tbuckley/cabot-search huggingface dataset:
Real time PCR quantification of COX-2 mRNA in human ovarian epithelial neoplasm and its correlation with clinical outcome
Authors: K. Rodabaugh, Y. Wu, D. Driscoll, K. Odunsi, S. Lele, P. K. Singhal
Journal: Journal of Clinical Oncology (2005)

5055 Objectives: COX-2 has been implicated as tumorogenic in various tumor models. Our previous immunohistochemistry work has shown that normal ovarian epithelium, normal inclusion cysts, serous cystadenofibromas and normal fallopian tube epithelium express COX-2 in a uniform intense pattern while epithelial ovarian carcinoma (EOC) tissues showed variable patterns of COX-2 staining, tending to correlate to the level of tissue differentiation. Our study goals were to quantify COX-2 mRNA expression in a large panel of EOC and to examine for correlation with clinical outcome. Methods: Frozen specimens were obtained from 44 patients with EOC treated between 1995 and 2002. Total tissue RNA was extracted from EOC and 13 benign ovarian tissue samples. COX-2 mRNA was quantitatively analyzed by monitoring the increase in fluorescence by the binding of SYBR green to double-stranded DNA during real-time PCR (Sequence detection system, TaqMan; Applied Biosystems, CA). The copy numbers of cDNA for COX-2 were standardized to glyceraldehyde-3-phosphate dehydrogenase from the same samples. The χ2 test, log-rank test and Kaplan-Meier methods were used for statistical analysis. Results: COX-2 is expressed in benign and malignant ovarian tissues with no significant difference in level of COX-2 mRNA expression. All EOC patients had cytoreductive surgery followed by adjuvant platinum-based chemotherapy. The median follow up was 27 months (CI:1, 109) There were no significant relationships between stage, grade, histology, survival and level of COX-2 mRNA expression. Conclusions: COX-2 is expressed in all benign and malignant ovarian tissues. It is possible that despite a comparable mRNA expression of COX-2 in normal and malignant tissues, that molecular analysis of this enzyme and possible cofactors may still uncover mutations or regulatory factors that implicate COX-2 in the early steps of tumorigenesis, in a manner similar to other tumor models. No significant financial relationships to disclose.
Heterogeneity of response to bevacizumab in multifocal and multicentric glioblastomas.
Authors: S. S. Ong, V. K. Puduvalli
Journal: Journal of Clinical Oncology (2010)

2019 Background: Bevacizumab (BEV) is approved for treatment of recurrent glioblastoma (GBM). However, whether the subset of pts with multifocal (MF) or multicentric (MC) GBM respond favorably to BEV has not been described. Hypothesizing that MF/MC lesions may represent an initially more invasive and biologically heterogeneous phenotype in GBM which may exhibit varied responses to BEV, we examined their patterns of radiologic response and correlation with clinical outcome. Methods: Clinical and MRI data from pts with recurrent GBM who received BEV were reviewed to identify those with MC or MF disease who had adequate baseline and follow-up MRI. Enhancing and nonenhancing (FLAIR) disease were analyzed for response to BEV and categorized in each pt as homogeneous (similar changes in all lesions) or heterogeneous (varied across lesions) in response or progression. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method and log rank test. Results: Of the 179 evaluable pts, 31 (17.3%) had multiple lesions (16 pts - MF, 15 pts - MC) prior to BEV treatment. Patients with MC/MF lesions had a significantly worse outcome than those with unifocal lesions in both PFS (Median 19 wks vs. 24.4 wks, p = 0.0124, HR 1.84, CI [1.14, 2.9]) and OS (Median 31 wks vs. 45.9 wks, p = 0.0011, HR 2.42, CI [1.42, 4.12]). Unlike previous reports of BEV response in recurrent GBM pts, MRI responders (homogenous or heterogeneous) among pts with MC/MF lesions did not have a better OS compared with nonresponders. In addition, no significant difference was seen in PFS or OS between patients with homogenous versus heterogeneous progression. There was no significant difference in median PFS (median 17.6 wks vs. 18.4 wks) or median OS (median 27.7 wks vs. 32.3 wks) between pts with MC versus MF GBM. Conclusions: The subset of GBM pts with MF/MC lesions had a worse outcome to BEV treatment compared with those with unifocal disease. Although a homogenous radiological response of all lesions to BEV was the commonest pattern on MRI, neither radiologic response nor pattern of radiologic progression correlated with improved PFS or OS. Our data also suggests that outcome of pts MC/MF GBM may need to be analyzed separately in studies with BEV containing regimens. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IMEDEX Celgene, Lilly, MGI Pharma, Pfizer
A novel selective therapeutic targeting heme oxygenase-1 revealed a potent antimetastatic activity in androgen-refractory human prostate cancer models
Authors: M. A. Alaoui-Jamali, A. Gupta, W. A. Szarek, T. A. Bismar, R. Gheorghe, H. M. Schipper
Journal: Journal of Clinical Oncology (2009)

