tbuckley/cabot-search huggingface dataset:
Prognostic significance of high-risk human papilloma virus (HPV), p16, and p53 status in women with vulvar squamous cell carcinoma (VSCC).
Authors: Ghassan Allo, Mei Ling Yap, Julie Cuartero, Helen Mackay, Michael Milosevic, Joan Murphy, Suzanne Kamel-Reid, Melania Pintilie, Blaise Clarke
Journal: Journal of Clinical Oncology (2012)

5105 Background: The incidence of VSCC is increasing. Studies suggest the presence of two histologically and molecularly distinct subsets of VSCC; one contingent on and another independent of HPV infection. However, it is uncertain if HPV status has prognostic significance. HPV oncoproteins can result in degradation of the tumor suppressor p53, cell cycle deregulation and abnormal expression of cyclin dependant kinase inhibitor p16. The aim of this study was to investigate HPV infection, p16 and p53 in relation to clinical parameters in women with VSCC. Methods: Sequential cases of VSCC from patients (pts) treated at Princess Margaret Hospital (PMH) from 2000 to 2008 were reviewed. HPV infection was evaluated by Roche Linear array. A tissue microarray was constructed. p16 and p53 immunohistochemistry was performed. Clinical data was abstracted from medical records and PMH Cancer Database. Survival analysis was performed using Kaplan-Meier curves and log rank test. Results: We identified124 pts with VSCC. HPV was detected in 43/123 (35%) pts (median age 71 ± 16 yrs). HPV16 was the most common serotype (38/43; 88.4%). p16 was expressed in 30/115 (26%) pts and p53 in 59/117 (50.4%) pts. Median age of pts was not different in relation to HPV, p16 and p53 status. Expression of p16 (p&lt;0.0001) and loss of p53 (p=0.007) were associated with HPV infection. Pts with HPV positive tumors were less likely to recur (recurrence rate at 5 years (RR) 12.5% vs 50.3%, p=0.009). HPV positive VSCC were not associated with better 5 yr disease free survival (DFS), 58% vs 31%; p=0.15, or overall survival (OS), 61% vs 61% ; p=0.94. p16 positive tumors had a lower RR at 5 yrs, 23.8% vs 59%, p=0.006 and better 5yr DFS (61% vs 27% ; p=0.009) but not significant for OS (65% vs 59%; p=0.94). Among pts with HPV positive VSCC, OS and DFS were not different between p16 positive and negative VSCC. In the 46 pts treated with radiotherapy, HPV and p16 positive tumors were associated with a lower RR (p=0.004 and 0.005). p53 expression was not prognostic in any pt group. Conclusions: Women with HPV-positiveVSCC have a lower risk of disease recurrence. p16-expressing VSCC are associated with reduced disease recurrence and improved DFS.
A randomized, open-label phase II study of single-agent vintafolide versus vintafolide plus docetaxel versus docetaxel alone in second-line NSCLC patients with all target lesions expressing folate-receptor (TARGET).
Authors: Martin J. Edelman, Hong Ma, Wendy Perez, Alex A. Adjei, Nasser Hanna
Journal: Journal of Clinical Oncology (2013)

