tbuckley/cabot-search huggingface dataset:
Use of progression-free survival (PFS) to predict overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).
Authors: S. Halabi, B. I. Rini, W. M. Stadler, E. J. Small
Journal: Journal of Clinical Oncology (2010)

4525 Background: PFS has been used as a clinical trial endpoint evaluating the efficacy of novel agents in mRCC, and has led to the approval by the FDA of VEGF targeted therapeutics. This approach is attractive as a major challenge in designing trials in mRCC has been the attenuation of potential impact on survival by second line and beyond therapies with emerging active agents. A data set from a prospective randomized phase III trial was analyzed to assess whether progression-free survival (PFS) can be used as a predictor of overall survival (OS) and to investigate the dependence between PFS and OS in patients with mRCC. Methods: Data from CALGB 90206, which enrolled 732 patients in a randomized phase III trial of interferon alpha vs. interferon alpha/bevacizumab, were analyzed. Patients were eligible if they had metastatic RCC, a clear cell histologic component, no prior systemic therapy for RCC, Karnofsky performance status of ≥ 70%, adequate bone marrow, hepatic, cardiac and renal function, blood pressure controlled to < 160/90 mmHg and lack of central nervous system metastases. Landmark analyses of PFS at 3 and 6 months from randomization were performed to minimize lead time bias. The log rank test and the proportional hazards model were used to assess the significance effect of PFS at 3 and at 6 months in predicting OS. The association between OS and PFS was investigated using Kendall's tau. Results: The median survival time among patients who experienced progression at 3 months was 6.0 months (95% CI = 5.3-6.9) compared to 25.2 months in patients who did not progress at 3-months (95% CI=22.2 – 28.5), log-rank p-value <0.0001). Compared to patients who did not progress at 3 and at 6 months, the adjusted hazard ratios for death were 2.6 (95% CI=2.1 – 3.1, p-value <0.001) and 2.9 (95% CI=2.4 – 3.5, p-value<0.001) for men who progressed at 3 and 6-months, respectively. The association between PFS and OS was 0.52 (95% confidence limits=0.48-0.55). Conclusions: Although PFS at 3 and at 6 months predict OS in patients with mRCC, the association was modest. PFS is not an optimal intermediate endpoint. These observations require prospective validation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Determining the frequency of quality of life (QL) assessment in chemotherapy treatment: Using the LCSS-Meso in the randomized pemetrexed + cisplatin (C) trial in 448 patients with mesothelioma (MPM) as an example
Authors: P. J. Hollen, R. J. Gralla, J. T. Symanowski, A. M. Liepa, G. A. Bizette
Journal: Journal of Clinical Oncology (2004)

