tbuckley/cabot-search huggingface dataset:
Defining gefitinib sensitivity/resistance in non-small cell lung cancer (NSCLC) cell lines by affymetrix gene arrays
Authors: F. R. Hirsch, W. A. Franklin, S. E. Witta, B. Helfrich, R. Lapadat, C. D. Coldren, M. Sugita, P. A. Bunn
Journal: Journal of Clinical Oncology (2004)

7027 Background: Gefitinib (Iressa) and other EGFR inhibitors are active in 12–19% of NSCLC patients previously treated with chemotherapy. Currently, there are no selection criteria for determining which NSCLC patients will benefit from this treatment. EGFR expression does not predict Gefitinib sensitivity. Using a panel of NSCLC cell lines with varying sensitivity to Gefitinib we defined a panel of biomarkers that predict sensitivity or resistance. Methods: Gefitinib sensitivity was determined in 18 NSCLC cell lines using MTT assays. Cell lines were classified as Gefitinib sensitive (IC50<1μM), resistant (IC50>10μM) or intermediate sensitivity (IC50 1–10μM). Oligonucleotide microarray (Affymetrix HGU 133A, 22,000 genes) analysis was performed on 10 cell lines. Three distinct filtration and normalization algorithms were used to process the expression data and a list of genes was generated that was both statistically significant (unadjusted p=0.001 cutoff) and corrected for occurrence of false positives. This approach was used in combination with 5 distinct machine learning algorithms to build a test set for predictor genes that was successful in 100% of test cases. The best discriminators (>3 fold difference in expression between sensitive and resistant cell lines) were selected for quantitative real-time RT-PCR. Results: A list of 144 genes was generated from the Affymetric array analysis. By using the mathematical algorithm 16 candidate genes were selected for RT-PCR. Thirteen of the 16 genes were verified to discriminate between sensitive and resistant cell lines by quantitative real-time RT-PCR. Conclusions: Based on NSCLC cell line studies it was possible to identify 13 different genes, which strongly discriminated Gefitinib sensitive cell lines from the resistant ones. This biomarker panel may be of significant value for selecting NSCLC patients for Gefitinib treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen; AstraZeneca Allos Therapeutics; AstraZeneca Eli Lilly
Cure prevents more than transmission of hepatitis C virus
Authors: Harel Dahari, Scot J. Cotler, Jordan J. Feld
Journal: Hepatology (2016)

Supported by NIH grants P20‐GM103452 and R01‐AI078881. Potential conflict of interest: Dr. Feld consults and received grants from AbbVie, Gilead, Janssen, and Merck. He consults for Bristol‐Myers Squibb and received grants from Abbott. To the Editor: We read with interest the study by Cousien et al.,1 which presents a comprehensive and elegant modeling approach to the treatment of hepatitis C virus (HCV) in people who inject drugs (PWID) in France that includes liver disease progression/regression, the overall cascade of anti‐HCV care, and rich field data. However, we were surprised that the model assumed no liver‐related benefit after HCV eradication (termed sustained virological response [SVR]) with direct‐acting antiviral treatment in patients with cirrhosis. In their model, the authors made the assumption of no reduction in complications of cirrhosis after SVR in patients with established cirrhosis by citing our study,2 which actually showed that the rate of all complications, including hepatocellular carcinoma (HCC), liver‐related mortality, and even all‐cause mortality, was markedly reduced after SVR. Others have shown that cirrhosis actually resolved in half of patients who achieved SVR, with a >70% reduction in the risk of HCC and a 90% reduction in the risk of liver‐related mortality and liver transplantation (www.hcvguidelines.org). While the proportion of PWID with cirrhosis is relatively small, it would be helpful for the authors to report whether their results would change, assuming that PWID with cirrhosis who achieve SVR will have a marked reduction in the risk of HCC, decompensation, and liver disease‐related mortality as supported by our data and others.2 Fortunately, taking into account the benefits of SVR would only strengthen the rationale for advancing treatment in PWID, which seems relatively feasible according to their projections. This revision to the model would strengthen the credibility of the results and is of particular importance when modeling projections in PWID populations are used to evaluate the impact of treatment scenarios in absolute numbers. In conclusion, the model from Cousien and colleagues provides important insights into the potential impact of treatment as prevention for the management of HCV in PWID. However, the assumptions of the model should include the significant reduction in all‐cause complications post‐SVR, including HCC and decompensation along with regression in fibrosis, among PWID with established cirrhosis. This assumption is of importance for accurate modeling predictions and policy‐making in countries (e.g., United States) with barriers restricting access to direct‐acting antiviral treatment for PWID.3
Iron Metabolism and Erythropoietic Stress in Myelodysplastic Syndromes.
Authors: Valeria Santini, Alessandro Sanna, Lorena Duca, Antonella Gozzini, Domenico Girelli, Agostino Cortelezzi, Gianluigi Reda, Natascia Campostrini, Maria Domenica Cappellini
Journal: Blood (2009)
Immune evasion by melanoma and ovarian tumor cells through upregulation of the immunosuppressive molecule CD200
Authors: A. Siva, H. Xin, F. Qin, A. Mickel, S. Faas, A. Kretz-Rommel, K. S. Bowdish
Journal: Journal of Clinical Oncology (2006)

