tbuckley/cabot-search huggingface dataset:
E2F1 overexpression associated with TS and survivin gene expressions in non-small cell lung cancer
Authors: C. Huang, D. Liu, J. Nakano, S. Ishikawa, H. Yokomise, M. Ueno
Journal: Journal of Clinical Oncology (2007)

7669 Background: The thymidylate synthase (TS) expression is related to 5-FU sensitivity. The survivin expression is associated with tumor apoptosis, an indicator to predict the efficacy of chemotherapy. Recently, TS and Survivin have been reported to be E2F1 target genes. We investigate the clinical significance of the E2F1 gene expression in relation to gene expressions of TS and Survivin among non-small cell lung cancer (NSCLC). Methods: One hundred and twenty-seven NSCLC patients were investigated. Quantitative RT-PCR was performed to evaluate gene expressions of E2F1, TS, and survivin. The Ki-67 proliferation index and the apoptotic index using TUNEL method were also evaluated. Results: The E2F1 gene expression was significantly higher in stage II to III tumors than in stage I tumors (p=0.006). The E2F1 gene expression significantly correlated with the Ki-67 proliferation index (p&lt;0.001), while no correlation was observed between the E2F1 gene expression and the apoptotic index. Regarding E2F1-target genes, the E2F1 gene expression significantly correlated with the TS gene expression (p&lt;0.001). The E2F1 gene expression also significantly correlated with the survivin gene expression (p&lt;0.001). The TS expression and the survivin expression significantly correlated with the Ki-67 proliferation index (p&lt;0.001 and p&lt;0.001, respectively). There was a significant inverse relationship between the survivin expression and the apoptotic index (p&lt;0.001). The overall survival was significantly lower in patients with high-E2F1 tumors than in those with low-E2F1 tumors (p=0.002), especially among patients with stage II to III NSCLCs (p=0.018). The Cox regression analysis demonstrated that the E2F1 status was a significant prognostic factor for NSCLC patients (p=0.026). Conclusions: The present study revealed the E2F1 gene expression to correlate with TS and survivin gene expressions, and tumor proliferation. E2F1 overexpression could occur to produce more aggressive tumors with high proliferation rate and chemo-resistance during progression of NSCLCs. The suppression of E2F1 by RNA interference would be a useful strategy for cancer gene therapy. No significant financial relationships to disclose.
Comparison of four tumor response criteria (RECIST 1.0, tumor shrinkage, radiodensity, and Choi) in assessing outcome to VEGF-targeted therapy in advanced renal cell carcinoma.
Authors: K. M. Krajewski, D. Y. Heng, I. Pedrosa, N. H. Ramaiya, J. P. Jagannathan, A. D. Van Den Abbeele, M. B. Atkins, D. F. McDermott, F. A. Schutz, T. K. Choueiri
Journal: Journal of Clinical Oncology (2010)

4526 Background: Vascular endothelial growth factor (VEGF)-targeted therapy has become a standard for the treatment of patients (pts) with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and sometimes minimal tumor shrinkage (TS), RECIST response may not be optimal for predicting outcome. We evaluated whether TS, radiodensity changes (using Hounsfield Unit [HU] scale), and Choi criteria were more useful in predicting outcome than RECIST 1.0 in this setting. Methods: Seventy mRCC pts with 155 target lesions treated with VEGF-targeted agents had thoracic and abdominal CT scans performed at baseline and first follow-up (median of 2.6 months [mos]) following therapy. Tumor measurements were performed according to RECIST 1.0 (J Natl Cancer Inst 2000;92:205–16), Choi criteria (J Clin Oncol. 2007;25:1753-1759), TS of ≥ 10% decrease in sum of the longest unidimensional diameter (SLD), a mean of 15% or 20% decrease in HU. Correlation with progression- free survival (PFS) and overall survival (OS) were compared stratified by response to each of the radiologic criteria. Results: Tumor response was 11 partial response (PR) by RECIST 1.0, 49 PR based on Choi criteria, 31 pts with ≥ 10% decrease in the sum of longest diameters (SLD), 36 pts with ≥15% decrease in HU, and 32 pts with ≥20% decrease in HU. Only the threshold of 10% reduction in the SLD was statistically significant in predicting PFS and OS. Pts with SLD reduction of ≥ 10% versus those without had a median PFS of 10.3 mos vs. 5 mos and OS of 32 mos vs. 15 mos (p= 0.02 for PFS and 0.003 for OS). Choi criteria and radiodensity changes using 15% or 20% cutoffs in HU decrease were not significantly predictive of PFS and OS. RECIST 1.0 response was predictive of OS (p=0.01) but not PFS (p=0.5). Conclusions: A reduction of 10% in the SLD at the first follow-up CT scan is the best early predictor of outcome in mRCC pts receiving VEGF-targeted agents. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Agennix, AVEO, Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer Bayer/Onyx, Genentech, Pfizer
Can primary recurrences in surgical stage I-II uterine papillary serous carcinoma (UPSC) patients be salvaged?