8125 Background: Accurate and practical assessment of QL in trials and patient (pt) management are important goals. It should be sensitive to detect relevant changes but not produce excessive burden for pts or staff. This analysis provides a rational basis for the frequency of repeating QL assessment. Methods: Pts were randomized to pemetrexed (P)+ C vs C only (all given q 3 wks). Results demonstrated survival (p=0.02), tumor response (p<0.001, Vogelzang JCO 2003) and QL advantages (p=0.01, Gralla ASCO 2003) for P+C. Pts were prospectively evaluated with the LCSS-Meso, a validated QL instrument, at baseline and weekly while on study. 90% of expected assessments were completed. This analysis evaluates 3 outcomes: total score (mean of all 8 items), average symptom burden index (mean of 5 symptoms), and global QL. Results from weekly assessment for each outcome and for each study arm (P+C or C) were considered as an idealized standard. Area (score × time) was calculated for each interval up to 18 wks; areas were then summed. Goal was to determine whether less frequent assessment would retain similar results to weekly evaluation with lower 95% CI still exceeding 85% (minimal adequacy recommendation, Simon & Wittes Cancer Treat Rep 1985). Results: Results indicate that each assessment period retains >90% of weekly scoring; however, only every 3 wk evaluation exceeds the minimally acceptable CI level. Only 3 wk assessment showed significant between arm differences similar to the weekly interval. Conclusions: Every 3 wk evaluation of QL provides results similar to more burdensome wkly assessment in pts with MPM. A prior analysis in a NSCLC sample yielded the same recommendation (Gralla ASCO 1999), suggesting that every 3 wk evaluation is appropriate in many malignancies with similar clinical characteristics. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co.
SAT0270 Backfill is a Specific Sign of Axial Spondyloarthritis Seen on MRI
Authors: Z. Hu, Q. Lv, J. Qi, Z. Lin, M. Yang, Z. Liao, J. Gu
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Backfill (BF) is a specific sign seen on magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS). BF is considered to be a key intermediary in the development of ankylosis in patients with AS. But the research on BF is rare. <h3>Objectives</h3> To summarize the characteristics of BF in axial Spondyloarthritis (SpA) patients and patients with non-specific back pain (NSBP) and healthy controls, and to assess the value of BF in diagnose axial SpA. <h3>Methods</h3> Three readers blinded recorded BF seen on T1SE MRI scans from 647 subjects: 297 patients with AS, 126 patients with non-radiographic axial SpA (nr-axSpA), 147 patients with NSBP, and 77 healthy controls. The SPARCC SIJ Structural Score (SSS) method was used to assess BF. The changes of BF were evaluated by the follow-up MRI scans from 157 patients. We summarized the characteristics of BF and calculated its sensitivity and specificity for diagnosing axial SpA. <h3>Results</h3> BF was recorded in 78.8% AS patients, 11.1%nr-axSpA patients, 1.8% patients with NSBP, and no healthy control. BF affected more frequently at ilium bone, lower half of sacroiliac joints in axial SpA (both p&lt;0.05), but not in patients with NSBP. The SSS score of BF was much higher in axial SpA than in patients with NSBP (both p&lt;0.01) and it did not correlate with demographics and BASDAI, BASFI, and CRP (all p&gt;0.05). BF score only positively correlated with symptom duration in AS (r=0.251, p&lt;0.01) and in nr-axSpA (r=0.743, p&lt;0.01) patients. Only 8.9% patients had the change of BF in an average follow-up time of 1.09 years. BF had high specificity (0.98) and moderate sensitivity (0.59) for diagnosing axial SpA. <h3>Conclusions</h3> We summarized the characteristics of BF and found that BF is a specific sign of axial SpA seen on MRI. <h3>References</h3> Chiowchanwisawakit P, Lambert RGW, Conner-Spady B, et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011;63:2215-25. Maksymowych WP, Wichuk S, Chiowchanwisawakit P, et al. Fat Metaplasia and Backfill are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients with Ankylosing Spondylitis. Arthritis Rheumatol 2014;66(11):2958-67. <h3>Disclosure of Interest</h3> None declared
Radiologic detection of bone metastasis in patients with hepatocellular carcinoma: A single-center experience
Authors: E. Farrand, L. Ferrante, R. B. Staron, R. S. Brown, A. B. Siegel
Journal: Journal of Clinical Oncology (2009)

e15644 Background: We investigated current practices and their relative abilities to effectively screen for and detect bone metastases (mets). It is unknown what percentage of HCC bone mets are blastic versus lytic, and what imaging modality best identifies them. Methods: We retrospectively assessed all adults diagnosed with HCC at our center from 1/1997 - 8/2008. Primary outcomes were the percentage of lytic lesions, and the sensitivity and specificity of bone scans in detecting bone mets. Results: 462 patients were included. Mean age at diagnosis was 60 years; 80% were male, and hepatitis C was the most common etiology of HCC (58%). 54% of all patients received bone scans. 67% were considered diagnostic, whereas the remaining scans required a confirmatory test(s) (23% PET, 41% plain X-ray, 54% CT, and 10% MRI). 5% of all patients were diagnosed with bone mets (n=24), of which 42% were diagnosed at presentation, 20% during continued follow-up, and 38% during post-operative surveillance. 96% of all bone lesions were lytic, of which 13% were undetected by bone scan (sensitivity = 79%, specificity = 98%). None of the lesions were blastic and 4% remained indeterminate after independent review with an attending bone radiologist. Of those patients who underwent resection or liver transplantation (n=205) 35 patients recurred (31% with bone recurrence and 6% with bone mets as their only site of disease). Within this surgical group, patients with bone mets only had higher 1,3,and 5 year survival rates compared to patients with other extrahepatic lesions, although only significant for 3 year survival (p=0.013). 4 of the 24 patients with bone mets received a biopsy. All 4 confirmed metastatic HCC. Conclusions: Due to the high specificity, bone scans serve as a good initial screening test to rule out bone mets in the HCC population. However in populations at higher risk of presenting with bone mets (post-tranplantation/resection) a more sensitive test may be needed. Additional studies are warranted to determine whether other modalities, such as PET/CT or skeletal survey, are more sensitive tests for the detection of bone mets. No significant financial relationships to disclose.
Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa)
Authors: Alvaro Perdomo-Sabogal, Katja Nowick, Ilaria Piccini, Ralf Sudbrak, Hans Lehrach, Marie-Laure Yaspo, Hans-Jörg Warnatz, Robert Querfurth
Journal: Molecular Biology and Evolution (2016)

