bluuebunny/crossref_metadata_2025_split huggingface dataset:
An explorative analysis of TOP1 copy number alterations in a chemonaive stage III CRC patient cohort.
Authors: Smith David Hersi , Rømer Maria Unni , Jensen Niels Frank , Nygaard Sune Boris , Christensen Ib Jarle , Müller Sven , Nielsen Hans J. , Brunner Nils , Nielsen Kirsten Vang 
Published: February 2017

66 Background: Topoisomerase I (TOP1) is the target of TOP1 inhibitor chemotherapy. The TOP1 gene, located at 20q12, is frequently gained in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene alterations in advanced CRC. Methods: Nine CRC cell line metaphase spreads were analyzed with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN20) or chromosome 2 (CEN2). Tissue sections from 154 stage III CRC patients, previously studied with TOP1/CEN20, were analyzed with TOP1/CEN2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and to local recurrence (LR; rectal cancer only) were analyzed using multivariate statistics. Results: TOP1 alterations were observed in 4 cell line metaphases. In 3 cases, TOP1 gain involved CEN20, indicating either gain of chromosome 20 or 20q. In all cell lines CEN2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN2 ratio ≥ 1.5). A total of 151 patient tumor sections were analyzed with TOP1/CEN2. Among these, 99 patients (65.6%) had TOP1 gain of which 15 patients (10 %) harbored TOP1 amplification (TOP1/CEN20 ratio ≥ 2.0). For OS, TOP1 amplification showed a trend towards longer OS and TTR (HR: 0.59; 95% CI: 0.31-1.14; p = 0.11; HR: 0.50; 95% CI: 0.23-1.09; p = 0.08; respectively), whereas TOP1 gain did not. For LR in rectal cancer patients (n=70), TOP1 gains were significantly associated with shorter time to LR (HR: 1.98, 95% CI: 1.02-3.84; p = 0.04), whereas TOP1 amplifications showed a trend towards longer time to LR (HR: 0.40; 95% CI: 0.14-1.11; p = 0.08). Conclusions: TOP1 gene gain occurs frequently in stage III CRC in a mechanism that often includes CEN20. Using CEN2 as a measurement for tumor ploidy levels, we were able to discriminate between gains and amplifications. TOP1 amplifications showed a trend towards longer OS, TTR and time to LR, whereas TOP1 gains were associated with shorter time to LR. Future studies will investigate the difference between TOP1 gains and amplifications in a larger TOP1 inhibitor treated patient population.
Cell-free EBV DNA in Hodgkin lymphoma.
Authors: Kanakry Jennifer Ann , Gellert Lan L. , Kasamon Yvette L. , Lemas M. Victor , Toure Marie Valerie , Ambinder Richard F. 
Published: February 2017

7 Background: EBV is associated with a subset of Hodgkin lymphoma (HL), identified by tissue-based techniques such as EBER in situ hybridization of tumor specimens. Recent evidence suggests that cell-free EBV DNA may be a surrogate for EBER and serve as a tumor marker in HL. Methods: EBV DNA copy number was quantitated by RT-PCR of plasma, serum, and peripheral blood mononuclear cells (PBMCs) from HL patients and compared using Pearson’s correlation. Receiver operator characteristic (ROC) curves determined thresholds for EBV DNA copy number to discriminate EBER status. Kaplan-Meier curves and Cox proportional hazards models were constructed to analyze failure-free survival (FFS). Results: Plasma and serum EBV DNA (n=30 paired samples) were correlated (r=0.96, p<0.0001), while plasma and PBMC EBV DNA were not correlated (n= 25 paired samples, r=0.35, p=N.S.). Detectable plasma EBV DNA was 85% concordant with EBER status (n=34 paired samples) while detectable PBMC EBV DNA had a low concordance of 50% with EBER (n=78 paired samples). In a prospective clinical trial of HL patients treated with rituximab-ABVD, we confirmed the association between pre-treatment plasma EBV DNA and EBER (n=33 paired samples) and found a cut-off of > 60 viral copies/100 µL plasma to have optimal test characteristics with 100% sensitivity, 93% specificity, and 94% concordance with EBER. We observed that EBV DNA was cleared from the plasma of patients with EBER(+) HL within one month of treatment, corresponding to a durable remission in each instance. In a larger prospective trial of HL (E2496), pre-treatment plasma EBV DNA was 95% concordant with EBER (n=121 paired samples), with a sensitivity of 92% and specificity of 96% at the same cut-off of 60 viral copies/100 µL plasma. Pre-treatment plasma EBV DNA positivity was found to be an independent predictor of inferior FFS with a hazard ratio of 2.0 (95% CI 1.2 – 3.5), as presented at ASCO 2012 (abstract #8003). Failure to clear the plasma of EBV with treatment corresponded to inferior 3-year FFS (44% vs 69%, log-rank p=0.03). Conclusions: These findings suggest that cell-free EBV DNA may be a useful tumor marker in HL, demonstrating concordance with EBER, prognostic significance prior to therapy, and utility as a marker of treatment response during therapy.
Trastuzumab-reactive antibodies (TR-abs) in serum and trastuzumab (Tzb) benefit prediction in patients with HER2-overexpressing breast cancer.
Authors: Pohlmann Paula Raffin , Miller Todd W. , Blum David L , Pareh Dipti , Yan Heping , Sutton Cammie R , Dugger Teresa C , Salazar Lupe G , Wu William , Reyzer Michelle L. , Disis Mary L. , Mernaugh Ray , Arteaga Carlos L. 
Published: February 2017