TPS8125 Background: Folate receptor (FR) is frequently overexpressed in NSCLC and is a potential biomarker for therapy selection. Vintafolide (EC145) is designed to target FR expressing cells and consists of folate linked to desacetylvinblastinehydrazide. The FR targeted imaging agent, 99m Tc-etarfolatide (EC20), consists of folate coupled to technetium and identifies lesions that overexpress FR which may respond to vintafolide treatment. A phase II study of single-agent vintafolide in heavily pre-treated lung adenocarcinoma patients (pts) showed promising activity in clinical benefit response (50% vs. 14.3%) and overall survival (OS, 47.2 wks vs. 14.9 wks), in pts whose target lesions all expressed FR [FR (100%)] vs pts whose target lesions were not all FR positive (Edelman et al, JTO 2012:7:1618-21). This trial assesses the benefit of vintafolide as second-line therapy in NSCLC FR (100%) pts. Methods: This is a randomized, open-label phase II study of vintafolide vs. vintafolide + docetaxel vs. docetaxel in second line NSCLC FR (100%) pts ( NCT01577654 ). Key eligibility criteria include: cytologic or histologic diagnosis of NSCLC, 1 prior systemic therapy for advanced disease, and PS 0-1. At baseline, pts undergo 99m Tc-etarfolatide imaging to detect FR-positive lesions. FR (100%) pts are randomized 1:1:1 to vintafolide, vintafolide + docetaxel, or docetaxel. Vintafolide (2.5 mg) is administered on d 1, 4, 8, and 11 of a 3-wk cycle. Docetaxel (75 mg/m 2 ) is given on d 1 of a 3-wk cycle. Treatment continues until disease progression or unacceptable toxicity. Pts receiving vintafolide + docetaxel who discontinue docetaxel due to toxicity may continue vintafolide alone. Disease status is evaluated by RECIST v1.1 criteria every 6 wks and adverse events are monitored throughout. The primary objective of this study compares PFS between the docetaxel control arm and each experimental arm with the goal of demonstrating a hazard ratio of ≤0.67 favoring the experimental arms. Secondary objectives include response rate, disease control rate, OS, and safety/tolerability. Enrollment to the study is ongoing. Clinical trial information: NCT01577654.
Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: Analysis of pooled data from three clinical trials
Authors: G. Gonzalez, C. Viada, E. Neninger, T. Crombet, I. Leonard, B. Garcia, A. Lage
Journal: Journal of Clinical Oncology (2004)

2548 Background: During the last 10 years we have studied the effect of vaccination against self EGF, both in the preclinical setting, and in several pilot clinical trials in advanced non-small cell lung cancer (NSCLC) patients. Here, we undertake the analysis of aggregated data from these trials, addressing particularly the issue of the relationship between immunization and survival. Methods: Pooled data from 3 pilot clinical trials in 75 patients, considered not amenable to any other modality of onco-specific treatment, were used. For survival analysis, 27 NSCLC patients were considered as a non-randomized concurrent control group. This group of patients has features which make it adequate for comparison: compliance with inclusion criteria, simultaneity in time, and treatment in the same hospital by the same physician staff. Vaccination using different adjuvants (alum and Montanide ISA51), cyclophosphamide pre-treatment or not, as well as different dosages of the Vaccine were compared. Results: On vaccinated patients, 80% showed seroconversion, of which 47% developed a good antibody (Ab) response. Geometric mean of maximal Ab titers was 1:3949 (sera dilution). Adjuvant, vaccine dose and cyclophosphamide pre-treatment significantly influenced immunogenicity whereas the other analyzed variables (sex, age, clinical stage, previous treatment) did not. The immune response was short lasting (2.64 +/- 1.89 months) and non-boostable. To maintain Ab titers continuous re-immunizations were required. No serious adverse events were registered. Vaccinated patients survived significantly more (mean: 9.13 months; median: 8 months) than the control group (mean: 4.85 months; median: 4.53 months) (p=0.0003). Patients who seroconverted survived significantly more than patients who did not. Patients with good Ab response showed a significant improvement in survival as compared with those with poor Ab response. Conclusions: Vaccination with EGF was safe, immunogenic and improved survival in advanced NSCLC patients as compared with concurrent controls. These results are currently being verified in a randomized trial. No significant financial relationships to disclose.
Expression of somatostatin receptor subtypes, aurora kinase A, and interleukin-6 in prostate cancer before androgen ablation.
Authors: Angela Gernone, Senia Trabucco, Leonardo Resta, Anna Napoli
Journal: Journal of Clinical Oncology (2017)