Authors: A. Nickles Fader, P. G. Rose, H. Frasure, P. A. Gehrig, K. N. Moore, L. J. Havrilesky, W. K. Huh, A. E. Axtell, D. M. O'Malley, K. M. Zanotti
Journal: Journal of Clinical Oncology (2009)

e16503 Background: There is an absence of data in the literature on salvage rates for vaginal, pelvic, and extra-pelvic recurrences for early-stage UPSC patients (pts). The purpose of this study is to determine whether primary recurrences can be salvaged with chemotherapy or radiotherapy. Methods: A retrospective, multi-institution study of pts with stage I-II UPSC diagnosed from 1993–2006. All pts underwent comprehensive surgical staging. Postoperative treatment included either observation (OBS), radiotherapy (RT: brachytherapy, pelvic, abdominal or combo) or ≥ 3 cycles carboplatin/paclitaxel (CT) alone or with RT (CT+RT). Results: We identified 197 stage I-II pts; 44/197 (22.3%) experienced a primary recurrence during a median follow-up of 35 months. Patterns of recurrence analysis revealed that 17 (38.6%) were vaginal/pelvic (V/P) and 27 (61.4%) were extra-pelvic (EP). Multi-site relapses occurred in 13/44 (30%). Pts initially treated with adjuvant CT±RT (n = 108) had a significantly decreased risk of primary recurrence (9.9%) when compared to those patients treated with RT alone (n = 45; 37%) or OBS (n = 43; 35%; p &lt; 0.001). There were no distinguishing risk factors for development of V/P versus EP recurrence. Median time to recurrence after diagnosis was 16 months. The majority of pts (86%) were not salvaged by second line therapy, with a median time from recurrence to death of 8.9 months. However, more pts with isolated vaginal recurrences (5/12 or 42%) were salvaged when compared to those with pelvic or EP recurrences (1/32 or 3.1%; p = 0.004). The 5 pts who are NED after vaginal relapse were treated with CT±RT (n = 3) or RT (n = 2); 80% had not received prior treatment and 20% had received prior CT. To date, more pts with EP recurrence are dead of disease (23/27) than with V/P recurrences (7/17; p = 0.003). Conclusions: Stage I-II USPC pts are more likely to experience an extra-pelvic than vaginal/pelvic primary recurrence, are unlikely to be salvaged and will have a short interval from recurrence to death. The exception is in those with isolated vaginal recurrence, who may be salvaged in select cases. The current best strategy to avoid primary recurrences in this setting is an initial staging surgery followed by adjuvant carboplatin/paclitaxel. No significant financial relationships to disclose.
Surgical management of the primary tumor in stage IV colorectal cancer: A validation study.
