tbuckley/cabot-search huggingface dataset:
Decline in serum soluble E-cadherin and low baseline matrix metalloproteinase-9 are associated with response to combination celecoxib and erlotinib therapy in advanced non-small cell lung cancer
Authors: K. L. Reckamp, B. K. Gardner, R. A. Figlin, D. Elashoff, K. Krysan, M. Dohadwala, L. Inge, A. Rajasekaran, S. M. Dubinett
Journal: Journal of Clinical Oncology (2007)

7640 Background: Cyclooxygenase-2 (COX-2) overexpression may mediate resistance to EGFR TK inhibition through prostaglandin E2 (PGE2)-dependent promotion of epithelial to mesenchymal transition (EMT). Thomson, et al. reported that the suppression of epithelial markers such as E-cadherin led to resistance to erlotinib (Cancer Res 2005;65:9455). In addition, PGE2 downregulates E-cadherin expression by upregulating transcriptional repressors including ZEB1 and Snail, as described by Dohadwala et al (Cancer Res 2006;66:5338). These findings suggest that COX-2 inhibition may enhance the efficacy of EGFR TKI therapy in NSCLC. Methods: A phase I, dose escalation trial to was performed investigating the combination of celecoxib and erlotinib in pts with advanced NSCLC. Soluble E-cadherin (sEC) was evaluated by ELISA in pt serum at baseline and weeks 4 and 8 of treatment. Other markers of COX-2 gene expression were evaluated by ELISA, including matrix metalloproteinase (MMP)-9, MMP-2 and tissue inhibitor of MMP (TIMP1). Results: 22 pts were enrolled and 21 were evaluable for the determination of the optimal dose, toxicity assessment and response (reported in Clin Cancer Res 2006;12:3381). Here we report serum sEC and MMP-9 levels, which were analyzed according to best response (PR, SD or PD) in 21 pts. SEC was analyzed according to best response (PR, SD or PD). We found a significant decrease in sEC between baseline and week 8 in pts with PR when compared to those with SD or PD (p = 0.021). In pts who responded to the combination therapy, baseline MMP-9 was significantly lower compared to non-responders (p = 0.006). Conclusions: SEC, MMP-9 and other downstream markers of COX-2 gene expression may be useful for assessing response to combination celecoxib and erlotinib in pts with advanced NSCLC. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, to evaluate the efficacy of this combination therapy and to assess these and other biomarkers in both serum and tumor tissue. Supported by ASCO Young Investigator Award, UCLA Lung Cancer SPORE NCI P50 CA 90388 and GLAVAHS Career Development Award. No significant financial relationships to disclose.
Biochemical Study of Nuclei Isolated From Normal Lung and Lung Tumors. I. Isolation of Nuclei and Characterization of Nuclear RNA&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: E Yazdi, F Györkey, H Busch, P Györkey
Journal: JNCI Journal of the National Cancer Institute (1971)

With the citric acid procedure, nuclei were isolated from “normal” lung tissue and lung tumors: squamous cell carcinoma, adenocarcinoma, and anaplastic carcinoma. The purity of the isolated nuclei was defined by light and electron microscopy. The RNA/DNA ratios of nuclei in neoplastic lung tissue differed significantly from those of the controls. Although the base compositions of nuclear DNA from normal and neoplastic lung tissues did not differ significantly, the nucleotide composition of nuclear RNA from the normal lungs differed from that of the tumors; i.e., the uridylic acid content was significantly lower in the tumors than in the normal lungs, and the cytidylic acid content was significantly higher. On the other hand, the nucleotide compositions of nuclear RNA of 4 different normal lungs used as controls were not significantly different nor were those of the lung tumors.
A model to predict delivery of reduced chemotherapy dose intensity in the first three cycles of treatment among patients with non-Hodgkin's lymphoma and breast cancer
Authors: V. Caggiano, V. A. Morrison, M. Fridman, D. J. Delgado
Journal: Journal of Clinical Oncology (2004)