A substantial fraction of phenotypic differences between closely related species are likely caused by differences in gene regulation. While this has already been postulated over 30 years ago, only few examples of evolutionary changes in gene regulation have been verified. Here, we identified and investigated binding sites of the transcription factor GA-binding protein alpha (GABPa) aiming to discover cis-regulatory adaptations on the human lineage. By performing chromatin immunoprecipitation-sequencing experiments in a human cell line, we found 11,619 putative GABPa binding sites. Through sequence comparisons of the human GABPa binding regions with orthologous sequences from 34 mammals, we identified substitutions that have resulted in 224 putative human-specific GABPa binding sites. To experimentally assess the transcriptional impact of those substitutions, we selected four promoters for promoter-reporter gene assays using human and African green monkey cells. We compared the activities of wild-type promoters to mutated forms, where we have introduced one or more substitutions to mimic the ancestral state devoid of the GABPa consensus binding sequence. Similarly, we introduced the human-specific substitutions into chimpanzee and macaque promoter backgrounds. Our results demonstrate that the identified substitutions are functional, both in human and nonhuman promoters. In addition, we performed GABPa knock-down experiments and found 1,215 genes as strong candidates for primary targets. Further analyses of our data sets link GABPa to cognitive disorders, diabetes, KRAB zinc finger (KRAB-ZNF), and human-specific genes. Thus, we propose that differences in GABPa binding sites played important roles in the evolution of human-specific phenotypes.
Detection of aberrant <i>SHP-1</i> promoter methylation, an implication in advanced non-small cell lung cancer.
Authors: C. Vinayanuwattikun, V. Sriuranpong, A. Mutirangura
Journal: Journal of Clinical Oncology (2010)

10627 Background: Epigenetic modification at the promoter-2 region of SHP-1 or PTPN6, a non-receptor protein tyrosine phosphatase gene, may implicate in regulation of epithelial cell and tissue-specific gene expression. Previous study has shown 100% methylation of the promoter-2 in several epithelial cancer cell lines in sharp contrast with the null methylation status in hematopoietic cells. We hypothesize that SHP-1 promoter-2 methylation may serve as a potential plasma biomarker for epithelial cancer detection and risk assessment. Methods: We prospectively collected plasma of pretreatment 38 advanced non-small cell lung cancer (NSCLC) patients and 51 age and sex matched healthy volunteers. In second cohort, we chose to evaluate methylation status of SHP-1 promoter-2 in 58 NSCLC patients in correlation to several clinical parameters. The quantitative real-time PCR with dual hybridization probes were used to assess SHP-1 promoter-2 methylation status. Results: Level of SHP-1 promoter-2 methylation was significantly elevated in lung cancer patient comparing to those of age and sex matched healthy volunteers with median 0.0042 ngmL-1 (0-26.5) in cancer group and 0 ngmL-1 (0-0.21) in control group (p < 0.01). Level of SHP-1 promoter-2 methylation at 0.035 ngmL-1 has 89% sensitivity and 91% specificity to distinguish lung cancer patients from healthy volunteers. Calculated area under the receiver operating characteristic curve (AUC-ROC) showed value at 0.93. Level of promoter-2 methylation < 0.8 ngmL-1 correlated with patients who had favourable prognosis with better median PFS (5.2 vs 2.6 months, p-value = 0.006) and better median overall survival (over 11.7 vs 7.6 months, p-value = 0.003). The multivariate Cox proportional-hazards regression showed that SHP-1 promoter-2 methylation was the most significant predictors for progression-free and overall survival. Conclusions: Measuring level of epithelial specific gene SHP-1 promoter-2 methylation in plasma has a promising accuracy in non invasive diagnosis and management for lung cancer patients. No significant financial relationships to disclose.
Vascular endothelial growth factor and matrix metalloprotease in lymphomatous meningitis
Authors: E. T. Wong, M. Yu, S. Song, S. Jeyapalan, M. Groves, K. D. Swanson, S. Gautam
Journal: Journal of Clinical Oncology (2008)

