimate mutations frequencies due to limited sensitivity. We and others have shown that tumor-specific mutations such as KRAS can be detected in tumor DNA shed into patient plasma (Kimura, Ann N Y Acad Sci, 2004). Here we describe the performance of an allele- specific real-time PCR system utilizing Scorpion primers (kindly provided by DxS, UK) to detect EGFR mutations in plasma. Methods: DNA was extracted from archival tumor blocks, slides and plasma obtained from consenting patients. In order to determine the sensitivity of this technique both in terms of the ratio of mutant-to-wild-type genomic DNA as well as the minimum amount of DNA required for detection, a dilution experiment was conducted. Genomic DNA from cell lines containing either the exon 21 L858R point mutation or the exon 21 E746–750 deletion was diluted with wild-type genomic DNA at ratios ranging from 1:2 to 1:10,000. Clinical specimens including plasma and/or tissue from 35 advanced stage NSCLC patients treated with EGFR-TKIs were examined. Results: Mutant DNA was successfully detected when it comprised as little as 0.1% of the total sample or as low as 25 pg of mutant-positive genomic DNA in a pool of 2.5 μg of total DNA. EGFR mutations were identified by this approach in both plasma and tissue of 2 patients who were complete responders to EGFR-TKI therapy, only one of which was detectable by direct sequencing. For the 7 patients where only tissue was available, two were positive both with the Scorpion primers and direct sequencing while the rest were wild-type. Of 21 patients where only plasma was available, 6 mutations were detected using the Scorpion primers. Conclusions: Allele-specific Scorpion technology is 1) highly specific and sensitive for EGFR mutation analysis, 2) able to detect mutations that were not observable by direct sequencing in plasma and tissue, 3) capable of detecting mutations in shed tumor DNA in plasma of advanced NSCLC patients and 4) may be suitable for monitoring response or detecting recurrence. No significant financial relationships to disclose.
Prognostic value of nuclear DNA quantification and cyclin A in epithelial ovarian cancer
Authors: J. Kim, Y.-T. Kim, S.-H. Kim, C.-S. Lee, D. J. Chung, N.-H. Cho
Journal: Journal of Clinical Oncology (2004)

5106 Backgrounds: To investigate the relationship between DNA ploidy, S phase fraction(SPF), cyclin A and clinical prognostic factors such as stage, grade and CA 125, and overall survival in epithelial ovarian cancer. Correlations between DNA ploidy, SPF and cyclin A were also assessed. Methods: Study group consisted of 31 cases of epithelial ovarian cancer, 10 of borderline ovarian tumor and 5 of benign ovarian tumor diagnosed from Feb 2000 to Jan 2003. Patients' sera were sampled after 6th postoperative chemotherapy and the level of CA 125 was assessed with cut off value of 35U/ml. DNA ploidy and SPF were evaluated by flowcytometry of fresh ovarian tissue obtained at the operation. The expression of cyclin A was evaluated by conjugating anticyclin antibody, anti-mouse and rabbit-Ig and streptovidin-HRP to paraffin- blocks of ovarian tissue. Expressivity of 5% was considered as positive expression. Two-sample t-test, chi-square test, and Kaplan-Meier survival curve were used for statistics. Results: DNA aneuploidy was expressed 0% in benign ovarian tumor, 10% in borderline tumor, and 42.0% in epithelial ovarian cancer. (p=0.004) Levels of SPF were 2.3±0.3 in benign tumor, 5.7±3.3 in borderline tumor, and 8.2±4.7 in epithelial cancer.(p=0.001). Positive expressions of cyclin A were observed 0% in benign and borderline tumor but 42.0% in epithelial ovarian cancer(p=0.001). Number of aneuploidy, percentage of SPF, and expressivity of cyclin A were significantly higher in patients with higher grade, more advanced stage and higher level of CA 125(>35U/ml)(p=0.004, 0.009, 0.05 in aneuploidy, p=0.06, 0.01, 0.04 in SPF, p=0.03, 0.004, 0.06 in cyclin A). Aneuploidy and more than 10% of SPF and cyclin A were also associated with poorer overall survival (p=0.02, 0.02, <0.0001). Positive correlations were observed among these factors. Conclusions: Number of aneuploidy, percentage of SPF, and expression of cyclin A were higher in more advanced stage, higher grade, and higher CA 125 and associated with poorer overall survival. Thus, DNA flowcytometry and setimation of expression of cyclin A may provide major information about progosis of disease in epithelial ovarian caner patients. No significant financial relationships to disclose.
A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform
Authors: J. F. Deeken, T. Cormier, D. K. Price, S. Steinberg, K. Tran, D. J. Liewehr, S. B. Ockers, P. Hardenbol, W. Dahut, X. Miao, W. D. Figg
Journal: Journal of Clinical Oncology (2007)