Authors: Shahid Ahmed, Punam Pahwa, Selliah Kanthan, Anthony L.A. Fields, Duc Minh Le, Kamal Haider, Bruce Reeder, Osama Ahmed, Riaz Alvi, Nayyer Iqbal, Tahir Abbas, Adnan Zaidi, Florence Arnold, Sunil Yadav, Amer Sami, Anne Leis
Journal: Journal of Clinical Oncology (2015)

675 Background: The observational studies have demonstrated superior survival of patients with stage IV CRC who undergo surgical resection of the primary tumor (SRPT). Yet the results are not confirmed in the setting of a randomized controlled trial. Lack of randomization and failure to control the prognostic variables that affect survival including performance status (PS) are the major critiques to the findings of observational studies. Our group has demonstrated that SRPT improves survival of stage IV CRC patients, who were diagnosed between 1992-2005, independent of age and PS (Cancer. 2014;120:683). The current study is undertaken to validate our findings in patients who are treated with modern chemotherapy. Methods: A cohort of 569 patients with stage IV CRC diagnosed between 2006-2010 in Saskatchewan was evaluated. Cox regression model was used to adjust survival for important prognostic variables. Results: Median age was 69 years (59-95) and M:F was 1.4:1. 35% had ECOG PS of &gt;1. 313 (55%) patients underwent SRPT. Median followup time was 11 months (inter-quartile range 2-26). 57.3% received chemotherapy, 91.4% received FOLFIRI or FOLFOX and 67% received anti-EGFR inhibitors and or bevacizumab. Median overall survival (OS) of patients who had SPRT and received chemotherapy was 27 months compared with 14 months if they did not have surgery (p&lt;0.0001). Median OS of patients who received all active agents and had SPRT was 39 months (95% CI: 25.1-52.9). On multivariate analysis SRPT, hazard ratio (HR) for mortality of 0.44 (95% CI: 0.35-0.56), use of chemotherapy, HR 0.33 (95% CI: 0.26-0.43), metastasectomy, HR 0.43 (95% CI: 0.31-0.58), second line therapy, HR 0.50 (95% CI: 0.35-0.70), and third line therapy, HR 0.58 (95% CI: 0.41-0.83) were independently correlated with superior survival. Elevated alkaline phosphatase, (HR 1.50 (95% CI: 1.20-1.78), grade 3 tumor, HR 1.33 (95% CI: 1.10-1.62), leukocytosis, HR 1.32 (95% CI: 1.05-1.66), stage IVb disease, HR 1.31 (95% CI: 1.10-1.56), and ECOG PS&gt;1, HR 1.30 (95% CI: 1.04-1.57) were correlated with inferior survival. Conclusions: Our study supports SRPT in patients with stage IV CRC who are treated with modern combination of chemotherapy and biologics.
Correlation between product parameters and overall survival in three trials of sipuleucel-T, an autologous active cellular immunotherapy for the treatment of prostate cancer.
Authors: F. P. Stewart, C. P. dela Rosa, N. A. Sheikh, D. G. McNeel, M. W. Frohlich, D. L. Urdal, N. M. Provost
Journal: Journal of Clinical Oncology (2010)

4552 Background: Sipuleucel-T is an investigational autologous active cellular immunotherapy for treatment of metastatic castration-resistant prostate cancer (CRPC). It contains peripheral blood mononuclear cells including antigen-presenting cells (APCs), that have been incubated with a recombinant fusion protein, PA2024, comprising the antigen prostatic acid phosphatase (PAP) fused to GM-CSF. Three multicenter, randomized, double-blind, placebo-controlled trials provided evidence that sipuleucel-T prolongs overall survival (OS) in CRPC. Methods: The correlation between key product parameters and OS was assessed in patients who received ≥1 sipuleucel-T infusion (N=476) using a Cox regression model both unadjusted and adjusted for baseline prognostic variables (PSA [ln] and LDH [ln]), while stratifying by study. Parameters included CD54 upregulation, CD54+ cell count, and total nucleated cell (TNC) count. CD54 upregulation is the fold increase in the average number of CD54 molecules expressed on final product APCs. CD54 was chosen as a biologically relevant marker because of its role in the immunologic synapse between APCs