6100 Background: Reduction of chemotherapy dose intensity is common among patients receiving treatment for non-Hodgkin's lymphoma (NHL) and breast cancer. A recent publication suggests that neutropenia is a cause of dose modifications, and that maintaining chemotherapy dose intensity in the initial cycles may be associated with improved outcomes. We evaluated possible risk factors associated with delivery of reduced chemotherapy dose intensity in the first 3 cycles of treatment among a sample of patients with NHL or breast cancer. Methods: A historical case series of 1617 patients (704 NHL and 913 early-stage breast cancer) who received initial chemotherapy at 16 community and academic oncology practices between 1991 and 1999 were studied. Reduced average relative dose intensity (ARDI) was defined as at least a 20% or 15% reduction in dose intensity for NHL and breast cancer patients, respectively. Stepwise logistic regression was used to select risk factors significantly associated with a reduction in ARDI. Results: 427 of 1617 patients (26%) received reduced ARDI within the first 3 cycles of chemotherapy. Factors significantly associated with delivery of reduced ARDI in a multiple logistic regression model included age greater than or equal to 65 years (odds ratio [OR] 2.4; 95% CI 1.8–3.2), presence of heart, renal, or hepatic comorbidity (OR 2.2; 95% CI 1.6–3.2), low body surface area (OR 1.3; 95% CI 1.1–1.7), and no preemptive growth factor in cycle 1 (OR 1.7; 95% CI 1.0–2.6). Patients with NHL were less likely to have a reduction in ARDI (OR 0.6; 95% CI 0.4–0.8). Conclusions: Increased age, comorbidity (heart, renal or hepatic), low body surface area, and no preemptive growth factor in cycle 1 were associated with increased risk for delivery of reduced chemotherapy dose intensity in cycles 1 through 3 after controlling for differences in diagnosis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Inc.; Schering-Plough Amgen, Inc. Amgen, Inc.
<i>BRCA</i> haploinsufficiency in human breast tumorigenesis
Authors: T. A. King, W. Li, C. Yee, M. L. Gemignani, N. Olvera, E. Brogi, M. E. Robson, K. Offit, L. Norton, P. I. Borgen, J. Boyd
Journal: Journal of Clinical Oncology (2005)

9512 Background: For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity (LOH) affecting the wild-type allele is considered obligatory for cancer initiation. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency. Here, we test the hypothesis that BRCA haploinsufficiency is associated with human breast tumorigenesis. Methods: Archival breast tissue specimens were obtained from 14 BRCA1-linked breast cancer cases, four BRCA1-linked prophylactic mastectomy (PM) cases, 10 BRCA2-linked breast cancer cases, and six BRCA2-linked PM cases. Laser-catapult microdissection was used to isolate cells from invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and normal epithelium (NE). Following DNA isolation, the ratio of mutant to wild-type allele in each sample was assessed using quantitative real-time PCR. Six BRCA1-linked and six BRCA2-linked cases of ovarian cancer were also analyzed. Results: Seven of 12 (58%) BRCA1-linked IDCs showed partial or no LOH; one IDC showed complete LOH of the mutant allele. Five of nine (56%) BRCA2-linked IDCs showed partial or no LOH; one case showed complete LOH of the mutant allele. Six of 11 (55%) BRCA1-linked DCIS lesions showed partial or no LOH; one case showed complete LOH of the mutant allele. Three of six (50%) BRCA2-linked DCIS lesions displayed partial or no LOH; one case displayed complete LOH of the mutant allele. In 11 samples of NE associated with BRCA1-linked IDC, one case showed complete LOH of the wild-type allele and six cases showed complete LOH of the mutant allele. In eight samples of NE associated with BRCA2-linked IDC, two cases showed LOH of the wild-type allele and one case showed LOH of the mutant allele. Similar data were obtained from PM specimens containing NE, ADH, and DCIS. In all 12 ovarian cancers, complete LOH of the wild-type allele was observed. Conclusions: These data indicate that LOH affecting the wild-type BRCA allele is not obligatory for breast tumorigenesis. These data have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population. No significant financial relationships to disclose.
A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors
Authors: A.W. Tolcher, K.P. Papadopoulos, A. Patnaik, K. Wilson, S. Thayer, J. Zanghi, A.T. Gemo, W.M. Kavanaugh, H.N. Keer, P.M. LoRusso
Journal: Annals of Oncology (2015)
Oral Contraceptives and Thromboembolism
Journal: BMJ (1967)