77 Background: Trastuzumab (Tzb) is a humanized monoclonal antibody (MAb) approved for treatment of HER2-overexpressing breast cancer. Unfortunately not all patients benefit from it and lack of response cannot be predicted. We detected TR-abs in serum of mice and patients treated with Tzb. We hypothesized that TR-abs would associate with response to therapy. Methods: Direct/competition ELISA, dot blot, and mass spectrometry were used to detect and characterize TR-abs in sera from Tzb treated FVBMMTV/HER2transgenic mice, from hybridoma MAbs stemming from transgenic mice responding favorably to Tzb (992-18 mMAb), and in sera of 22 patients with metastatic breast cancer enrolled in a phase I clinical trial. WST-1 viability assay was used to assess biological activity of 992-18 on SKBR3 or BT474 human breast cancer cell lines. Results: From 12 mice bearing HER2-overexpressing tumors and treated with Tzb, 5 responded to therapy and 7 exhibited progressive disease (PD). All 5 responders had elevated TR-abs, whereas TR-abs were low/undetectable with PD (p=0.002; Mann-Whitney two-tailed). This was confirmed in a second cohort of 16 mice, in which TR-abs were undetectable prior to treatment, but gradually detected with Tzb therapy and tumor regression. TR-MAb 992-18 directly targeted also SKBR3 and BT474 in cell-based ELISAs and immunofluorescence assays. Treatment with 992-18 reduced BT474 and SKBR3 cell viability in comparison to isotype-matched control Ab (p<0.0001). In sera from patients with metastatic breast cancer, higher concentrations of TR-abs were significantly associated with lower risk of disease progression (p=0.023, Cox regression, univariate analysis). Conclusions: Low serum TR-abs are associated with poor response to Tzb in mice and with shorter progression free survival in women with HER2 overexpressing stage IV breast cancer. In addition, TR-abs (e.g. 992-18) produced in response to therapy may be pharmacologically active. Results support prospective evaluation of patients undergoing treatment with therapeutic antibodies to determine if this non-invasive immunoassay detecting anti-therapeutic antibodies would predict benefit to therapy.
Interleukin-8 (IL8) and transforming growth-factor beta (TGF-β) as drugable biomarkers of response, progression-free survival (PFS), and overall survival (OS) with pazopanib (PZP): A phase II study in relapsed urothelial cancer (UC).
Authors: Necchi Andrea , Zaffaroni Nadia , Mariani Luigi , Giannatempo Patrizia , Nicolai Nicola , Raggi Daniele , Pennati Marzia , Morosi Carlo , Lanocita Rodolfo , Crippa Flavio , Daidone Maria Grazia , Gianni Alessandro M. , De Braud Filippo G. , Salvioni Roberto 
Published: February 2017