2545 Background: Immune escape by tumors can occur by multiple mechanisms, each a significant barrier to immunotherapy. Upregulation of the immunosuppressive molecule CD200 on chronic lymphocytic leukemia cells inhibits Th1 cytokine production required for an effective cytotoxic T cell response. CD200 expression on human tumor cells in animal models prevents human lymphocytes from rejecting the tumor; treatment with an antagonistic anti-CD200 antibody restored lymphocyte-mediated tumor growth inhibition. This study evaluated CD200 expression on other cancers, and its effect on immune response. Methods: CD200 levels in ovarian adenocarcinoma and metastatic melanoma samples were evaluated by RT-QPCR and immunohistochemistry. Cell-surface CD200 on melanoma and ovarian cancer cell lines was assessed by flow cytometry. The effect of CD200 on cytokine production in mixed lymphocyte reactions (MLR) was assessed by adding the cells to cultures containing human monocyte-derived dendritic cells and allogeneic T cells. Th1 and Th2 cytokines in culture supernatants were detected by ELISA. Results: RT-QPCR showed CD200 expression levels upregulated in serous ovarian adenocarcinoma compared to normal samples. In malignant melanoma, CD200 expression in jejunum metastases was significantly higher than in normal samples, and 2 of 6 lung metastases showed CD200 upregulation. IHC showed strong, membrane-associated CD200 staining on malignant cells of two melanoma patients. Three ovarian cancer patients showed varying levels of CD200 tumor staining; all showed strong stromal staining. CD200 was highly expressed on the cell surface of SK-MEL-24 and SK-MEL-28 melanoma and OV-CAR-3 ovarian cancer cell lines and moderately expressed on the melanoma cell line SK-MEL-5. Addition of these cell lines to MLRs downregulated the production of Th1 cytokines; addition of CD200-negative cell lines did not. Inclusion of an antagonistic anti-CD200 antibody during the culture restored Th1 cytokine responses. Conclusion: Melanoma and ovarian tumor cells can upregulate CD200, thereby potentially suppressing anti-tumor immune responses. Therapy with an antagonistic anti-CD200 antibody may permit an effective cytotoxic immune response against the tumor cells. [Table: see text]
UFT after sequential chemo and radiotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC)
Authors: R. Martins, P. De Biase, E. Toscano, D. Madeira, C. Pereira, A. Cavalcante, I. Pinel, W. Roriz, M. Zukin
Journal: Journal of Clinical Oncology (2004)