and T cells, and because its increased expression correlates with APC activation. Experiments have demonstrated that CD54+ APCs take up the PA2024 antigen and present PAP epitopes to HLA-restricted PAP-specific T cell lines. The product variables analyzed represent the sum of values infused into each patient (up to 3 infusions). Results: A positive correlation (p < 0.05) was observed for each of the product parameters assessed as a continuous variable, in both the unadjusted and adjusted Cox models. Conclusions: There was a significant correlation between OS and each of the three cell product parameters, which appeared to be independent of baseline prognostic factors. These data support the conclusion that broad engagement of the immune system contributes to the sipuleucel-T survival findings. Cell product parameter P value Unadjusted (N=476) Adjusted for PSA and LDH (N=476) Cumulative TNC (x 109) < 0.001 < 0.001 Cumulative CD54+ cell count (x 109) 0.016 0.005 Cumulative CD54 upregulation 0.002 0.041 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dendreon Dendreon Dendreon Dendreon
Neoadjuvant GM-CSF and thalidomide in men with high-risk prostate carcinoma undergoing radical prostatectomy
Authors: J. A. Garcia, C. Magi-Galluzzi, J. Rothaermel, P. Elson, M. Zhou, E. Klein, R. Dreicer
Journal: Journal of Clinical Oncology (2006)

4564 Background: Granulocyte macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DC’s) and promotes uptake of tumor antigens by DC’s leading to T cell cross-priming. Thalidomide is an anti-inflammatory agent with immunomodulatory and antiangiogenic activity. Administration of GM-CSF and Thalidomide can induce PSA responses in 20–25% of patients (pts) with Hormone-Refractory Prostate Cancer (HRPC). In an effort to further evaluate this novel combination we conducted a phase II trial in pts with locally advanced PCA. Methods: High-risk PCA pts undergoing radical prostatectomy (RP) were eligible. ECOG 0–1, adequate organ function, and no prior hormonal therapy were required. All pts received GM-CSF at 250 μg administered SC three times weekly. Thalidomide was escalated to reach the study dose of 200 mg/day. Patients were assessed every 4 weeks with therapy continuing to a maximum of 8 weeks. The primary endpoints were pathologic response, rate of PSA decline and toxicity. High-throughput tissue microarrays (TMAs) were also used to assess exploratory tissue endpoints including tumor expression of PTEN, CD3, Ki-67, and CD68 by immunohistochemistry. Results: To date 22 of a total planned of 29 pts are enrolled. Median age is 59 (43–72), median PSA of 10.4 (3.6–64.8). Baseline Gleason Scores (9 pts-GS7, 10 pts-GS8, and 3 pts GS9). 19/22 pts received all 8 weeks of therapy. Three pts discontinued therapy early due to toxicity or drug intolerance. A maximum PSA decline of 15–55% was observed in 86% of pts. Grade (G) 1–2 toxicities included dizziness/paresthesias (68%), constipation (64%), injection site reactions (64%) and fatigue (50%). Only one pt developed G3 toxicity (DVT). Tumor tissue expression of PTEN, Ki-67, CD3 and CD68 was significantly higher in treated pts when compared with matched controls (PTEN p = 0.03, Ki-67 p = 0.004, CD3 p &lt; 0.001, and CD68 p &lt; 0.001). Conclusions: Neoadjuvant therapy with GM-CSF and Thalidomide is well tolerated, and does not appear to impact on the perioperative morbidity of RP. This combination therapy appears to induce overexpression of PTEN, Ki-67, CD3 and CD68 in PCA tissue. Ongoing tissue and serum immune studies are underway to better define the significance of these tissue findings. [Table: see text]
Palliative care (PC) education for medical students: An unresolved need
Authors: R. A. Sala, K. Zanini, S. Juarez, C. Rapelli, A. Pendido, A. Aronna, L. E. Fein
Journal: Journal of Clinical Oncology (2009)