e16090 Prostate cancer is a highly prevalent disease. Despite a significant improvement in the overall survival attributed in part to early detection and introduction of novel therapeutic modalities, many cancer patients at primary diagnosis present advanced disease or experience recurrence of the cancer. The progression of prostate cancer (PCA) to hormone-refractory phenotype (HRPCA) and to metastasis is an ominous event in patients with advanced PCA. Currently, clinically available drugs for hormone refractory PCA have only marginal efficacy. In this study, we identified heme oxygenase 1 (HO-1) to be significantly upregulated in epithelial PCA cells, but not in surrounding stromal cells, from hormone refractory prostate cancer cases compared to hormone-responsive prostate cancer and to benign tissues. We validated HO-1 as a novel therapeutic target for HRPCA. Specifically, inhibition of HO-1 gene in androgen-independent and highly invasive prostate cancer cells, PC3M, decreased HO-1 activity, oxidative stress, MAPKs activation, cell proliferation, and cell migration and invasion in vitro, as well as inhibition of prostate tumor growth and lymph nodes and lung metastases in vivo. The impact of HO-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively downregulates HO-1 activity, oxidative stress, and significantly inhibits cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity in inhibiting HRPCA metastasis formation was observed when OB-24 was combined with the chemotherapy drug taxol. The molecular and potential clinical impact of OB-24 alone and in combination with taxanes on HRPCA will be discussed. [Table: see text]
Pharmacokinetic (PK) and pharmacodynamic (PD) results from two phase I studies of the investigational selective Aurora A kinase (AAK) inhibitor MLN8237: Exposure-dependent AAK inhibition in human tumors.
Authors: A. Cervantes-Ruiperez, H. A. Burris, R. B. Cohen, E. C. Dees, J. R. Infante, H. J. Fingert, V. Shinde, K. Venkatakrishnan, A. Chakravarty, J. Tabernero
Journal: Journal of Clinical Oncology (2010)

3031 Background: AAK inhibition causes defects in centrosome separation, spindle assembly, and chromosome alignment, leading to transient mitotic delays followed by cell-cycle arrest or death. PK and PD results are reported from two phase 1 studies of MLN8237 in patients (pts) with advanced solid tumors. Methods: 117 pts took MLN8237 orally once daily (QD) or twice daily (BID) for 7-21 days (D) with a 14D rest between cycles. Cohorts of 3+ pts were enrolled to increasing doses until dose-limiting toxicity (DLT) was seen in ≥2 of 6 pts. Skin (2-3 mm) and tumor biopsies were obtained on D1 and D7. Using quantitative immunohistochemical methods, biopsies were assessed for mitotic index (skin and tumor), apoptotic index (skin), mitotic cell chromosome alignment (tumor), and spindle bipolarity (tumor). Results: MLN8237 was absorbed rapidly (median Tmax, 2h). PK was variable. Steady-state exposures were achieved by 7D and were dose-proportional over 5-200mg/day. The recommended phase II dose × 7D (50mg BID, determined in both phase 1 studies) produced steady-state average concentrations (geometric mean ∼1.7 μ M; n=16), exceeding the efficacious concentration estimated preclinically (1μ M). Mean t1/2 was ∼21h. At steady-state exposures, skin mitotic and apoptotic indices and tumor mitotic index increased, and tumor mitotic cell chromosome alignment and spindle bipolarity decreased, all demonstrating AAK inhibition. In evaluable pts with paired tumor biopsies (n=8), exposure-related changes were observed by D7, including decreases in chromosome alignment and spindle bipolarity. Conclusions: Exposure-related PD effects in skin and tumor tissue support proof of mechanism for AAK inhibition by MLN8237. Coupled with mechanistic toxicities in proliferative tissues observed in both phase I studies, the clinical data substantiate the PD methods and achievement of bioactive plasma concentrations. Taken together, these PK and PD results support the achievement of clinically relevant MLN8237 exposures, applicable to future clinical studies of MLN8237 as a single agent or combination therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Millennium Takeda Millennium Millennium
Abstract 19096: D-dimer Profile and Prognostic Implication in Different Classes of Acute Aortic Syndromes
Authors: Riccardo Gorla, Rolf A Janosi, Philipp Kahlert, Konstantinos Tsagakis, Heinz Jacob, Eduardo Bossone, Raimund Erbel
Journal: Circulation (2014)