7294 Background:Chemotherapy added to radiotherapy decreases systemic progression in patients with locally advanced NSCLC. However,distant failure remains a significant cause of morbidity and mortality in these patients. Randomized studies from Japan showed that UFT improves survival in patients (pts) with early NSCLC. The reduction in systemic relapsed is due to its effect on the micrometastatic disease.We conducted a phase II study to evaluate the effect of UFT on the systemic progression of pts with stage IIIB NSCLC. Methods:Patients with stage IIIB NSCLC were included. Pts had ECOG performance status (PS) 0 or 1 and normal end organ function.Pts were treated with induction chemotherapy with two cycles of cisplatin (100mg/m2 days 1 and 29) and vinblastine (5mg/m2/week for 5 weeks) followed by 60Gy of thoracic radiotherapy. Two weeks after the completion of radiotherapy they were started on a fixed dose of 400mg/day of UFT, administered continuously for one year. Results:Between May 1999 and October 2003 twenty four pts were included. Patient's characteristics: 15 male (62%), 10 adenocarcinoma and 10 squamous cell, 4 pts had NSCLC not otherwise classified, median age was 55 years, all pts had PS of 1. Only one pt was not a former or current smoker. Toxicity of the chemo/radiotherapy phase of the study was compatible with published literature with no toxic deaths. Toxicity of UFT was minimal. The most common side effect was fatigue. Median time on UFT was 6 months.In 6 pts (50%) the first clinical sign of progression was local, and in the other 6 patients it was systemic (2 brain). Five pts (21%) completed 12 months on UFT and 5 are on treatment. With a median follow-up of 12 months the median survival was 14 months. The actuarial 1,2 and 3-year survivals were 52, 35 and 25%, respectively. Conclusions:UFT in this fixed dose schedule was very well tolerated. However our results are almost identical to the published literature with sequential chemo and radiotherapy in stage IIIB NSCLC. This finding suggests that UFT may have little effect on the control of micrometastatic disease in pts with locally advanced NSCLC. Local control remains a critical issue in stage IIIB patients. No significant financial relationships to disclose.
Evaluation of serum hepcidin concentrations in cancer and leukemia patients
Authors: T. C. Arvedson, H. Li, M. J. Rose, O. Wang, B. J. Sasu
Journal: Journal of Clinical Oncology (2008)

20581 Background: Hepcidin controls iron homeostasis by regulating iron uptake and redistribution in response to systemic iron requirements: high circulating iron leads to hepcidin expression which in turn decreases circulating iron. Hepcidin can also be induced by inflammation, which may lead to inappropriately low circulating iron levels, as seen in functional iron deficiency, a proposed causative factor in the anemia of inflammation. This study aimed to establish the hepcidin concentrations and hence the potential role of functional iron deficiency in contributing to anemia in cancer and leukemia patient populations. Methods: Sera from the following populations were analyzed: chemotherapy-induced anemia (CIA, n=100), anemia of cancer (AoC, n=30), sepsis (n=25), myelodysplastic syndrome (MDS, n=8), healthy controls (n=60), iron deficiency anemia (IDA, n=12), acute myeloid leukemia (AML, n=13), acute lymphoblastic leukemia (ALL, n=4), chronic myeloid leukemia (CML, n=10), multiple myeloma (MM, n=8) and chronic lymphocytic leukemia (CLL, n=11). Serum hepcidin concentrations were assessed by a sensitive, quantitative HPLC-MS/MS method. Iron indices and CRP (as an inflammatory marker) were also measured. Results: Serum hepcidin was elevated in a subset of patients with CIA (84±86ng/ml), AoC (100±97ng/ml), sepsis (189±204ng/ml), MDS (238±159ng/ml) and leukemia (223±203ng/ml). Serum hepcidin was not elevated in healthy donors (7±19ng/ml) or patients with IDA (9±14ng/ml). Further analysis of leukemia patient sera revealed elevated serum hepcidin in all patients with AML (354±153ng/ml) and ALL (532±266ng/ml), a spectrum of hepcidin concentrations within CML (156±179ng/ml) and MM (162±112ng/ml) patient populations. Hepcidin concentrations were elevated in CLL patients (59±29ng/ml), albeit to a lesser degree than observed in the other subsets evaluated. In some patient populations, elevated CRP and hepcidin concentrations were both present. Conclusions: This study demonstrates that hepcidin concentrations are elevated in multiple cancer and leukemia patient populations raising the possibility that functional iron deficiency may play a role in the etiology of anemia in cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc.
Long-term progression-free survival (PFS) in patients with metastatic breast cancer (BC) treated with tandem autologous followed by allogeneic stem cell transplantation (SCT).
Authors: C. Becker, H. Al-Ali, D. Langanke, F. Hoffmann, U. von Gruenhagen, D. Niederwieser
Journal: Journal of Clinical Oncology (2010)