e20704 Background: Chapters contained in subjects other than PC lack the specificity and the integration of concepts to impact quality of care. Since 2005 an elective subject is part of the undergraduate curriculum of the medical school of the UNR. Teaching is case based in large groups with elective rotations to an acute care hospital PC team. Methods: To evaluate if this subject, as it is outlined, produces sensitization about PC, results of initial surveys (IS) (358) and final surveys (FS) (292) performed each year were compared and changes over time evaluated. Summary measures were calculated and hypothesis tests were done. Results: Students average age: 23 years. Female sex: 75.8%. Global answer rate of IS: 86.77% (range: 76.2% to 96%) and of FS: 76.65% (range: 68% to 85.9%). Composition of courses according to year of study. Quantity of IS and FS/ year. Differences in identification of the objectives of PC between IS and FS was statistically significant (p = 0.002) only in 2005. In 2006 (p = 0.195), 2007 (p = 0.318), and 2008 (p = 0.10) there was not statistical significance. Average 97.3% (range: 93% to 100%) of students considered the contents of the subject will impact in their practice and 95,75% (range: 91.5% to 98.5%) found them useful. 87% (range: 87.3% to 94.1%) positively changed their vision of interdisciplinary team work. Conclusions: Few students have a correct knowledge of PC at the beginning of the course; this knowledge is increased at the end of each course without reaching statistical significance except in 2005 (p = 0.002), when all the students were in the third year of study. [Table: see text] No significant financial relationships to disclose.
Cost containment in oncology: A single-centre model for drug waste reduction
Authors: M. Aita, G. Aprile, A. Follador, M. Mansutti, L. Marini, L. Mattioni, M. Tosolini, G. Fasola
Journal: Journal of Clinical Oncology (2007)

6557 Background: To control costs while maintaining or improving the quality of patient care is challenging for physicians and health care managers. The problem has become critical in oncology, due to the increasing number of cancer cases and the recent availability of new drugs, with a dramatic rise in health care expenditure. Here we report the experience of our Medical Oncology Department, where centralization of chemotherapy (CT) manufacturing and development of a computerized physician order-entry (CPOE) system allowed an effective planning of CT services with a substantial waste minimization and a significant cost saving. Methods: Starting January 2005 we collected data about drug demand, real consuming and resulting wastes and quantified the economic value of drug leftovers. Finally, based on a web literature search and a survey among other Cancer Services, an internal protocol for waste limitation was developed. Main adopted measures were: 1) a rational, per pathology distribution of CT sessions over the week, allowing waste recovery while respecting drug stability; 2) the use of multi-dose vials, that maintain microbial and chemical stability for up to 28 days; 3) a reasonable dose rounding, to fit with available vial sizes/leftovers; 4) the selection of the most convenient vial size when more options are available. Results: The baseline analysis focused on 29 drugs over a 1-year period. Considering their price per milligram and the amount of wastes, we found that 74% of the expense was attributable to six compounds only (cetuximab, docetaxel, gemcitabine, oxaliplatin, pemetrexed and trastuzumab) and that the economic loss due to their waste equaled 4.5% of the annual drug expenditure. Following the application of the above listed measures, the monetary loss due to unused drugs showed an impressive 45% reduction throughout 2006. Conclusions: Our experience may represent an accessible model in addressing the issue of cost rising in oncology. A critical evaluation and planning of CT daily workload, provided by CPOE, and a multidisciplinary effort to pursue specific waste reduction strategies produce a relevant cost saving. No significant financial relationships to disclose.