e564 Background: Neuroendocrine differentiation (NED) in prostate cancer (PC) can be detected by immunohistochemistry as single cells in conventional adenocarcinoma. The extent of NED is associated with poor prognosis and early onset of castrate resistant prostate cancer. Aurora kinase A (AURKA) and Interleukin-6 (IL-6) cooperate to induce NED. The aim of this study was to correlate the expression of somatostatin receptor (SSTR) 1- 2- 3- 4- 5 subtypes, AURKA and IL-6 in primary PC with NED pattern and OS. Methods: PC tissues were reviewed from 60 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2010 to 2016. 10 samples expressed histologically chromogranin A (CgA), a marker of NED expression. Median age was 67 years (47-80), Gleason score ≥ 7, median PSA was 60 ng/ml (1.3-1000), ECOG 0/1 and bone-visceral sites measurable in 90% of cases. For comparison purposes, 8 pathology specimens from pts with primary PC were used. Results: SSTR1-2-4-5 were detected in the nucleus of PC cells in 10/10 samples. SSTR3 and AURKA were not expressed in all 10 samples. IL-6 was detected in 9/10 samples. All 10 pts were associated with a more aggressive clinical course and OS was &lt; 12 mos. Conclusions: In metastatic prostate cancer, pretreatment NED pattern can be a predictor for progression and survival after hormonal and chemotherapy. SSTRs and somatostatin analogs are not potential targets for prostate cancer.
Abstract 64: Conditional Knockout of Activin Like Kinase-1 (ALK-1) Leads to Heart Failure Without Maladaptive Remodeling
Authors: Kevin Morine, Vikram Paruchuri, Xiaoying Qiao, Emily Mackey, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Richard Karas, Paul Oh, Navin K Kapur
Journal: Circulation Research (2015)

Activin like kinase 1 (ALK1) mediates signaling via the TGFb family of ligands. ALK1 activity promotes endothelial proliferation and migration. Reduced ALK1 activity is associated with arteriovenous malformations. No studies have examined the effect of global ALK1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of ALK1 promote maladaptive cardiac remodeling. Methods: We employed an ALK1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase mediated excision of floxed ALK1 alleles. Tamoxifen treated wild-type (WT-Tam; n=5) and vehicle treated ALK1-cKO mice (cKO-Veh; n=5) served as controls for tamoxifen treated ALK1-cKO mice (cKO-Tam; n=15). Results: ALK1 cKO-Tam mice demonstrated reduced 14-day survival compared to cKO-Veh controls (33% vs 100%, respectively, p&lt;0.01). Seven days after treatment, ALK1 cKO mice began to exhibit reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-Tam not cKO-Veh mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume increased in cKO-Tam, not cKO-Veh mice. LV ALK1 mRNA and protein levels were reduced in cKO-Tam, not cKO-Veh mice. LV levels of other TGFb-family ligands and receptors (ALK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFB1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-Tam mice, but LV levels of b-MHC, SerCA, and calcineurin were unchanged. No increase in cardiac fibrosis Type I collagen, CTGF, or PAI-1 levels were observed between groups. No differences were observed for any variable studied between cKO-Veh and WT-Tam mice. Conclusion: Global deletion of ALK1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of ALK1 in cardiac remodeling are required.
Impact of primary tumor location (TL) on outcomes of first-line (1L) FOLFOX-4 (F) ± cetuximab (cet) in patients (pts) with <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 3 TAILOR trial.
Authors: Shukui Qin, Jian-Ming Xu, Liwei Wang, Ying Cheng, Tian Shu Liu, Jiongjie Chen, Wen-Feng Chen, Jin LI
Journal: Journal of Clinical Oncology (2017)

683 Background: In the RAS wt population of TAILOR, adding cet to 1L F significantly improved progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). In this subgroup analysis, we evaluate the impact of TL. Methods: TAILOR is a randomized phase 3 trial that includes a modified intention-to-treat (mITT) population of 393 pts from China with RASwt mCRC treated with F ± cet. The primary endpoint of TAILOR is PFS; key secondary endpoints include OS and ORR. TL was categorized in evaluable pts in the mITT population (left-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right-sided = appendix, cecum, ascending colon, hepatic flexure, ± transverse colon). Results: Efficacy data for the TL subgroups are summarized in the table. Additionally, the prognostic effect of TL (left- vs right-sided) within the treatment arms could be shown for PFS (HR = 1.72; p = .007), OS (HR = 1.84; p = .002), and ORR (OR = 0.40; p = .014) in the cet + F arm and PFS (HR = 1.97; p = .002), OS (HR = 1.43; p = .073), and ORR (OR = 0.41; p = .028) in the F arm. Regarding the potential predictive value of TL, the p values for the interaction between TL and treatment are: PFS (.676), OS (.339), and ORR (.986). Conclusions: In TAILOR, adding cet to 1L F clearly benefitted RAS wt pts with left-sided tumors in terms of PFS, OS, and ORR; for pts with right-sided tumors, the HRs for PFS and the ORs for ORR also consistently suggested a benefit showing a trend in favor of cet. Clinical trial information: NCT01228734. [Table: see text]
The Metabolic Phenotype of Myeloma Plasma Cells Differs Between Active and Residual Disease States
Authors: Brian Koss, Whitney Tevebaugh, Brian A Walker, Carolina Schinke, Frits van Rhee, Maurizio Zangari, Sharmilan Thanendrarajan, Faith E Davies, Joshua Epstein, Shmuel Yaccoby, Gareth J Morgan, Sarah K. Johnson
Journal: Blood (2016)
Prognostic value of KRAS exon 2 gene mutations in stage III colon cancer: Post hoc analyses of the PETACC8 trial.
Authors: Julien Taïeb, Jean-François Emile, Karine Le Malicot, Aziz Zaanan, Josep Tabernero, Enrico Mini, Philippe Rougier, Jean Luc VAN Laethem, John A. Bridgewater, Gunnar Folprecht, Ramon Salazar, Ayman Zawadi, Eric Van Cutsem, Come Lepage, Pierre Laurent-Puig, Helene Blons
Journal: Journal of Clinical Oncology (2014)