78 Background: Final results of INT70/09 trial of PZP in 41 multi-relapsed patients (pts) with UC reported one of the highest response-rates as 7 pts (17%) had a confirmed PR, 14 a confirmed SD (51% clinical benefit) after independent review (AACR and ASCO 2012). Final achievements on circulating biomarkers are presented. Methods: From 02/2010 to 07/2011, pts received PZP 800 mg once daily until PD or unacceptable toxicity. 50 mL of EDTA blood samples were collected at baseline (T0) and after 4wks (T1) together with disease restaging in all pts to analyze plasma levels of VEGF, sVEGFR-1,-2 and -3, c-Kit, HGF, TGF-β, IL-6, 8 and 12 by multiplex ELISA plates. Changes in marker levels were analysed with the Wilcoxon signed-rank test and matched with RECIST response with the covariance analysis. A logistic regression and Cox regression model evaluated the association with response probability, PFS and OS. Biomarker level was modelled as a continuous time varying covariate. Results: Significant increase from T0 to T1 was observed for VEGF (p<0.0001), HGF (p=0.017), IL6 (p<0.0129) and IL8 (p<0.0013) and decrease for VEGFR2 and c-Kit (p<0.0001 each). Increasing IL8T1 level associated with lower response probability at covariance analysis (p=0.0104). Both TGF-βT0 (p=0.0019) and TGF-βT1 (p=0.0017) levels associated with PFS while elevated IL8T0 (p=0.0170), IL8T1 (p=0.0107) as well as TGF-βT0 (p=0.0472) and TGF-βT1 (p=0.0013) levels associated with OS. Elevated VEGFT1 also associated with shorter OS (p=0.0084) but significance was lost when jointly modelling biomarkers. Pts having IL8T1 levels < 80 pg/ml had greater response (80%) and 6-month OS (60%) probability than those with a level ≥ 80, for whom a dramatic fall was observed. Conclusions: Both IL8 and TGF-β had a prognostic value while IL8 modulation was also associated with response probability. These markers may serve to select pts most likely to get a benefit from PZP. There is a rationale for a sequence/combination with PZP and a phase II study of an anti-TGF-β receptor ALK1 moAb (PF-03446962) for refractory UC is currently recruiting (NCT01620970).
Comparison of SearchLight and Luminex multiplex assays: A case study of 27 cytokines in 156 melanoma blood serum samples.
Authors: Lin Yan , Butterfield Lisa , LaFramboise William A , Potter Doug M , Lin Hui-Min , Sander Cindy , Kirkwood John M. , Tarhini Ahmad A. 
Published: February 2017

79 Background: Searchlight and Luminex are two popular multiplex immunoassay platforms. Yet, very few studies have directly compared the performance of these two platforms on real clinical samples. Here we report a case study of 27 cytokines assayed by both platforms on 156 previously banked melanoma serum samples. Methods: Searchlight (Aushon) and Luminex (Invitrogene) assays were carried out according to protocols specified by the manufactures. Intra-experimental coefficients of variation (CV) of the intensities were calculated using the technical duplicates. The detection rate for each marker was calculated based on the cutoffs specified by the manufactures. Spearman’s correlation coefficient (r) was used to quantify the agreement of the measurements of each marker between the two platforms. Wilcoxon signed-rank tests were used to compare CVs and detection rates between the platforms. Results: We observed significantly higher intra-experimental CVs in the Searchlight data (median=8.9%, range=4.9%-11.9%) than in the Luminex data (median=4.1%, range=2%-7.5%, p<0.0001). The CVs were not correlated between platforms (r=-0.08, p=0.69), suggesting that the CVs were not sample specific. We also observed a higher detection rate using the Searchlight platform (median=99%, range=26%-100%) than the Luminex platform (median=94%, range=18%-100%). However, the difference was not statistically significant (p=0.62). Spearman’s r for cytokine concentrations between platforms ranged from -0.13 to 0.86 (mean=0.44). The disagreement for 5 of the 6 cytokines with r<=0.1 can be explained by their standard curves. Conclusions: In this case study of 156 samples, Luminex platform demonstrated significantly better reproducibility measured by CV and the Searchlight platform appeared to be more sensitive measured by the detection rate and the overall range of the measurements. The agreement between the two platforms ranges widely among the markers. Careful examination of the standard curves is critical to interpretation of the cytokine data. Assays of the cytokines by single analyte ELISA is ongoing.
Identification of multifunctional cytotoxic T-cell subsets as immune correlates with clinical outcomes in a phase II study of AGS-003, an autologous dendritic cell-based therapy administered to patients with newly diagnosed, metastatic RCC.
Authors: DeBenedette Mark , Jurisica Igor , Gamble Alicia H. , Tcherepanova Irina Y. , Williams W. Lee , Plessinger Doug , Miesowicz Fred , Nicolette Charles A. 
Published: February 2017