2031 Background: Because vascular endothelial growth factor (VEGF) and matrix metallproteases (MMPs) promote tumor angiogenesis, we determine whether cerebrospinal fluid (CSF) levels of VEGF165 and MMPs correlated with cytology in lymphomatous meningitis. Methods: One hundred twenty-two CSF samples were obtained from 42 patients with suspected lymphomatous meningitis. These samples were analyzed using enzyme-linked immunosorbent assay (ELSIA) for VEGF165, MMP-9, and MMP-2, as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) zymography for MMP-9, activated MMP-9, MMP- 2, and activated MMP-2. Results: Samples with positive cytologies had a median white blood cell count of 11 cells/μL versus 1 cell/μL for those with negative cytologies (P=0.09). Using ELISA, we detected a median VEGF165 level of 4.72 pg/mL for positive and 1.02 pg/mL for negative CSF cytologies (P=0.009). While the normalized median MMP-9 levels by ELISA were not significant, 1.01 for positive versus 1.01 for negative CSF cytology (P=0.42), MMP-9 activity assayed by zymography was significant. Mean MMP-9 levels were significantly higher in CSF samples with atypical cytology as compared to negative cytology, 89.35 versus 2.52 (P=0.0175), and when both positive and atypical cytologies were combined as compared to negative cytology, 49.74 versus 2.52 (p=0.180). There was no significant correlation between CSF cytology and activated MMP-9, MMP-2, activated MMP-2, total protein, or glucose. Conclusions: CSF VEGF165 level and MMP-9 activity correlated with lymphomatous meningitis. Our MMP-9 ELISA did not detect a correlation due to poor sensitivity, but our SDS-PAGE zymography did. Both VEGF165 and MMP-9 may be components of the angiogenesis pathway in lymphoma meningitis. No significant financial relationships to disclose.
Comprehensive analysis of expression patterns of insulin-like growth factor and Src pathway in patients with non-small cell lung cancer: Two large, independent series of tissue microarray.
Authors: J. Kim, E. S. Kim, D. Liu, J. Lee, L. Solis, P. Yuan, C. Behrens, W. K. Hong, I. I. Wistuba, H. Lee
Journal: Journal of Clinical Oncology (2010)

10531 Background: IGF-1R and Src-family kinase (SFK) signaling pathways have been implicated in non-small cell lung cancer (NSCLC) and suggested to cooperate for enhanced tumor activities. Here we assessed the potential prognostic roles of the activation status of IGF-1R and Src pathways in patients with NSCLC. Methods: Expressions of the IGF-1R signaling axis, including phospho-IGF-1R/IR (pIGF-1R/IR), IGF- 1, IGF-2, IGF-1R and phospho-Src (pSrc) were evaluated in tissue microarrays of NSCLC from two independent databases (N=352, and 458, respectively). The expression levels of these biomarkers were correlated with clinicopathologic characteristics and patient survival. Univariate and multivariate analyses were performed to assess whether the expression levels of these biomarkers were independent prognostic factors. Results: pIGF-1R/IR (p=.037), IGF-1R (p<.0001), IGF-2 (p<.0001), and pSrc (p<.0001) expressions were significantly associated with squamous cell carcinoma (SCC), while IGF-1 (p<.0001) expression was significantly correlated with adenocarcinoma (ADC). pIGF-1R/IR (p=.009) and pSrc (p=.005) were positively correlated with smoking history. The expression of pSrc serves as a predictor of poor survival in these patients by multivariate analysis. Conclusions: Our data suggest that: 1) IGF-1R and Src are highly activated in patients with NSCLC, especially those with SCC or smoking history, and should be investigated as therapeutic targets in NSCLC patients; and 2) Src activity may counteract the antitumor action of targeting agents against IGF-1R, providing the rationale to integrate Src-targeting agents in treatment regimens with IGF-1R inhibitors for NSCLC patients. NIH grants R01 CA109520 and CA100816 (H-Y. Lee), and in part by DOD grant W81XWH-04-1-0142-01-VITAL (W.K. Hong). No significant financial relationships to disclose.
Serum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical cancer
Authors: A. Mitsuhashi, K. Suzuka, K. Yamazawa, H. Matsui, K. Seki, S. Sekiya
Journal: Journal of Clinical Oncology (2005)

