tbuckley/cabot-search huggingface dataset:
Ploidy as a biomarker for targeting metabolism in ovarian cancer.
Authors: Matthew Whybird, Amy Purdon, Angus Harding, Jermaine Coward
Journal: Journal of Clinical Oncology (2015)

e16563 Background: Hyperdiploid cells are a hallmark of ovarian cancers that display chemoresistance and poor survival. Aneuploid hyperdiploid (AHD) cells are key targets, because genomic instability confers an evolvable phenotype protected from deleterious mutations by elevated DNA content. Ploidy scales with cell size, increasing metabolic demand and creating a vulnerability to indicate clinically viable metabolic therapies. Methods: We characterised the ploidy, cell size, cell cycle and carboplatin sensitivity of a panel of ovarian cancer cell lines. Anti-proliferative effects of glycolysis (2-deoxyglucose; 2DG) and glutaminolysis (acivicin) antimetabolites were investigated alone and in combinations with carboplatin. Drug interactions were formally defined with compusyn software. Media containing glucose (3mM) and β-hydroxybutyrate (5mM) concentrations reflecting those of blood during a ketogenic diet (ketone media; KM) were tested in combination with carboplatin and acivicin. Results: AHD cell lines were more sensitive to 2DG than diploid A2780 cells. HEY1 and IGROV1 proliferated significantly less in KM than complete media, whereas diploid A2780 cells were unchanged. KM and 2DG in combination with carboplatin increased chemoresistance. However, the interaction between carboplatin and acivicin is synergistic for A2780, and especially for SKOV3. Furthermore, KM increased the overall efficacy, but not potency, of acivicin in A2780 and SKOV3. Conclusions: AHD cells are larger and more sensitive to therapies targeting metabolism than diploid cancer cells, suggesting DNA content and cell size could be biomarkers for these therapies. The simplicity of translating a dietary treatment makes the effect of KM on proliferation in AHD cell lines HEY1 and IGROV1 an intriguing result. SKOV3 had a very synergistic interaction with acivicin and carboplatin, suggesting a corollary sensitivity to glutaminolysis blockade in cells resistant to glucose deprivation. Overall, diploid A2780 cells were less amenable to metabolic therapies, indicating ploidy as a potential biomarker. Ploidy, 2DG IC50, and sensitivity (+) or resistance (-) to KM. Ploidy 2DG IC50 KM A2780 Diploid 19.56mM - HEY1 AHD 1.014mM + IGROV1 AHD 1.811mM + SKOV3 AHD 4.904mM -
An immunodiagnostic assay for quantitation of specific IgE to the major pollen allergen component, Pas n 1, of the subtropical Bahia grass
Authors: Timbrell, L. Riebelt, C. Simmonds, C. Butler, J. Upham, P. Smith, S. van Nunen, W. Smith, A. McLean-Tooke, G. Solley, A. Kober, D. Langguth, J. M. Davies
Journal: Allergy (2014)
Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004
Authors: G. Somlo, F. Atzori, L. Strauss, A. Rybicki, X. Wu, W. Gradishar, J. Specht
Journal: Journal of Clinical Oncology (2009)

1012 Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m 2 ) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort. [Table: see text]
Phase II study of erlotinib in recurrent GBM: Molecular predictors of outcome
Authors: T. Cloughesy, A. Yung, J. Vrendenberg, K. Aldape, D. Eberhard, M. Prados, S. Vandenberg, B. Klencke, P. Mischel
Journal: Journal of Clinical Oncology (2005)