It is noted that the data on a correlation between thromboembolism and oral contraceptive use are imprecise obsolete and misunderstood.  The original roughly estimated factors of increased risks have been trea ted as though they were precise quantities.  The calculations were derived at a time when 53% of the oral contraceptives sold in the U.K.  contained more than 50 mcg of estrogen.  A 50% drop in the mortality rate was predicted if only oral contraceptives containing 50 mcg of estrogen were used.  During the first 6 months of 1973 about 97% of combined oral contraceptives sold contained no more than 50 mcg of estrogen.  A combined pill containing 30 mcg of estrogen has further reduced the relevance of the original estimates of risk.  There has also been a substantial replacement of oral contraceptives containing mestranol by those containing ethinyl estradiol which carry fewer risks.  The impossibility of proving the attribution of any individual thrombosis to an oral contraceptive is noted.  It is recommended that the original workers review the data that have accumulated during the past 4 years and produce a report that will not only revise the estimates of the various thromboembolic risks in terms of the oral contraceptives  used at present but also make clear the limitations of those estimates.
Anti-tumor activity of ADH-1 in vitro and in vivo in combination with paclitaxel in ovarian cancer cell lines
Authors: M. Gupta, D. Barnes, J. Losos, G. Spehar, M. Bednarcik, W. P. Peters
Journal: Journal of Clinical Oncology (2007)

16050 Background: ADH-1 is a novel N-cadherin (Ncad) antagonist. Ncad is a protein present on certain tumor cells and established tumor blood vessels. Its expression on tumor cells increases as they become more aggressive, invasive and metastatic, making it an important target for anti-cancer therapy. ADH-1 was well tolerated in phase I studies and demonstrated evidence of anti-tumor activity in 7 patients whose tumors expressed Ncad. Patient enrollment in two phase II single agent trials concluded at the end of 2006. We report on the anti-tumor activity of ADH-1 in combination with paclitaxel in cancer cell lines in vitro and in the A2780 (Ncad positive) ovarian xenograft model in vivo. Methods: In vitro cytotoxicity of SKOV-3 (ovarian) cells exposed to a fixed ratio of ADH-1 and paclitaxel simultaneously was evaluated by the WST-1 cell proliferation assay. In vivo anti-tumor activity of ADH-1, paclitaxel, and the combination was evaluated in the A2780 xenograft model. ADH-1 100 mg/kg was administered bid IP for 21 days and paclitaxel was administered qod IV for 5 days. Results: In vitro cytotoxicity assays evaluated for combination effects using CalcuSyn software indicated a strong synergistic effect of ADH-1 in combination with paclitaxel (CI &lt;1). In vivo paclitaxel treatment produced a median Time to Endpoint (TTE) (tumor volume &gt;2gm or study end at 60 day) of 32.1 days and 73% Tumor Growth Delay (TGD), compared to control (p=0.028). For the paclitaxel group, there was only one Tumor Free Survivor (TFS) and one transient Complete Responder (CR). ADH-1 produced a TTE of 16.1 and a -13% TGD (p&gt;0.05). The combination of ADH-1 and paclitaxel produced a median TTE of 48.6 days, corresponding to 161% TGD (p&lt;0.0016 compared to untreated controls, p&lt;0.003 for vehicle treated, and p&lt;0.005 compared to paclitaxel alone). The combination therapy generated durable CR in 5 animals, 1 transient CR and 2 PR. The combination therapy had similar toxicity to paclitaxel alone. Conclusions: In this ovarian cancer model, the combination of ADH-1 with paclitaxel produced a synergistic anti-tumor effect. Based in part on these encouraging pre-clinical results, a clinical program of ADH-1 in combination with chemotherapeutic agents has been initiated. No significant financial relationships to disclose.
Abstract 19053: Embolic Particles Show Surprising Size Dependent Predilection for Cerebral versus Peripheral Arteries: Results from Computational Fluid Dynamic Modeling
Authors: Shawn C Shadden, Naohiko Nemoto, Wesley R Pedersen, John R Lesser, Robert S Schwartz
Journal: Circulation (2012)

Background: Embolic particles originating at the aortic valve or ascending aorta can have devastating consequences if they enter the cerebral circulation. Little is known about anatomic embolic origin and cerebral events, as this relationship is difficult to observe. To better understand emboli arising from procedures such as TAVR, we built a computational fluid dynamic (CFD) model of cerebral emboli originating at the aortic valve and ascending aorta. Methods: An exact computer model of a human aorta and arteries to the brain was derived from CT angiography. Blood flow was modeled by the Navier-Stokes equations using pulsatile inflow at the inlet and physiologic Windkessel models at the outlets. Embolic particulate was injected at the level of the aortic valve and tracked using modified Maxey-Riley equations. Results: Aortic emboli that entered the cerebral circulation through the carotid or vertebral arteries were localized to specific locations of the proximal aorta, most closely in the region of the right and non-coronary aortic valve cusps. The percent of released particles embolic to the brain was markedly dependent on particle size. Particles 1.0 mm diameter had a 28% chance of reaching the brain, whereas particles 2.5 mm dia or greater had 5% chance of reaching the brain. Conclusions: Embolic particles reaching the brain appear have specific anatomic locations of origin, and may exhibit a strong size-destination relationship, with larger particulate (greater than 2.5 mm dia) less likely to traverse the cerebral vessel by a factor of 5 or greater. Particles less than 2 mm dia and originating from the right and noncoronary cusps appear more likely to cause cerebral injury according to this model. These data are consistent with sparse literature based on transesophageal echo observations. This CFD modeling method may prove useful for limiting aortic emboli to the brain during cardiovascular procedures.
Results of a phase II pilot study of 13-cis-retinoic acid with gemcitabine in patients with unresectable pancreatic cancer
Authors: A. Michael, A. Maraveyas, M. Hill, A. Dalgleish, F. Lofts
Journal: Journal of Clinical Oncology (2005)