1141 Background: Metastatic BC is still an incurable disease with poor long-term PFS. Previous studies using allogeneic SCT were performed in patients with advanced metastatic disease irrespective of the response at the time of SCT. In this study we evaluated 6 patients with responsive metastatic BC after tandem SCT, a protocol showing promising results in previous studies with related donors. Methods: Between December 2005 and December 2008 the feasibility of autologous followed by allogeneic SCT was tested in 6 patients with metastatic breast cancer, aged 41.5 (range 37-50) years. Two patients expressed ER/PR receptor, two patients over expressed HER2/neu, and two patients were hormone receptor triple negative. Patients received a median of two chemotherapy lines to treat metastatic disease (range 1-3). The disease was responsive to chemotherapy leading to CR in one patient, PR in four and SD in one. Conditioning consisted of mitoxantrone (45 mg/m2) on day -5 and thiotepa (600 mg/m2) on day -4 for autologous SCT and consisted of fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 from day -4 to -2 for allogeneic SCT. Cyclosporine and MTX were given as GVHD prophylaxis. Results: All 6 patients engrafted with a median T-cell chimerism of 77.5 (range 35-100) % on day 28. One patient who developed a secondary graft failure received a second allogeneic SCT from another unrelated donor resulting in complete engraftment. Two patients developed grade ≤ 2 acute GVHD and one of them chronic GVHD responsive to immunosuppression. With a median follow up of 34 months, the median PFS is 8.5 months (47+, 46+, 1, 8, 1, 9) and the actual median overall survival (47+, 46+, 12, 22+, 2, 12+ months) has not been reached. The patients in complete remission 47 and 46 months after allogeneic SCT both received an unrelated SCT and were in CR and PR before SCT. Conclusions: Tandem auto-allo SCT is feasible leading to long term DFS in 2 of 6 patients with advanced metastatic BC. No significant financial relationships to disclose.
Capecitabine (X) combined with cisplatin (P) as 1st-line therapy in Chinese patients (pts) with advanced gastric cancer (AGC)
Authors: M. Jin, L. Shen, B. Hu, J. Yu, Z. Wen, Y. Su, B. Wang, L. Chen, H. Ying, L. Chen
Journal: Journal of Clinical Oncology (2004)

4047 Background: Despite a recent fall in incidence, gastric cancer remains common in China. 5-FU plus P is a standard treatment for AGC, producing response rates of 27–51% in randomized trials, although few Chinese data are available. We evaluated the efficacy and safety of replacing the 5-FU component with X (Xeloda) as 1st-line therapy in Chinese AGC pts. Methods: We enrolled 145 pts between Jun 2002 and May 2003. All had measurable AGC (WHO), and adequate Karnofsky PS, bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was permitted. Patients received capecitabine 1000 mg/m2 orally twice daily on days 1–14 plus fractionated cisplatin 20 mg/m2 i.v. on days 1–5, every 3 weeks. Results: Baseline characteristics of the 130 pts evaluable to date: 98 men, 32 women; median age 53.7 years (range 23–80); median Karnofsky PS 80 (60–100); 82% of pts had 1 metastatic site, and 18% had ≥2, the most common being the lymph nodes (44%), liver (42%), and stomach (17%). The median treatment duration is currently 6 cycles (range 2–6). Efficacy findings are shown in the table: response rate 45% (95% CI, 36–53%). Median progression-free and overall survival have not yet been reached. There were no grade 4 and very few grade 3 adverse events (all <5%): SGPT and SGOT, hand-foot syndrome, nausea, vomiting, anemia, diarrhea, anorexia, anaphylaxis. Most events were easily managed with dose adjustment and/or suitable treatments, except 1 pt with anemia who withdrew after 2 cycles. Conclusions: X combined with fractionated P is highly active and very well tolerated as first-line treatment for AGC, with comparable results to 5-FU/P. These results provide the rationale for randomized testing of the combination, although standard single infusion of P would enhance convenience. No significant financial relationships to disclose.
Impact of RASSF1A methylation on survival of stage IIIb and IV NSCLC patients treated with gemcitabine
Authors: J. R. Fischer, U. Ohnmacht, N. Rieger, C. Stoffregen, C. Manegold, H. Lahm
Journal: Journal of Clinical Oncology (2006)