1507 Background: Erlotinib (Tarceva) is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from this phase II trial of erlotinib for GBM in first relapse have been reported (ASCO 2004, Abs#1555). Updated clinical results and molecular characterization of archival tissue samples are now available. Methods: A multi-institutional phase II clinical trial of single agent erlotinib until disease progression enrolled GBM patients with measurable disease in first relapse. Individual dose titration until dose-limiting toxicity (diarrhea, rash, other) was allowed in 2 dose cohorts: patients taking enzyme-inducing anti-epileptic drugs or not. Subjects were evaluated for response every 8 weeks. Submission of archival tissue was mandatory. Depending on the amount of tissue available, the following assays were performed: EGFR amplification by FISH (Vysis); and EGFR, EGFRvIII (Zymed) and PTEN expression by IHC. Results: Forty-eight subjects (19 female, 29 male) with a median age of 51 years (37–73) were enrolled over 3 months from 4 centers. The investigator determined response rate (WHO criteria) was 8.4% (3 PR, 1CR), with SD as the best response in 37.5% (n=18). One SD patient who died of an MI at day 84 had only microscopic foci of viable tumor amidst significant necrosis on autopsy. The 6 month PFS rate was 17% and median survival was 10 months. Tissue is missing from 1 PR with the longest ongoing response. EGFRvIII analysis is ongoing. Conclusions: Erlotinib is active in recurrent GBM, with a promising response rate, 6 m PFS and median survival. Molecular analyses show a slight trend towards better outcome with EGFR expression however, the differences are not significant due to the small numbers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
Interleukin-15 expression in lung cancer.
Authors: Faisal Adhami, Jason C Steel, John Charles Morris
Journal: Journal of Clinical Oncology (2012)

e21064 Background: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates the differentiation and proliferation of T, B, and NK cells. IL-15 is normally tightly bound by its receptor, IL-15Rα. Dendritic cells and monocytes/macrophages primarily express both IL-15 and IL-15-Rα; however, expression has been detected on epithelial cells including those of the lung. In the lung, IL-15 is thought to play a role in the induction of immune responses to infection. Over expression of IL-15 has been shown to induce NK cell activation and cytotoxic T-lymphocyte (CTL) responses leading to tumor regression. Little is known about IL-15 or IL-15Rα expression in lung cancer. Methods: mRNA from 146 primary lung cancers were analyzed by multiplex qPCR for expression of IL-15, IL-15Rα and b-actin (internal control) and compared to expression in normal lung tissue from 45 patients. Of the 146 patients, 50 were stage I (IA=20, IB=30), 49 stage II (IIA=9, IIB=40), 36 stage III (IIIA=18, IIIB=18), and 11 stage IV. Results: Comparing the expression of IL-15 between normal lung and tumor, we found tumors expressed significantly less IL-15 than normal lung (P&lt;0.001). Lung cancers at any given stage, expressed significantly less IL-15 than that seen in normal lung. When comparing stages, stage IV tumors expressed significantly less IL-15 than tumors of stages I (P=0.021), II (P=0.020), or III (P=0.024). There was no difference in expression between stages I, II or III (P&gt;0.05). When examining the expression of IL-15Rα we found no differences between normal lung and tumor. No differences were seen between normal lung and stages I-IIIA; however, significantly less IL-15Rα expression was noted in stages IIIB and IV compared to normal lung. Between stages, stages I and II had significantly more IL-15Rα expression than stage IV tumors. There were no differences between stages I, II and III. Conclusions: Pro-inflammatory cytokines such as IL-15 may be important for the induction of lung immunity. IL-15 expression is down regulated in lung cancers and this down regulation increases with stage. We posit that the down regulation of IL-15 by lung cancers may aid in their evasion of immune responses allowing progression and dissemination of tumor.
An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers
Authors: Ana I. Robles, Eri Arai, Ewy A. Mathé, Hirokazu Okayama, Aaron J. Schetter, Derek Brown, David Petersen, Elise D. Bowman, Rintaro Noro, Judith A. Welsh, Daniel C. Edelman, Holly S. Stevenson, Yonghong Wang, Naoto Tsuchiya, Takashi Kohno, Vidar Skaug, Steen Mollerup, Aage Haugen, Paul S. Meltzer, Jun Yokota, Yae Kanai, Curtis C. Harris
Journal: Journal of Thoracic Oncology (2015)
The prevalence and prognostic significance of autoantibodies detected in patients with high risk melanoma receiving adjuvant therapy with high-dose interferon
Authors: D. Tsoutsos, J. Ioannovich, K. Frangia, D. Bafaloukos, A. Stratigos, S. Stavrianos, I. Potouridou, M. Mantzourani, C. Markopoulos, H. Gogas
Journal: Journal of Clinical Oncology (2005)