4213 Introduction: Gemcitabine is currently the standard treatment for patients (pts) with unresectable pancreatic cancer. It is beneficial but not associated with a high response rate. Retinoids are derivatives of vitamin A that have numerous effects on tumour cells, including inhibition of cell growth, and induction of differentiation and apoptosis. The effects of retinoic acid (RA):9-cis-RA or all-trans-RA (ATRA) on pancreatic tumour cell lines include inhibition of in vitro and in vivo growth, accompanied by differentiation, apoptosis, or both. Some studies evaluating combinations of RA and chemotherapeutic agents such as cisplatin, etoposide and paclitaxel have demonstrated synergy. Our data showed that pretreatment of pancreatic cell lines with RA followed by gemcitabine resulted in a dramatic increase in apoptosis. We therefore conducted a phase II pilot study of gemcitabine in combination with 13-cis RA in pts with locally advanced or metastatic carcinoma of pancreas. Methods: Study treatment was: gemcitabine 1,000 mg/m2 on d 8, 15, 22 plus 13-cis RA 1 mg/kg PO on d1–14 for 6 cycles. Results: 30 pts were recruited, 20 were evaluable (8 patients received only one to two cycles and developed severe disease related symptoms requiring withdrawal of chemotherapy, 1 withdrew consent, 1 developed acute confusional state not related to study medication). Pts characteristics: male/female:16/14, median age 65 yrs (range 44–79), median Karnofsky PS 80% (range 60–100%).1 pt achieved partial remission, 7 pts had stable disease, and 12 developed progressive disease. Toxicity was mainly haematological with 8 cases of grade 3 and 4 cases of grade 4 neutropaenia, thrombocytopaenia and anaemia. None of the serious adverse events reported was caused by study medication. Median survival was 7.8 months. Conclusion: Combination of gemcitabine with 13-cis-RA is well tolerated but we did not see improvement in response rate, further studies with other retinoids may be beneficial to pts with unresectable pancreatic cancer. No significant financial relationships to disclose.
Prognostic significance of pathological biomarkers in patients with stage II-III colorectal cancer
Authors: C. Funaioli, C. Pinto, C. Ceccarelli, F. Di Fabio, D. Cuicchi, F. L. Rojas Llimpe, R. Lombardi, C. Longobardi, M. Bottazzi, A. A. Martoni
Journal: Journal of Clinical Oncology (2007)

14518 Background: Biopathological colorectal cancer (CRC) studies have provided information on pathogenesis, but it is unclear how important biomarkers actually are in predicting prognosis. The aim of our study was to define the prognostic significance of biomarkers and a biopathological profile that could predict an increase in the disease relapse risk in stage II-III CRC patients (pts). Methods: The primary tumor of the CRC pts treated with surgery was immunohistochemically evaluated on the Ki67, p53, bcl-2, TS, EGFR, MLH1 and MSH2 expressions. All 7 markers were measured using standard immunohistochemical techniques. The biomarker evaluations were scored by just one pathologist. Results: Between March 2001 and October 2006 the primary tumor of 242 consecutive pts was investigated. Pt characteristics were: males 141(58.3%), females 101(41.7%); median age 68.5 (24–88); primary tumor site: right colon 94(38.8%), left colon 148(61.2%); stage II 102(42.1%), stage III 81(33.5%), stage IV 59(24.4%). 5-fluorouracil based adjuvant chemotherapy was performed in 121 (66.1%) pts. After a median follow up of 30 months (1–80), 34 pts (10 pts stage II, 24 pts stage III) of 183 stage II-III pts (18.6%) had a disease recurrence. In a univariate analysis of stage II-III pts, a higher expression of Ki67 (= 50% positive cells) was significantly associated with an improved DFS (p= 0.014) and overall survival (OS) (p=0.010). Expression of p53, bcl-2, TS, EGFR, MLH1 and MSH2 were not significantly associated with DFS and OS. In a multivariate analysis adjusted for the impact of the disease stage and adjuvant chemotherapy, a higher expression of Ki67 was significantly associated with diminished risk of recurrence (HR: 0.395; 95% CI: 0.183–0.855, p=0.018) and death (HR: 0.179; 95% CI: 0.046–0.696, p=0.013). The evaluation of DNA mismatch repair status (MLH1, MSH2) demonstrated that the lack of MLH1 is more frequent in non-relapsed II-III stage pts than in IV stage pts (p= 0.024). Conclusions: This analysis showed a significant correlation between higher Ki67 expression and better DFS and OS in pts with stage II-III CRC. An higher frequency of MLH1 deficiency was observed in non-relapsed pts with stage II-III than in advanced disease. No significant financial relationships to disclose.
Nuclear Magnetic Resonance Studies on Human Breast Dysplasias and Neoplasms&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: D Medina, C F Hazlewood, G G Cleveland, D C Chang, H J Spjut, R Moyers
Journal: JNCI Journal of the National Cancer Institute (1975)