Differences in treatment in stage III breast cancer in African American women
Authors: M. Rizzo, N. Reisman, S. G. Gabram, H. L. Bumpers, J. Okoli, O. W. Brawley, M. Lund
Journal: Journal of Clinical Oncology (2007)

504 Background: Stage III breast carcinomas account for about 6–7% of all invasive breast cancers diagnosed annually in the US. Locally advanced breast cancer (Stage IIIA) and inflammatory breast cancer (Stage IIIB T4d) are now recognized as two distinct clinical pathologic entities, characterized by different prognostic factors profiles. The aim of this study was to compare differences in treatment in women with Stage III breast cancer in an inner city Cancer Center serving a large African American population. Methods: Retrospective review was performed on all Stage III primary breast cancers diagnosed and or treated from 2000 to 2005. Results: Of the 684 primary invasive breast cancers, 96 (14%) were Stage III (45 were Stage IIIA, 33 were Stage IIIB and 12 were inflammatory breast cancer) and 83 of the 96 (86%) were among African American women. The 6 Stage IIIC cases were excluded from analyses. To all patients was offered a combination of chemotherapy, surgery and radiation therapy. All patients with primary or residual tumors ≥ 5 cm or ≥ 3 positive axillary nodes were considered for chest wall and axillary radiation therapy; 48 of 74 received radiotherapy. Stage IIIA patients were less likely to receive neoadjuvant chemotherapy and were more likely to have ≥ 3 positive axillary nodes. Nineteen patients refused chemotherapy. The table summarizes our findings. Conclusions: In this predominantly African American female population, Stage III breast cancers were about twice as prevalent as observed nationally and a high number of these Stage III patients refused adjuvant and neoadjuvant chemotherapy. The benefit of chemotherapy and radiotherapy in improving prognosis for Stage III breast cancers is well established. Thus, reasons for refusal of chemotherapy and lack of radiotherapy need further investigation. [Table: see text] No significant financial relationships to disclose.
Elevated levels of thioredoxin (Trx) in serum correlate with poor outcome in docetaxel (doc)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: M. Molina, C. Camps, R. de las Peñas, G. Alonso, G. Lopez-Vivanco, M. Provencio, J. Gonzalez-Larriba, F. Salazar, J. Sanchez, R. Rosell
Journal: Journal of Clinical Oncology (2007)

7628 Background: Chemotherapy causes the production of reactive oxygen species (ROS), which facilitates cancer cell death. Trx protein functions as a ROS scavenger and a negative regulator of apoptosis signal regulating kinase-1 (ASK-1). High levels of Trx are associated with chemoresistance. 14–3-3s proteins are involved in cell cycle control and protein trafficking. Methods: Trx ELISA and 14- 3–3s methylation-specific PCR were performed in baseline serum from 107 stage IV NSCLC p treated with doc/cis. Results: Median age, 60 (range, 32–79); male, 87 (81.3%). PS: 0, 27 (25.2%); 1, 80 (74.8%). Adenocarcinoma, 46 (43.8%); squamous cell carcinoma, 40 (38.1%); 21 p had large cell or unspecified histology. Complete response, 1 p; partial response, 20 p; overall response rate, 20%. Median Trx level, 97.4 (range, 18.8–763.1). Serum was available for 14–3-3s methylation analysis in only 88 p. 14–3-3s was methylated in 43 p (48.9%). A significant correlation was observed between 14–3-3s methylation status and Trx levels ( Table ). 4 p with methylated and 17 with unmethylated 14–3-3s had Trx levels &gt;182.8 (P=0.003). Median Trx levels were 103.5 in responders and 94.3 in non-responders (P=0.96). Time to progression (TTP) was 5.6 months (m) for 27 p with Trx &lt;49.6, 4.4 m for 53 p with Trx 49.6–182.8, and 3.8 m for 27 p with Trx &gt;182.8 (P=0.02). In a Cox multivariate analysis, Trx levels emerged as an independent variable for TTP when 14–3-3s was included in the model. Hazard ratios: 1.3 for PS1 (P=0.84); 1.05 for 14–3-3s unmethylated (P=0.22); 1.4 for Trx 49.6–182.8 and 1.95 for Trx &gt;182.8 (P=0.04). Conclusions: Serum Trx levels can predict TTP in doc/cis-treated p. The additional role of 14–3-3s methylation may be more clearly demonstrated in cis/gemcitabine regimens. No significant financial relationships to disclose. [Table: see text]