7519 Background: Immunotherapies that have shown a benefit in advanced melanoma have been shown to induce the collateral appearance of autoimmune responses as thyroid autoantibodies and depigmentation. The purpose of this study was to assess the prevalence of autoantibodies in the serum of stage IIB and III melanoma patients on high dose adjuvant interferon and the appearance of vitiligo, and address their prognostic significance. Patients and Methods: Two hundred patients were included in the study. Peripheral blood was obtained prior to initiation of adjuvant interferon at completion of 1 month of intravenous interferon and at three monthly intervals. Serum samples were tested for antithyroid, antinuclear, anti-DNA, anticardiolipin antibodies by enzyme linked immunosorbant assay (ELISA). Patients were examined for the appearance of vitiligo. Results: The patients were followed for a median time of 36 months. Autoantibodies were detected in fifty two (26%) of 200 patients. 111 patients have relapsed and 78 have died. The median time to progression was 24 months and the median survival was 43.9 months. The median time to progression for the patients who tested negative for autoantibodies was 14.8 months and has not been reached yet for the 52 patients who developed autoantibodies (105 vs 6 p<0.0001). The median survival was 30.7 months for those who were negative and has not been reached yet for the other group (76 vs 2 p<0.001). In multivariante analysis the presence of autoimmunity was an independent favorable prognostic marker. Conclusion: The detection of autoantibodies and appearance of vitiligo was associated with a lower risk of relapse, longer disease free and overall survival. The induction of autoimmunity may be a surrogate marker for monitoring the efficacy of adjuvant treatment with interferon in stage IIB and III melanoma patients. No significant financial relationships to disclose.
Phase I and pharmacokinetic trial of oral administration of CYC682, a novel 2’ deoxycytidine type anti-metabolite pro-drug, in patients with advanced solid tumors or lymphoma
Authors: A. Tolcher, R. B. Cohen, B. Benettaib, L. Frenz, A. Gianella-Borradori, E. Calvo
Journal: Journal of Clinical Oncology (2005)

2026 Background: CYC682 is converted by intestinal and plasma amidases to the active agent CNDAC [1-(2-C-cyano-2-deoxy-β -D-arabino-pentafuranosyl)-cytosine] and intracellularly activated by deoxycytidine kinase to CNDAC triphosphate. The mechanism of action includes inhibition of DNA polymerase, cessation of DNA strand elongation and DNA strand breakage. A previous phase I study of a 5 days/week, for 4 weeks every 6 weeks schedule determined a maximum tolerated dose (MTD) of 40 mg/m2/day (d), with neutropenia as the principal toxicity. To maximize plasma exposure we have evaluated twice daily oral administration on days 1–14 of a 21-day cycle (cyc), with the determination of the MTD and the recommended phase II dose (RD) as objectives. Methods: MTD was defined as ≥2/3 or 3/6 patients (pts) with dose limiting toxicity (DLT) in cyc 1 and RD as next lowest dose level (DL). DL of 20, 40, 66, 100 mg/m2/d were explored. Blood samples for pharmacokinetic (PK) analysis of CYC682 and CNDAC were drawn on d 1 and 14 of the 1st cyc and d 14 of the 3rd cyc. Results: 15 pts have received 22 cyc. M/F: 8/7; median age 59 (range 43–72); PS 0/1: 1/14; principal tumor types: breast (2 pts), NSCLC (3), ovarian (2), colon (2). All but one had been pre-treated with numerous chemotherapy regimes (median 4, range 1–6). DLT of febrile neutropenia (FN) and thrombocytopenia (T) occurred in 2/6 pts at DL3, with the MTD due to FN in 3/3 pts reached at DL4. Expanded accrual is ongoing at 66 mg/m2/d as the potential RD. Non-hematologic toxicities including diarrhea have been observed but are manageable. PK data are available for 12 pts, and demonstrate a moderate correlation between CNDAC exposure and CYC682 dose. The inter-patient variability of CYC682 Cmax and AUC0–8hr observed at DL3 is approximately 4-fold. Terminal half-life in DL3 is 2.3 ±0.9 hr. Conclusion: The MTD for this schedule is 100 mg/m2/d with febrile neutropenia as DLT. DL (mg/m2/d) No. pts (cyc) No. pts DLT NCI-CTC toxicity by pt (grade) Cmax (ng/mL) AUC0–8hr (hr*ng/mL) FN N T Diarrhea N/V 20 3 (4) - - - 1 (2) 1 (2) 2 (1) 1.8±2.3 4.7±7.6 40 3 (7) - - 1 (2) - 1 (2) 1 (2) 6.1±2.3 13.7±21.6 66 6 (4) 2 2 (DLT) 1 (3) 1 (4,DLT) 1 (1) - 5.2±2.8 12.0±6.4 100 3 (3) 3 3 (DLT) - - - - - - Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CAC SA, Kremlin-Bicetre, France, Cyclacel Ltd., Dundee, UK CAC SA, Kremlin-Bicetre, France
Maximum Standardized Uptake Values on Positron Emission Tomography Correlates with Iaslc/Ats/Ers Histologic Subtypes and Prognosis of Clinical Stage Ia Lung Adenocarcinoma
Authors: Y. Miyata, T. Yoshiya, T. Mimae, S. Sasada, N. Tsubokawa, H. Nakayama, M. Okada
Journal: Annals of Oncology (2014)
ERCC1, BRCA1, thymidylate synthase (TS), class III beta tubulin (bTubIII), p53R2, RRM2 immunohistochemical expression in stage I-III non-small cell lung cancer (NSCLC): A tissue microarray (TMA) study.
Authors: F. Grossi, D. F. Merlo, S. Salvi, D. Bordo, C. Genova, E. Rijavec, M. Taviani, P. Pronzato, G. B. Ratto, M. Truini
Journal: Journal of Clinical Oncology (2010)