80 Background: AGS-003 is an autologous dendritic cell (DC) immunotherapy prepared from matured monocyte-derived DC co-electroporated with the subject’s own amplified tumor RNA and synthetic CD40L RNA. The mechanism of action (MOA) of AGS-003 was evaluated in combination with sunitinib for treatment of advanced renal cell carcinoma (RCC) in AGS-003-006, an open label phase II trial including subjects with newly diagnosed, unfavorable-risk, metastatic clear cell RCC. The goal of the immune monitoring platform is to identify unique cytotoxic T-cell (CTL) signatures that correlate with clinical outcome in subjects receiving AGS-003 in combination with sunitinib. Methods: Multiparametric flow cytometry was used to identify tumor-reactive CTL subsets induced by AGS-003 based on combinatorial expression patterns of surface markers CD28, CD45RA, CD27 and CCR7. Moreover, further partitioning of each CTL subset identified combinatorial expression patterns of Markers of Immune Function (MIFs) defined as cytokines (IFN-γ TNF-α, IL-2), cytolytic markers (Granzyme b, CD107) and proliferation. Correlates of CTL signatures with clinical outcome were analyzed using an adaptation of a binary tree-structured vector quantization (BTSVQ) approach, originally developed to cluster and visualize large microarray data sets. The BTSVQ approach implements a two-way unsupervised clustering that allows a subject’s CTL signature to be mapped based on both surface marker and MIFs expression patterns to identify unique clustering patterns linked to clinical outcome. Results: Data analysis identified a unique CTL signature (CD28+/CCR7+/CD45RA- phenotype) displaying a broad MIFs profile as a statistically significant correlate to PFS and OS in patients treated with AGS-003. Conclusions: These results support the intended MOA of AGS-003 in vivo, as the induction of anti-tumor central and effector memory CTL responses. These data warrant further immunological evaluation of AGS-003 in the randomized phase III ADAPT study using AGS-003 in combination with standard treatment in RCC subjects.
Predictive value of preoperative peripheral lymphocyte count on recurrence of resectable non-small cell lung cancer.
Authors: Zhang Jian , Huang Shaohong , Li Hui , Chen Xiuling , Li Yun , Wang Cuiping , Gu Lijia 
Published: February 2017

81 Background: Recently, the prognostic value of cancer-related inflammatory response has been revealed. Previous studies showed that peripheral neutrophils and lymphocytes had significant impact on the prognosis of advanced and early node-negative non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of preoperative lymphocyte and neutrophil counts in patients with NSCLC who underwent radical surgery and adjuvant chemotherapy. Methods: Retrospective analyses were performed to examine the impact of preoperative peripheral lymphocyte and neutrophil counts on disease-free survival (DFS) and overall survival (OS) and to analyze the relationships of these factors to clinicopathological factors. Results: 142 patients with NSCLC were evaluated totally. 57 (40.1%) patients had local recurrence or metastasis. Multivariate analysesrevealed that peripheral lymphocyte count was an independent favorable prognostic factor of DFS (hazard ratio: 0.548; 95% confidence interval: 0.351-0.857; p=0.008) but not OS (p=0.164). The maximum log-rank statistical value was 9.504 (p=0.002) when the cutoff value of lymphocyte was 1800mm-3. The median DFS were 318.0 days (95% confidence interval: 226.0-410.0) for lymphocyte≤1800mm-3 group and 669.0 days (95% confidence interval: 0.0-1431.0) for lymphocyte>1800mm-3 group. Low lymphocyte count was related with lymphatic invasion (p=0.012) and recurrence of NSCLC (p=0.022). Peripheral neutrophil count had no impact on DFS or OS when analysis included all the 142 patients. In addition, T stage (p=0.001), N stage (p=0.001) and vascular invasion (p=0.021) were also independent unfavorable prognostic factors of DFS. Pathological stage (p=0.001), vascular invasion (p=0.011), and ECOG score (p=0.009) were independent unfavorable prognostic factor of OS. Conclusions: Preoperative peripheral lymphocyte count, which is related with lymphatic invasion, is an independent favorable prognostic factor of DFS in patients with NSCLC who underwent radical surgery and adjuvant chemotherapy.
Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector.
Authors: Gabitzsch Elizabeth Susan , Morse Michael , Hobeika Amy , Xu Younong , Balint Joseph , Balcaitis Stephanie , Lyerly H. Kim , Jones Frank R. 
Published: February 2017