Background: D-dimer has been reported to be elevated at presentation in acute aortic dissection (AAD). However, little is known about D-dimer in the setting of intramural hematoma (IMH) and penetrating aortic ulcer (PAU) as well as its time course during hospitalization. Methods: Clinical and laboratory data of 300 patients with acute aortic syndromes (208 AAD, 45 IMH and 47 PAU) were prospectively collected from 2000 to 2014. D-dimer blood levels were measured at presentation and daily during hospitalization with a latex-enhanced turbidometric test (250 μg/l upper limit of normal; D-dimer Plus - Dade Behring) until 2009 and with a microparticle-enhanced immunoassay (0,55 mg/l upper limit of normal; Innovance - Dade Behring) from 2010. Analysis of variance with Bonferroni post hoc analysis and Student T test were applied as appropriate. Results: At presentation, AAD and IMH showed significantly higher D-dimer levels than PAU (p&lt;0,01). Similarly, D-dimer levels during hospitalization were found significantly higher in AAD and IMH, as compared to PAU (p&lt;0,001). From a subgroup analysis according to in-hospital outcome, D-dimer levels were significantly increased in patients complicated with major adverse events (a composite of extension/new dissection, aortic rupture and death) as compared to others (n=86, 29% and n=214, 71%; D-dimer: 1432 ± 855 μg/l vs. 787 ± 215 μg/l, p&lt;0,001; 10,5 ± 6,3 mg/l vs. 8,3 ± 2,1 mg/l, p&lt;0,05 respectively). (Table 1) Conclusions: D-dimer levels were found markedly increased both at presentation and during hospitalization in AAD and IMH, but not in PAU. Interestingly, higher values during hospital stay were associated with in-hospital major adverse events. Further studies are needed to integrate D-dimer testing in AAS clinical diagnostic and prognostic risk stratification scoring tools.
A phase I clinical study of biweekly carboplatin and gemcitabine in patients with advanced solid tumors
Authors: P. Kumar, M. Keshtgarpour, H. Kumar, A. Dudek
Journal: Journal of Clinical Oncology (2006)

12024 Background: Carboplatin (CBDCA) and gemcitabine (GEM) in combination is used commonly in lung cancer and is administered on a 21 day cycle. The purpose of this study was to determine the maximum tolerated dose (MTD) of CBDCA and GEM administered on a biweekly schedule and to assess safety and efficacy of this schedule. Methods: GEM was given intravenously (IV) over 30 minutes followed by CBDCA also given IV over 30 minutes. This combination was given on day 1 every 2 weeks. The dose levels examined are shown in the Table . A total of 26 patients were studied (18 male, 8 female) with median age of 56 (range 41–83 years); ECOG performance status of 24 patients were 0 (5), 1 (16), 2 (2), 3 (1); prior chemotherapy ranged from 0 to 4 regimens; median number of cycles administered per patient was 3 (range 1–9) with a total of 81 cycles. The primary tumors were lung (11), melanoma (4), head and neck (3), squamous cell penile/toe (2), bladder (2), kidney (1), gastric (1), esophageal (1) and ovary (1). Results: No DLTs were seen in any of these patients and the MTD was not reached. Delay in treatment was seen in total of 6 cycles due to myelosuppression and 1 cycle due to nausea and anorexia. Grade 3/4 hematological toxicity rates: anemia - 3/81 cycles (3.7%), neutropenia - 20/81 cycles (25%), and thrombocytopenia - 4/81 cycles (5%). Non-hematological toxicity was mild. The median time to progression was 40 days (range 4–133) and of 18 evaluable patients partial response or stable disease was seen in 7 (38.8%). Conclusions: Even at maximum tested dose of GEM at 2000 mg/m 2 and CBDCA at AUC of 3.0, this schedule is well tolerated. Hematological toxicity such as neutropenia and thrombocytopenia was minimal. We plan to study this schedule of GEM and CBDCA in appropriate tumor types in combination with biologic agents. [Table: see text] [Table: see text]
Definitive results of hybrid chemotherapy with intravenous (iv) oxaliplatin (OXA) and folinic acid (FA), and intra-hepatic infusion (HAI) of 5-fluorouracil (5-FU) in patients with colorectal liver metastases
Authors: I. Garassino, C. Carnaghi, L. Rimassa, M. Zuradelli, G. Abbadessa, G. Gullo, I. Marcon, A. Santoro
Journal: Journal of Clinical Oncology (2005)