17028 Background: The epigenetic inactivation of genes plays an important role in lung cancer carcinogenesis. We have investigated the methylation status of seven genes (APC1A, DAPK, FHIT, p14 ARF , p16 INK4a , RARβ, RASSF1A) in serum DNA of NSCLC patients and analyzed their potential prognostic value. Methods: Blood samples were drawn pretherapeutically. Genomic DNA was purified from serum and subjected to sodium bisulfite treatment to convert unmethylated cytosine bases. Epigenetic alteration was detected by a nested methylation-specific PCR. Results: We have investigated a group of 92 patients with histologically confirmed NSCLC (60 males, 32 females; 21 stage IIIb, 71 stage IV; median age 60.9 years, range 34–78). All patients received gemcitabine first-line alone or in combination with other drugs. The vast majority of samples (n = 87) showed at least one methylated gene. More than half of the tested genes were hypermethylated in 20 samples (21.7%). The methylation frequencies of individual genes were 30.8% (APC1A), 26.1% (DAPK), 47.3% (FHIT), 30.4% (p14 ARF ), 25.9% (p16 INK4a ), 44.6% (RARβ) and 33.3% (RASSF1A). The hypermethylation status of none of the genes altered median overall survival (11.0 ± 1.4 mo) of the total population significantly. However, patients with a methylated RASSF1A gene who showed a partial response (n = 27) survived significantly longer (33.6 ± 10.4 mo) compared to those with a wild-type allele (16.1 ± 4.7 mo, P = 0.0045). This difference was not seen in patients with stable (n = 40) or progressive (n = 20) disease. Conclusions: Our results show that the hypermethylation frequency of single genes and the accumulation of epigenetic alterations in individual samples of NSCLC patients may vary considerably. Molecular parameters such as RASSF1A hypermethylation may be useful prognostic markers in subpopulations. [Table: see text]
Cooperative antitumor activity between the retinoid X receptor (RXR)-selective agonist bexarotene and EGFR-tyrosine kinase inhibitors in preclinical models of NSCLC
Authors: R. P. Bissonnette, B. Fan, K. Roegner, S. Ng, M. Corpuz, R. Prudente, A. Negro-Vilar, W. Yen
Journal: Journal of Clinical Oncology (2006)

17073 Background: Gefitinib and erlotinib, small molecule inhibitors of the EGFR-tyrosine kinase (EGFR-TKI), can have antitumor activity in patients with advanced NSCLC. However, analysis of clinical samples and in vitro characterization of NSCLC cell lines has revealed EGFR mutations that correlate with the clinical responses. While EGFR-mutant cell lines are hypersensitive to EGFR-TKI-mediated growth inhibition and have a greater tendency to undergo apoptosis in response to EGFR inhibition, wild-type EGFR cell lines undergo growth inhibition only at high concentrations, and are resistant to apoptosis induction. Bexarotene (Targretin) is a RXR modulator with clinical activity enhancing survival in a subset of NSCLC patients. We have shown that bexarotene can suppress the growth of epithelial tumors by modulating the expression and function of the EGFR pathway. This study examined the effect of bexarotene/EGFR-TKI combinations in preclinical models of NSCLC, and evaluated the possible molecular mechanisms for cooperative antitumor activity between these agents. Results: Bexarotene enhanced the activity of gefitinib in most of the cell lines tested, and did so regardless of their EGFR mutation status or intrinsic sensitivity to gefitinib alone. Resistant lines were sensitized by the combination, which decreased gefitinib IC50s to clinically achievable concentrations. Bexarotene increased the pro-apoptotic activity of both gefitinib and erlotinib, an effect which was paralleled by enhanced repression of p-Akt and p-Her2 levels by the combinations. In ex vivo cultures of human NSCLC explant tissue, the addition of bexarotene enhanced the growth inhibitory activity of both gefitinib and erlotinib. Finally, combinations of bexarotene and EGFR-TKI produced growth inhibition of TKI-resistant A427 NSCLC xenograft tumors that was superior to either agent alone. Conclusions: These results indicate that bexarotene can sensitize NSCLC cells which are unresponsive to the effects of EGFR-TKIs, resulting in cooperative growth inhibition and apoptosis induction. Combination therapy using bexarotene in conjunction with EGFR-TKIs may provide a powerful new therapeutic strategy. [Table: see text]