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p&lt;0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.
Activation of the PI3K pathway and prognostic information in epithelial ovarian cancer.
Authors: D. D. Handolias, P. Chan, W. Phillips, S. B. Fox, R. Pearson, S. Sawyer, I. Campbell, R. Salemi, G. A. McArthur
Journal: Journal of Clinical Oncology (2010)

10610 Background: The PI3K/AKT/mTOR signaling pathway is a central network in a number of cancers, including EOC. Identifying associations between key molecules and clinical outcomes may help expose and develop therapeutic targets in this cancer. Methods: Clinical data, tissue microarrays (TMAs) and genomic DNA from 194 EOCs (100 serous, 58 endometrioid, and 34 clear cell) were obtained from the Australian Ovarian Cancer Study. These were analyzed for mutations in PIK3CA, AKT1, KRAS and BRAF using high resolution melt analysis and confirmed by sequencing. IHC for phosphorylated proteins (pAKT, pS6, p4EBP1) was performed on the TMAs and considered overexpressed if above the median value for the cohort. Statistical analyses included chi-squared and cox-multivariate tests and the Kaplan-Meier method for survival. Results: PIK3CA (exon 9 and 20) and KRAS (exon 2) mutations were most frequent in endometrioid (12% PIK3CA, 12% KRAS) and clear cell (8% PIK3CA, 8% KRAS) EOCs. Few mutations in these genes were found in serous subtypes (1%) and no AKT1 (exon 4) or BRAF (exon 15) mutations were found. Coexisting mutations in PIK3CA and KRAS occurred in two endometrioid tumors. There was a trend for endometrioid EOCs to have increased pAKT expression relative to other subtypes (p = 0.058). Furthermore, increased pAKT was associated with a significant improvement in survival of the whole group (HR 0.6 [p = 0.05]). This association was still evident but not statistically significant in a multivariate survival model accounting for tumor subtype (p = 0.175). There was a strong correlation between pS6 and p4EBP1 that are downstream of mTORC1 (p = < 0.01). Increased expression of p4EBP1 (p = 0.01) and pS6 (p = 0.02) was seen in serous and clear cell subtypes respectively, but did not affect clinical outcome. Conclusions: Mutations in genes and high expression of phosphoproteins related to the PI3K pathway are associated with specific subtypes of EOC and may contribute to differences in clinical outcome. Endometrioid EOC had a higher frequency of mutations in the pathway and higher expression of pAKT suggesting investigation of targeting PI3K or AKT is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
GPU MrBayes V3.1: MrBayes on Graphics Processing Units for Protein Sequence Data: Table 1.
Authors: Shuai Pang, Rebecca J. Stones, Ming-Ming Ren, Xiao-Guang Liu, Gang Wang, Hong-ju Xia, Hao-Yang Wu, Yang Liu, Qiang Xie
Journal: Molecular Biology and Evolution (2015)

We present a modified GPU (graphics processing unit) version of MrBayes, called ta(MC)3 (GPU MrBayes V3.1), for Bayesian phylogenetic inference on protein data sets. Our main contributions are 1) utilizing 64-bit variables, thereby enabling ta(MC)3 to process larger data sets than MrBayes; and 2) to use Kahan summation to improve accuracy, convergence rates, and consequently runtime. Versus the current fastest software, we achieve a speedup of up to around 2.5 (and up to around 90 vs. serial MrBayes), and more on multi-GPU hardware. GPU MrBayes V3.1 is available from http://sourceforge.net/projects/mrbayes-gpu/.
JAK2 V617F Mutation Status Predicts Thrombotic Complications, Including Arterial Thrombosis, in Patients with Essential Thrombocytosis (ET).
Authors: Helen Weston, Robert Bird, Vanessa Griffiths, Mark Jones, Karen Grimmett, Russell Saal, Anthony K. Mills, Devinder Gill, Paula Marlton, Peter Mollee
Journal: Blood (2007)
Patterns in the care of oligodendrogliomas and oligoastrocytomas: A single center experience
Authors: S. H. Kizilbash, L. Nadeau
Journal: Journal of Clinical Oncology (2009)