85 Background: The major limitation for the use of Ad5 and other vectored vaccines is the inability to be effective in the presence of pre-existing or concomitant vector immunity. An Ad5-based vector with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), by virtue of diminished late phase viral protein expression, avoids immunological clearance and induces immune responses. Methods: The Ad5 [E1-, E2b-] platform encoding tumor associated antigen(s) (TAA) such as a modified carcinoembryonic antigen (CEA(6D)), HER2 and HPV E6/E7, were evaluated for the induction of TAA specific immune responses and anti-tumor effects in murine models. In a phase I/II clinical trial, cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2b-]-CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3 immunizations. CEA-specific cell mediated immunity was measured by ELISPOT. Results: In murine immunotherapy studies, mice implanted with tumors expressing TAA and subsequently treated with the Ad5 [E1-, E2b-] platform expressing that TAA had significant inhibition of tumor progression. Pre-vaccination against the TAA utilizing the Ad5 [E1-, E2b-]-TAA resulted in inhibition of tumor establishment. In a clinical trial, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities. Conclusions: The results demonstrate that the novel Ad5 [E1-, E2b-] gene delivery platform can both break tolerance and generate significant CMI responses to the TAA CEA in the setting of both naturally acquired Ad5-specific immunity and/or immunization-induced Ad5 immunity.
Circulating mediators of inflammation in AIDS-related non-Hodgkin lymphoma.
Authors: Nolen Brian Michael , Jenkins Frank J. , Kingsley Lawrence , Jacobson Lisa P. , Rinaldo Charles R. , Lokshin Anna 
Published: February 2017

86 Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries, accounting for 3-6% of AIDS-defining illnesses and 23-30% of AIDS-related mortality. The risk of developing NHL is estimated to be 60 times greater in HIV-infected individuals in comparison to the general population and this rate has remained elevated despite the advent of HAART. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male patients diagnosed with high-grade B-cell NHL. Controls were matched to each case from among those participants who developed an AIDS-defining opportunistic infection in the absence of any malignancy. Matching criteria included age and CD4+ cell count. Sera obtained from each patient near the time of NHL or AIDS diagnosis was tested for a panel of 171 serum biomarkers using multiplexed bead-based immunoassays. Biomarker measurements were evaluated to identify significant alterations between the experimental groups, correlations with disease progression and interactions between biomarkers. Results: A subset of 21 biomarkers was identified to be significantly altered in A-NHL cases in comparison to the AIDS controls. This subset included cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators. Many of the biomarkers included in this subset were positively correlated with disease progression. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in response to persistent immune stimulation and inflammation. A network of inflammatory mediators was identified demonstrating correlations with disease progression and overexpression in A-NHL patients. Further analysis of these biomarkers should enhance our ability to diagnose, monitor, and treat this disease.
Ki-67 expression in residual triple-negative breast tumors after neoadjuvant chemotherapy to predict for recurrence-free survival.
Authors: Pinto Joseph A. , Doimi Franco F. , Balko Justin M. , Arteaga Carlos L. , Gómez Henry L. 
Published: February 2017

89 Background: Ki-67 expression in breast cancer has been described as predictive of pathological complete response and prognostic of recurrence free survival (RFS). Our aim was to evaluate in a retrospective cohort of triple negative breast cancer patients if tumor proliferation measured by ki-67 expression is correlated with the outcome. Methods: We evaluated a retrospective cohort of 109 cases of triple negative breast cancer (ER-, PR- and HER2- determined by immunohistochemistry). Ki-67 labeling index was determined in Formalin-Fixed, Paraffin-Embedded residual tumors after neoadjuvant chemotherapy. Patients were stratified in Ki67<15% and Ki67≥15%. Clinicopathological data was retrieved from clinical records. RFS and overall survival (OS) were calculated using the Kaplan–Meier method and variables compared using the log-rank or Breslow test and Hazard Ratios (HR) estimated by the Cox regression. Results: The median age for patients was 47.5 years, 55 (50.5%) were premenopausal and 54 (49.5%) postmenopausal. Eight patients (7.3%) were clinical stages II and 101 (92.7%) stages III. Median of Ki-67 expression was 35.97% (0.96% - 77.7%). There was not association between Ki-67 expression (<15% VS ≥15%) with tumor size, nodal involvement, clinical stage and menopausal status. After a median of follow of 21.6 months, 62 patients (56.9%) have relapsed and 53 (48.6%) have die. The median time for RFS and OS were 21.2 and 31.4 months, respectively. Median of RFS was 12.6 months for Ki67<15% vs 21.2 months for Ki67≥15%, P=0.421 (HR=0.91). Median of OS was 34.9 months for Ki67<15% vs 31.4 months for Ki67≥15%, P=0.755 (HR=1.18). Only nodal involvement was found predictor of shorter RFS (0 nodes, 25.2 months vs 1 -3 nodes, 26.1 months, vs >3 nodes, 9.4 months, P=0.020). Conclusions: Ki-67 labeling index was not related with the outcome in terms of OS and RFS in patients with residual triple negative breast tumors that were treated with neoadjuvant chemotherapy.