3670 Background: Liver is the dominant site of metastases in patients (pts) with colorectal cancer (CRC). Intrahepatic arterial chemotherapy should deliver higher doses of drugs to the liver, but extrahepatic disease progression are frequent. Methods: We started a phase II study with concomitant HAI of 5-FU and iv OXA and FA in pts with colorectal liver metastases. From March 2000 to May 2004 39 pts have been recruited. The majority (74%) of the catheters were implanted by laparotomy. The regimen consisted of iv OXA 85 mg/m2 d 1 and FA 75 mg/m2 d 1,2, followed by bolus HAI of 5-FU 300 mg/m2 d 1,2 and 22-hour HAI of FU 1200 mg/m2 d 1,2. The cycles were repeated every 2 weeks for a maximum of 16 cycles. The median age of pts was 59 yrs (range, 37–73), 30 pts (77%) had synchronous liver metastases, 11 pts (28%) had minimal extra-hepatic disease and 49% of the pts were chemonaive. The median follow-up time for living pts is 15 months (range, 2–51). Results: Three-hundred and thirteen courses of therapy have been administered, and the median number of cycles was 8 (range 2–16). Although the treatment was generally well tolerated, the high incidence (42%) of NCI-CTC grade 3–4 neutropenia required frequent dose reduction (45% of cycles) or treatment delay (27%). Early discontinuation of therapy was necessary in 11 pts (28%) due to problems related to the catheter. Thirty-four pts (87%) were assessable for response, there were 3 CR (9%), 11 PR (32%), for an overall response rate of 41%. Nineteen pts (56%) achieved a SD. The overall response rate was 53% and 29% for chemonaive and pretreated pts respectively. Six pts (15%) underwent radical surgery on the liver. The median reduction of the CEA level was 91%. The median time to progression was 9 months (range, 2–43) and the median overall survival was 22 months (range, 2–51+). Better results were obtained in chemonaive pts and in pts without extra-hepatic disease. Conclusions: These results suggest that this regimen is feasible and active. The relatively low response rate observed could be partially explained by the marked necrosis and peri-lesional edema, being the survival data very promising. No significant financial relationships to disclose.
Evaluation of post-operative complications and prolonged length of stay following cytoreductive nephrectomy.
Authors: Boris Gershman, Daniel M. Moreira, Stephen A. Boorjian, Christine M. Lohse, John C. Cheville, Brian Addis Costello, Bradley C. Leibovich, Robert Houston Thompson
Journal: Journal of Clinical Oncology (2015)