Journal Article Nuclear Magnetic Resonance Studies on Human Breast Dysplasias and Neoplasms Get access Daniel Medina, Daniel Medina Search for other works by this author on: Oxford Academic PubMed Google Scholar Carlton F. Hazlewood, Carlton F. Hazlewood Search for other works by this author on: Oxford Academic PubMed Google Scholar Gregor G. Cleveland, Gregor G. Cleveland Search for other works by this author on: Oxford Academic PubMed Google Scholar Donald C. Chang, Donald C. Chang Search for other works by this author on: Oxford Academic PubMed Google Scholar Harlan J. Spjut, Harlan J. Spjut Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert Moyers Robert Moyers Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 54, Issue 4, April 1975, Pages 813–818, https://doi.org/10.1093/jnci/54.4.813 Published: 01 April 1975 Article history Received: 07 March 1974 Revision received: 19 November 1974 Accepted: 13 January 1975 Published: 01 April 1975
Proteomic analysis of patients with mantle cell lymphoma identifies Hsp90, and other proteins as potential target(s) for drug therapy
Authors: I. M. Ghobrial, D. J. McCormick, S. H. Kaufmann, S. M. Ansell, A. J. Novak, M. J. Stenson, K. L. Krajnik, T. E. Witzig
Journal: Journal of Clinical Oncology (2004)

6530 Background: We employed antibody protein microarrays to measure changes in the patterns of protein expression between normal B-lymphocytes and those from patients with mantle cell lymphoma (MCL). Methods: The pattern of protein expression in MCL patients was measured on antibody protein microarrays (BD Clonetech, CA) with 512 monoclonal antibodies. CD19+purified B-lymphocytes from a normal tonsil were used as control for all experiments. CD19+ mononuclear cells were purified from 6 patients with MCL. Another patient with lymphoplasmacytic lymphoma (LPL) was performed for comparison to confirm that the pattern of expression is unique to MCL. A control experiment of tonsil B-cell extracts was performed to ensure the absence of non-specific protein expression patterns. Immunoblotting experiments with monoclonal anti-human Hsp90 were also performed in 10 different MCL patients. Results: Of the 6 MCL patients, 1 patient was heavily pretreated with chemotherapy and autologous stem cell transplantation and showed a distinct protein pattern from the other MCL patients. One patient was treated with 2-CDA and rituximab 1 year prior to analysis, and the other 4 patients were newly diagnosed. The median number of overexpressed proteins was 62 (range, 11–92), and the median number of underexpressed proteins was 65 (range, 5–175). The patient with LPL had a different protein expression pattern compared to patients with MCL. The common proteins that were overexpressed in MCL patients included: chaperone proteins (Hsp90, Hsp10), cell cycle regulators (RCC-1, p73a, MDM2, CDC25C), apoptosis regulators (caspase 7, Smac/DIABLO), and kinase regulators (PP5, AKAP450). IkBe (inhibitor of NFkB) was underexpressed in these patients. We confirmed the abundant expression of Hsp90 by immunoblotting in 10 different MCL patients. Conclusion: Hsp90 is highly expressed in patients with MCL, along with other possible candidates. These proteins may serve as potential targets for novel agents such as 17-AAG that targets Hsp90. Funded in part by NCI cancer center CA15083–29C1 and CA97274 No significant financial relationships to disclose.