e13034 Background: Although rare, oligodendrogliomas (ODs) and oligoastrocytomas (OAs) have established a unique identity due to their sensitivity to chemotherapy, especially if they exhibit combined loss of heterozygosity (LOH) of 1p and 19q. However, optimal management is still controversial and data is lacking on actual practice patterns. This study describes the epidemiology of ODs/OAs at a community based hospital in Michigan and evaluates the management of these tumors, especially with respect to 1p/19q LOH. Methods: A retrospective review was conducted of all cases of OD and OA that were managed at our institution from 1975 to 2007. 135 patients were isolated. Of these, 48 patients had already been evaluated for 1p/19q LOH. This latter subset underwent data collection and analysis. Results: 31 patients had low-grade tumors (either ODs or OAs) while 17 had high grade tumors (anaplastic ODs or anaplastic OAs). Of the low grade tumors, 35% had combined 1p/19q LOH. 71% underwent surgical resection, 35% received chemotherapy, and 26% received radiation therapy. As for the high grade tumors, 47% had combined 1p/19q LOH. 88% underwent surgical resection, 76% received chemotherapy, and 59% received radiation therapy. At a mean of 29 months of follow up, eight patients had tumor progression while 12 died. Median progression free survival (MPFS) for patients receiving chemotherapy was increased in patients with combined 1p/19q LOH, for both low-grade tumors (34 vs. 20 months) and high-grade tumors (14 vs. 8 months). Also, significantly more patients with low-grade tumors and combined 1p/19q LOH were offered chemotherapy when compared to those without 1p/19q LOH (64% vs 20%, p = 0.04, Fisher exact). However, in patients with high-grade tumors, knowledge of 1p/19q LOH did not significantly impact the choice to administer chemotherapy (88% vs. 67%, p = 0.67). Conclusions: Patients with ODs/OAs and combined 1p/19q LOH who have been treated with chemotherapy demonstrate increased MPFS when compared with those without this genotype. Despite this, determination of 1p/19q LOH significantly affects physician choice to offer chemotherapy only in patients with low-grade tumors, but not in those with high-grade tumors. A future study is in development to determine 1p/19q LOH status for the remaining 87 patients. No significant financial relationships to disclose.
Registry of Gastric Cancer Treatment Evaluation (REGATE): Staging and diagnosis of 10,124 patients (pts).
Authors: C. Wu, V. Soloviev, E. Semkina, M. Ter-Ovanesov, K. Govind Babu, A. Vila, S. Yalcin, A. Roth, E. B. Ecstein-Fraïssé, Y. Bang
Journal: Journal of Clinical Oncology (2010)

4090 Background: The second most common cause of cancer death worldwide is gastric cancer (GC) and it is often diagnosed at a late stage. The REGATE international disease registry was designed to describe regional patterns of treatment for pts with GC. Assessment of geographic differences in staging and diagnosis may help to improve pt care. Methods: Pts with newly diagnosed primary GC were enrolled from August 2004 to July 2008; data were collected at an initial visit and <10 months later. Target sample size was calculated according to GC prevalence in the 22 participating countries. Baseline staging and diagnosis are described globally and by region. Baseline pt and tumor characteristics, and surgical and non-surgical treatments are reported elsewhere. Results: Overall, 10,124 pts were enrolled in 5 regions: Europe (E) 32%, Asia-Pacific (AP) 31%, Latin America (LA) 20%, Indian subcontinent (IS) 12%, and North Africa (NA) 6%. AJCC staging was the most frequently used classification (99%). In AP, GC was diagnosed most frequently at stage I; pts in other regions were mostly diagnosed at stage IV. Stage III rates were similar in E, AP, and LA (19–21%), higher on the IS (30%), and lower in NA (13%). Histopathologic type was assessed using WHO, Lauren, and/or Ming classifications in 75%, 60%, and 31% of all pts, respectively. The most common WHO subtype was signet ring cell (41%). Tubular subtype occurred in 35% (LA) and 40% (AP) of pts vs. <10% of pts in other regions. Diffuse and intestinal Lauren subtypes were comparable in E, LA, and the IS; diffuse subtype was most common in AP (56%) and NA (60%). More pts on the IS (77%) had a grade 3 tumor vs. other regions (42–49%). CT scan was the most frequently used staging method (76%), but was used less often in E (47%) vs. other regions (86–94%). Conclusions: Regional differences were observed for staging and diagnosis in REGATE. Diagnosis with stage I disease occurred most often in AP; metastatic disease was more common in other regions. Staging and histopathologic classifications, and disease investigation techniques also varied by region. E AP LA IS NA N (%) 3202 (32) 3119 (31) 1988 (20) 1191 (12) 624 (6) AJCC (%) 98 99 99 99 98 Japanese (%) 25 53 21 9 36 AJCC stage I/IV (%) 12/42 38/28 16/36 6/49 18/57 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis
Symptom burden, quality of life, and distress in acute myeloid leukemia patients receiving induction chemotherapy: A prospective electronic patient-reported outcomes study.
Authors: Thomas William LeBlanc, Steven Wolf, Debra M. Davis, Greg Samsa, Susan C. Locke, Karen E. Steinhauser, Peter A. Ubel, James A. Tulsky, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2014)