420 Background: Cytoreductive nephrectomy (CN) has been associated with significant morbidity, but there is little data identifying patients at increased risk. We evaluated the association of clinicopathologic features with early post-operative complications and prolonged length of stay (pLOS) among CN patients. Methods: We identified 294 patients treated with radical nephrectomy for M1 renal cell carcinoma between 1990 and 2009 at the Mayo Clinic. All complications within 30 days of surgery were reported using standardized methodology according to the Clavien classification. Associations with the presence of any early complication and pLOS (defined as ≥8 days, the top 25th percentile) were evaluated using logistic regression models. Results: Thirty-five (12%) patients experienced at least one early complication and 15 (5%) patients experienced at least one Clavien grade ≥3 early complication. The median LOS was 6 days (IQR 5-7), and 68 (23%) patients had a pLOS. On univariate analysis, liver metastases, symptomatic presentation, intraoperative transfusion, and pathologic nodal stage were significantly associated with both early complications and pLOS (Table). Two multivariate models were constructed. In Model 1 (limited to pre-operative features), only liver metastases (p&lt;0.01) were associated with early complications while liver metastases (p=0.01) and open approach (p=0.02) were associated with pLOS. In Model 2 (all variables included), liver metastases (p=0.01), intraoperative transfusion (p&lt;0.01), and high nuclear grade (p&lt;0.01) were associated with early complications while intraoperative transfusion (p&lt;0.01) and positive nodes (p=0.05) were associated with pLOS. Conclusions: CN was associated with a low incidence of early post-operative complications, particularly Clavien ≥3 complications. Presence of liver metastases and intraoperative transfusion were independently associated with increased risk of both complications and pLOS. [Table: see text]
Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer
Authors: Joseph M. Herman, John P. Hoffman, Sarah P. Thayer, Robert A. Wolff
Journal: Journal of the National Comprehensive Cancer Network (2015)

New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.
Delaying skeletal-related events in a randomized phase III study of denosumab versus zoledronic acid in patients with advanced cancer.
Authors: D. H. Henry, R. von Moos, V. Hungria, L. Costa, P. J. Woll, G. Scagliotti, J. Wang, S. Jun, R. D. Dansey, H. Yeh
Journal: Journal of Clinical Oncology (2010)

9133 Background: In patients with solid tumor-related bone metastases, cancer cells stimulate RANKL-induced, osteoclast-mediated bone destruction, increasing the risk of skeletal-related events (SREs)—pathologic fracture, spinal cord compression, and radiation or surgery to bone. In a randomized phase 3 study of 1776 patients with solid tumors (except breast or prostate cancer) and bone metastases or multiple myeloma, the anti- RANKL antibody denosumab was shown to be noninferior to zoledronic acid (ZA) in delaying or preventing SREs (Henry D, 2009 ECCO/ESMO). From this study, we performed a subset analysis comparing the treatment effects in only patients with solid tumors and bone metastases (n=1597). Methods: In a double-blind, double-dummy study, patients with solid tumors (excluding breast and prostate cancer) or multiple myeloma received subcutaneous denosumab 120 mg or intravenous ZA 4 mg adjusted for creatinine clearance every 4 weeks and were urged to take daily calcium (>=500 mg) and vitamin D (>=400 IU) supplements. Time to first on-study SRE (Cox proportional hazards model) and first and subsequent SREs (Anderson-Gill model) were analyzed for patients with solid tumors. Results: Among patients with solid tumors, denosumab delayed the time to the first on-study SRE more effectively than ZA (HR 0.81; 95% CI 0.68–0.96; p<0.02). Denosumab also delayed the time to first and subsequent SREs more effectively than ZA (HR 0.85; 95% CI 0.72–1.00; p<0.05). Both treatment groups had similar rates of overall survival (HR 0.92; 95% CI 0.81–1.05; p=0.21), disease progression (HR 0.96; 95% CI 0.85–1.08; p=0.5), and overall adverse events (AEs) (denosumab 95.6%, ZA 95.5%). ZA-treated patients reported higher rates of AEs potentially associated with renal toxicity (denosumab 7.1%, ZA 10.3%) and acute phase reactions (denosumab 7.1%, ZA 14.8%). Denosumab-treated patients had higher rates of hypocalcemia of grades 3 or 4 (denosumab 4.4%, ZA 1.8%). Both treatment groups reported similarly low rates of osteonecrosis of the jaw (denosumab 0.8%, ZA 1.1%). Conclusions: Denosumab delayed or prevented SREs more effectively than ZA in patients with solid tumors and bone metastases. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Novartis, Ortho Biotech, Roche, Watson Pharmaceuticals Amgen Amgen, AstraZeneca, Lilly, Ortho Biotech, Roche, sanofi-aventis, Watson Pharmaceuticals Amgen, Novartis, Ortho Biotech, Watson Pharmaceuticals