e21094 Background: previous studies have shown that high levels of BRCA1, TS and bTubIII and low levels of ERCC1 and RRM1 expression are associated with poor prognosis in NSCLC patients (pts) treated with surgery alone. Also, clinical studies suggest that ERCC1, RRM1, BRCA1 and bTubIII expression is associated with resistance to several agents. Methods: tumor tissue samples from 82 pts with stage I-III NSCLC who underwent surgery between 7/2005-3/2007 were analyzed. Viable tumor was sampled in triplicate for TMA analysis and slides were stained by immunohistochemistry (IHC) with antibodies against ERCC1, BRCA1, TS, bTubIII, P53R2, RRM2. All tissue arrays were examined and independently scored by two observers (M.T. and S.S.), blinded to the patients. The score was calculated using the following formula: (1 + I) × PC, where I represents the staining intensity and PC represents the percentage of tumor cells that stained at each intensity, respectively. A categorical value (positive vs negative) was used for statistical analyses of marker expression. In addition, IHC expression profiles were correlated with clinicopathological features. Results: during a median follow-up time of 41 months (range 28-54), a total of 13 deaths was observed. In univariate analysis, P53R2 expression was significantly higher in adenocarcinoma compared to squamous samples (mean score 59.3 vs 4, p = 0.01), whereas TS expression was significantly higher in squamous tumors (mean score 39.2 vs 3.1, p = 0.03). bTubIII expression was significantly higher in stage I vs stage II pts (mean score 200.2 vs 49.2, p = 0.023). No significant association was seen between ERCC1, BRCA1, RRM2 expression and any clinicopathological features. The small number of deaths is insufficient for meaningful prognostic evaluation. Conclusions: this study confirms the different expression of TS in adenocarcinoma compared to squamous pts and suggests a possible role of p53R2 as a marker for histological differentiation. The significantly higher expression of bTubIII in stage I compared to stage II pts may explain a stage-specific different efficacy of adjuvant chemotherapy. No significant financial relationships to disclose.
Phase I study of BAY 43–9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors
Authors: S. Steinbild, F. Baas, D. Gmehling, E. Brendel, O. Christensen, B. Schwartz, K. Mross
Journal: Journal of Clinical Oncology (2005)