167 Background: Induction chemotherapy for acute myeloid leukemia (AML) is more intensive than many solid tumor treatments, and may be associated with a different symptom burden. Little is known about the most prevalent symptoms during AML induction, nor how they change over time. Methods: We enrolled AML inpatients at initiation of induction chemotherapy, and assessed their symptoms, quality of life (QoL), and distress weekly during their month-long hospitalization for treatment, using 3 validated instruments: Patient Care Monitor v2.0 (PCM); Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu); and NCCN distress thermometer (DT). Here we report results from the first 16 enrolled patients, using standard descriptive statistics. Results: Mean age of study participants was 59.6 (SD 12.2), and most were newly diagnosed with AML (SD 87.5%, n=14). Patients were mostly high-risk for recurrence, with 50% (8) being &gt;60 years old and 71% (10) having high-risk cytogenetics. Fatigue was the most prevalent symptom, with an average of 59% of patients reporting moderate to severe fatigue at each assessment. The other most prevalent moderate/severe non-functional symptoms were dysgeusia (50%), dry mouth (42%), diarrhea (41%), decreased appetite (37.5%), insomnia (37.5%), daytime sleepiness (36%), nausea (36%), hair loss (36%), and mouth sores (34%). Median QoL by FACT-Leu total score decreased substantially between weeks 1 and 2 (118.5 to 104.5); the most substantial decrements were in subscales for personal well-being and functional well-being (20.5 to 14.5, and 13.5 to 8.5, respectively). QoL did not return to baseline by week 4. Median DT score at baseline was 6.5, with a trend towards weekly improvements in distress (DT = 3 at week 4). Depressive symptoms like hopelessness and sadness were reported by an average of 25% and 31.3% of patients, respectively. Conclusions: AML patients receiving induction chemotherapy have significant symptom burden, impaired QoL, and psychological distress. The prevalence of these issues suggests sizeable unmet palliative care and psychosocial needs in AML patients receiving induction chemotherapy.
Comparative effectiveness of treatment options in elderly patients with colon cancer receiving adjuvant chemotherapy.
Authors: Sacha Satram-Hoang, Devi Ramanan, Luen F. Lee, Shui Yu, Carolina M. Reyes, Edward McKenna
Journal: Journal of Clinical Oncology (2012)

470 Background: While colon cancer (CC) is predominantly a disease of the elderly, older patients are underrepresented in clinical trials. We sought to evaluate whether the treatment patterns and benefits realized by trial participants pertain to older patients in the real-world setting. Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 3390 stage II and III CC patients diagnosed between 1/1/ 2004 to 12/31/2007, who were &gt;66 years, enrolled in Medicare Parts A and B, and received adjuvant treatment with 5FU/LV (n=1368), FOLFOX (n=1398), CAP (capecitabine; n=507), and CAPOX (CAP + oxaliplatin; n=117) within 3 months after surgery. Date of last follow-up was 12/31/2007. Chi-square test and ANOVA or t-test assessed differences in patient and disease characteristics by treatment. Propensity score weighted Cox regression assessed the relative risk of death by treatment. Results: Patients treated with CAP were older (mean age 77 years; p&lt;.0001), more likely female (61%; p&lt;.05), more likely non-white (19%; p&lt;.05) and had higher co-morbidity score (p&lt;.0001) compared to the other treatment groups. The mean time to chemo initiation after surgery were similar between the groups (mean 46-49 days) while mean duration of treatment were longer for 5FU/LV (149 days) and FOLFOX (144 days), compared to CAP (121 days) and CAPOX (111 days); p&lt;.0001. The incidence of adverse events (AEs) within 180 days after initiation of treatment were higher in patients treated with FOLFOX (82%) and 5FU/LV (78%) compared to CAP (74%) and CAPOX (71%); p=0.0002. Propensity score adjusted multivariate analysis demonstrated comparable survival for CAP-based regimens vs. 5-FU/LV- based regimens ( table ). Conclusions: Treatment outcomes for elderly patients observed in routine clinical practice were comparable between CAP-based and 5FU/LV-based regimens and consistent with results reported in randomized clinical trials. AEs associated with medical resource utilization were less frequent with CAP-based regimens. [Table: see text]