3549 Background: Prognostic value of KRAS mutations in resected colon adenocarcinoma remains debated. We examined the prognostic impact of KRAS exon 2 mutations in stage III patients receiving adjuvant FOLFOX + /- cetuximab patients from the PETACC8 Phase III trial. Methods: KRAS exon 2 mutations in codon 12 (p.G12V, p.G12R, p.G12S, p.G12A, p.G12C, p.G12D) and codon 13 (p.G13D) were examined in all patients with available material and signed translational research informed consent enrolled in the PETACC8 trial. Analyses were restricted to BRAF wild type tumors, since the prognostic impact of BRAFV600E in this population has already been described. Because no benefit or deleterious effect from adjuvant cetuximab was reported in this trial, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and disease-free survival (DFS) and type of KRAS mutation was evaluated using Cox proportional hazard model. Results: KRAS mutations were found in 638/1657 tumors, including 502 codon 12 and 136 codon 13 alterations. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; P<0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; P=0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors, independently of other covariates. Similar results were found for DFS. When anatomic sites were taken into account, the impact of KRAS mutations on TTR was only found for distal tumors (n=1043) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; P<0.0001) for KRAScodon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; P=0.051), as compared to KRAS/BRAFwild type patients. Similar results were found for DFS. Conclusions: KRAS exon 2 mutations are independent predictors of TTR or DFS for patients with stage III distal colon cancer receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and type of KRAS mutation as important stratification factors.
Vitamin Pharmacogenomics: New Insight into Individual Differences in Diseases and Drug Responses
Authors: Hai-Yan He, Mou-Ze Liu, Yue-Li Zhang, Wei Zhang
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract Vitamins are vital to sustain normal physiological function, metabolism, and growth for all living organisms. Being an integral component of coenzyme, vitamins can affect the catalytic activities of many enzymes and the expression of drug transporters. Genetic variations in metabolism and/or transporter genes of drugs can influence the exposure of the human body to drugs and/or their active metabolites, thus contributing to the variations in drug responses and toxicities. Nonetheless, pharmacogenomics studies on nutrients have been rarely summarized. In this article, we reviewed recent progress on vitamin pharmacogenomics, for a better understanding on the influence of vitamin-related gene polymorphisms on inter-individual differences in diseases and drug efficacy and safety.
Utilization of neoadjuvant therapy and rates of pathologic complete response at Commission on Cancer accredited centers across the United States.
Authors: Olga Kantor, Chi-Hsiung Wang, Erik Liederbach, David J. Winchester, Catherine Pesce, Katharine Yao
Journal: Journal of Clinical Oncology (2015)