5075 Background: Vascular endothelial growth factor (VEGF) and VEGF-C play a crucial role in the regulation of tumor growth and metastasis. This study examined the significance of serum VEGF and VEGF-C levels in relation to the conventional clinicopathologic parameters, response to treatment and survival in patients with cervical cancer. Methods: Between December 1999 and March 2004, serum VEGF and VEGF-C levels were analyzed in 78 patients with cervical cancer undergoing primary treatment (primary surgery 40; radiotherapy 38), as well as in 30 healthy controls. Serum VEGF and VEGF-C levels were assessed by enzyme-linked immunosorbent assay before treatment and within 2 weeks after treatment. Results: Serum VEGF and VEGF-C levels were higher in patients with cervical cancer than in the healthy control (p=0.0002 and p=0.0007, respectively). Both VEGF and VEGF-C concentrations were significantly raised in patients with squamous cell carcinoma (vs. normal control: p<0.0001 and p=0.0001, respectively), but not in adenocarcinoma (vs. normal control: p=0.2982 and p=0.7766, respectively). In an analysis of squamous cell carcinoma, the pretherapeutic serum levels of VEGF and VEGF-C were significantly correlated with advanced FIGO stage and large tumor size, but not with lymph node metastasis. The pretherapeutic serum level of VEGF-C was also significantly correlated with recurrence or persistence after treatment. Both serum VEGF and VEGF-C levels were significantly decreased after treatment. Conclusions: The serum levels of both VEGF and VEGF-C have potential usefulness as biological markers of squamous cell carcinoma of the uterine cervix. No significant financial relationships to disclose.
Alterations in Fibrinogen, Plasminogen, and Inhibitors of Plasmin With the Growth of V2 Carcinoma in Rabbits2
Authors: Gerda Mootse, Domenico Agostino, Eugene E. Cliffton
Journal: JNCI Journal of the National Cancer Institute (1965)

Growth of a transplanted V2 carcinoma in rabbits was accompanied by an increase of fibrinogen, plasminogen, and plasma inhibitor concentrations in the blood. These changes became significant at 2 to 3 weeks after transplantation. They appeared to be related to growth of the tumor.
Early identification of trastuzumab-related cardiotoxicity with speckle-tracking echocardiography.
Authors: N. Maurea, C. De Lorenzo, C. Coppola, G. Ragone, E. Di Pietro, G. Schiattarella, A. Barbieri, G. Palma, C. Arra, R. V. Iaffaioli
Journal: Journal of Clinical Oncology (2010)

e11096 Background: New targeted therapies have improved the prognosis of patients with breast cancer but cause several off-target effects, such as left ventricular dysfunction and heart failure that has still a 5-years mortality of 50%. Adjuvant treatment of breast cancer consists of combination chemotherapy with anthracyclines (A) and, in women with ErbB2 over-expressing disease, trastuzumab (T). A can cause an irreversible left ventricular dysfunction, named type I cardiomyopathy. T causes can cause left ventricular systolic dysfunction between 3% and 18%, and heart failure between 2% and 4%, but these are reversible and there seems to be no apparent ultrastructural changes (II type cardiomyopathy). Methods for measuring cardiac function in M-mode with shortening fraction (FA) and in B-mode with ejection fraction are not very sensitive in detecting early myocardial damage. The aim of this study was to evaluate if myocardial strain by speckle tracking technique (ST) was able to identify early left ventricular dysfunction in mice treated with doxorubicin (D) and T, alone or in combination (D+T). Methods: We measured radial myocardial strain (%) with ST and FA by assessing M-mode short axis projection in C57BL/6 mice at time 0, 2 and 6 days of daily administration of D (2.17 μg/g/day), T (2.25 μg/g/day), D + T (2.17 μg/g/day + 2.25 μg/g/day, respectively), and in a control group. Results: The second day we found a significant reduction of radial strain in the group D (p = 0.003), T (p = 0.03) and D+T (p = 0.003). The FA was reduced significantly on day 2 only in group D (p < 0.001) and D+T (p = 0.001), whereas in group T was normal, and decreased only at day 6 (p = 0.001). Conclusions: With myocardial strain obtained with ST technique it is possible to identify left ventricular systolic dysfunction early, before conventional echocardiography. The reason why this was found only in T group probably lies in the fact that T does not cause myocardial necrosis, in contrast to A, but reversible alterations (harder to detect early with the reduced FA). These studies will be extended to patients, to evaluate the clinical impact of early identification of T-related cardiotoxicity in the treatment of women affected by breast cancer. No significant financial relationships to disclose.