3115 Background: BAY 43–9006 (BAY), a Raf kinase and VEGFR inhibitor, inhibits tumor cell proliferation and angiogenesis. In preclinical studies BAY and irinotecan (CPT-11) had improved anti-tumor activity over single agents. Methods: This phase I study investigated the safety and pharmacokinetics (PK) of continuous oral BAY plus CPT-11 administered weekly for 4 weeks followed by a 2-week break. In an initial dose-escalation phase, patients (pts) with advanced, refractory solid tumors received CPT-11 125 mg/m2 and BAY 100, 200 and 400 mg bid (cohorts 1–3). In an extended phase, colorectal cancer (CRC) pts received fixed-dose CPT-11 140 mg and BAY 400 mg bid (cohort 4). Results: 32 pts (ECOG 0:1:2=10:21:1) were valid for safety. 20 pts were enrolled in the dose-escalation phase (common tumor types: CRC [n=9] and gastric cancer [n=4]) and 12 pts in the CRC extension. MTD was not reached. The most common drug-related AEs were diarrhea, alopecia, fatigue, nausea and vomiting. The most common ≥grade 3 AEs were blood/bone marrow related and gastrointestinal. 12/20 pts in cohorts 1–3 and 5/7 evaluable pts in cohort 4 had SD as best response. BAY 100 or 200 mg bid and CPT-11 125 mg/m2 had no marked impact on the PK of either drug. BAY 400 mg bid plus CPT-11 125 mg/m2 or 140 mg increased exposure to CPT-11 and the metabolite SN 38, but did not appear to increase clinical toxicity. CPT-11 140 mg had a negligible effect on the PK of BAY. Conclusions: MTD was not reached for BAY 400 mg bid plus CPT-11 125 mg/m2 or 140 mg. BAY 400 mg bid and CPT-11 125 mg/m2or 140 mg increased exposure to CPT-11 and SN 38. CPT-11 140 mg had a negligible effect on the PK of BAY. As patients are still being treated with 140 mg CPT-11 and BAY 400 mg bid, the recommended dose for CPT-11 in combination with BAY 400 mg bid will be made when these data are presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer
Randomized trial of acupuncture versus sham control for prevention of myelosuppression in patients with gynecologic malignancies
Authors: U. Matulonis, H. Lee, W. Lu, A. Goodman, A. Rosulek, A. Doherty, A. Kornblith, T. Atkinson, C. Gibson, E. Dean-Clower, R. Penson
Journal: Journal of Clinical Oncology (2007)

19524 Background: CIM is a significant toxicity that is treated with cytokine growth factors, dose reductions and/or delays. Preliminary uncontrolled Chinese studies suggest that acupuncture lessens CIM. Methods: Patients (pts) with newly diagnosed or recurrent gyn cancers receiving chemotherapy were eligible. Trial design was a double blinded, randomized trial of active acupuncture or sham for 5 weeks (administered 3x per week). Primary endpoints were first nadir WBC and ANC levels at chemo cycle 2; other endpoints were recovering counts following the cycle 2 nadir, QOL, G-CSF levels, and feasibility. Results: &gt;460 patients were screened. 21 pts were randomized to either active acupuncture (n=11) or sham control (n=10). Median age of the pts was 55 yrs (range: 28–81). 15 pts have completed the acupuncture treatment to provide the baseline and nadir WBC and ANC. Toxicities related to either sham or active acupuncture were minimal. The active pts group showed higher baseline WBC (median: 3,600 vs. 2,600, NS) and ANC (median: 2,269 vs. 1,922, NS) values. The nadir WBC was higher in the pts receiving acupuncture (median 3,600 vs. 2,300) but the difference was not statistically significant after adjusting for the baseline difference (p=0.16). Nadir ANC was higher among the pts receiving acupuncture (median: 2,424 vs. 1,274) but the difference was not statistically significant after adjusting for the baseline difference (p=0.1107). Recovering WBC in the pts receiving acupuncture was higher (median: 8,600 vs. 4,400) after adjusting for the baseline difference (p=0.045). The recovering ANC in the pts receiving acupuncture was higher (median: 6,530 vs. 4,038) but this difference was not statistically significant after adjusting for the baseline difference (p=0.0919). QOL and G-CSF data will be presented at ASCO. Conclusions: Although a larger randomized trial is necessary to determine the effects of acupuncture on CIM, there were consistent trends, and recovering WBC counts were significantly higher in patients receiving acupuncture. Formal evaluation of CAM is vital to confirm potentially clinically meaningful benefits. No significant financial relationships to disclose.