e12010 Background: Neoadjuvant chemotherapy (NAC) has become increasingly utilized in breast cancer, but few studies have examined trends in NAC therapy and response rates across the United States. Methods: We examined trends and independent predictors of NAC use from 2006-2012 utilizing the National Cancer Data Base in women with Stage I-IIIa tumors. Pathologic complete response (pCR) rates were stratified by tumor molecular subtype from 2010-2012 when information on all three molecular markers (ER, PR, Her2) was available. Results: NAC utilization increased from 7.8% in 2006 to 10.3% in 2012. The increase was most pronounced for women with ER- tumors (from 12.2% to 22.1%, p < 0.001). From 2010-2012, NAC was most common in younger women (34.5% of 18-29yo vs 0.8% of 80-90yo, p < 0.001), in triple negative (TNBC) and Her2 positive subtypes (20.2% and 18.2% vs 5.4% in luminal A tumors respectively, p < 0.001). Approximately 7% of TNBC and 6.7% of Her2 positive tumors ≤ 2cm underwent NAC. The strongest independent predictors of getting NAC over adjuvant chemotherapy were advanced clinical stage (OR 23.55, CI 22.37-24.78 for clinical stage 3), younger age (OR 3.49, CI 2.92-4.16 for 18-29yo), TNBC (OR 1.86, CI 1.80-1.93) or Her2 positive (OR 1.67, CI 1.62-1.73) subtypes, treatment at an Academic center (OR 1.62, CI 1.54-1.71) and minority race (OR 1.18, CI 1.14-1.23 for African Americans and OR 1.17, CI 1.11-1.23 for Hispanics). The overall pCR rate for women after NAC was 21.5% from 2010-2012. pCR was more likely in young women (26.8% vs 7.8% for 18-29 vs 80-90yo), and TNBC or Her2 positive tumors (30.5% and 34.2% vs 8.9% in luminal A)[all p-values < 0.001]. Independent predictors of pCR were young age (OR 4.04), grade III tumors (OR 4.01), TNBC (OR 3.36) and Her2 positive (OR 4.58) subtypes, and treatment at Comprehensive (OR 1.20) or Academic (OR 1.28) centers [all p-values ≤ 0.001]. African American race was associated with decreased pCR rates compared to Caucasians (OR 0.86, CI 0.79-0.93). Conclusions: Rates of NAC have increased over the study period and are most associated with tumor factors. pCR rates are highest among young women and TNBC and Her2 positive tumors but lower among African Americans.
Benefit from adjuvant chemoradiation to resected stage IIIC gastric cancer patients with D2 lymph node dissection.
Authors: Jin Peng, Fuxiang Zhou, Jing Dai, Yahua Zhong, Conghua Xie, Yu'e Qin, Jun Gong, Bing Xiong, Yunfeng Zhou
Journal: Journal of Clinical Oncology (2014)

e15028 Background: Adjuvant chemoradiation is standard adjuvant treatment for resected gastric cancer in North America. However, for D2 resected gastric cancer, there is still controversial. ARTIST trail failed to reveal the benefit from adjuvant chemoradiation in the entire group, but in subgroup analysis for lymph node positive patients, it showed profit in DFS. The aim of this study was to evaluate the role of adjuvant chemoradiation in D2 resected gastric cancer and to identify the population who may benefit from adjuvant chemoradiation. Methods: Resected gastric cancer patients in Zhongnan Hospital of Wuhan University in 2003 to 2012 were retrospective analyzed. The main eligible criteria included: 1) age 18-70; 2) stage T3-4 and/or N1-3 and M0; 3) completely resected with D2 lymph node dissection; 4) histologically confirmed gastric adenocarcinoma; Eligible patients were divided into two group: one group was given adjuvant chemoradiation plus chemotherapy (CRT) ; the other received only adjuvant chemotherapy (CT) ; Adjuvant chemotherapy regiments utilized in the research included FOLFOX, ECF, Capecitabine or S1 monotherapy or in combination regiments, docetaxel contained regiments and etc. Chemotherapy regiment used in concurrent chemoradiation was 5-FU/CF. Results: A total of 347 patients were included in our analysis, 128 patients in CRT group and 219 patients in CT group. The median follow-up time was 54 months. The main characteristic of the two group were comparable. Media survival in CRT group and CT group were 52.5 months and 45.8 months respectively (p=0.366), disease free survival were 40.7 months and 34.2 months (p=0.079); While, stratified analysis showed OS in stage IIIC were 25.7 months and 21.1 months respectively (p=0.041). DFS were 21.1 months and 14.8 months (p=0.033). Main adverse events (Grade 3-4 hematologic toxicity and gastrointestinal reactions did not show difference significantly in the two groups. Conclusions: Adjuvant chemoradiation in gastric carcinoma patients with D2 resection was well tolerable. For Stage IIIC patients, the addition of adjuvant chemoradiation was associated with a clinically benefit in OS and DFS compared to adjuvant chemotherapy only.