tbuckley/cabot-search huggingface dataset:
MicroRNA targeting for the therapy of colitis-associated colon cancer.
Authors: Christos Polytarchou, Daniel W. Hommes, Tiziana Palumbo, Maria Hatziapostolou, Georgios Koukos, Andrea E. van der Meulen-de Jong, Angelos Oikonomopoulos, Welmoed K. van Deen, Christina Vorvis, Marina Koutsioumpa, Eleni Birli, Jennifer Choi, Lin Chang, Peter A. Anton, Charalabos Pothoulakis, Hein W. Verspaget, Dimitrios Iliopoulos
Journal: Journal of Clinical Oncology (2015)

571 Background: Inflammatory Bowel Diseases (IBD) consist of ulcerative colitis (UC) and Crohn’s Disease (CD), which are characterized by activation of inflammatory responses. Patients with longstanding UC are at high risk of developing colorectal cancer. The identification of novel molecular targets with therapeutic potential for UC and UC-related dysplasia are of major importance. Methods: Using a high throughput functional suppressor screen of the human microRNAome, we identified microRNAs involved in the regulation nuclear factor kappa beta (NF-κB). We correlated microRNA expression levels with different clinicopathological parameters in 401 colonic specimens derived from patients with UC, CD, irritable bowel syndrome (IBS), sporadic colon cancer (CRC), colitis-associated cancer (CAC) and control subjects. Bioinformatic and molecular analyses were employed for the study of micoRNA-regulated signaling pathways. A microRNA specific chemical inhibitor was used to treat colonic biopsies ex vivo and murine CAC development in vivo. Results: The microRNA screen identified miR-214 as master regulator of NF-κB. MiR-214 levels are increased in colonic tissues from UC and CAC, but not from CD, IBS and CRC patients and positively correlate with UC disease activity and duration. STAT3 regulates miR-214 expression in colonocytes in vitro and STAT3 and miR-214 levels positively correlate in UC and CAC. MiR-214 regulates the expression of phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2) and both are decreased in colonic tissues of UC and CAC patients. MiR-214 is amplified through a feedback loop circuit and its overexpression increases the tumorigenic and invasive phenotype of colon cancer cells. A chemical miR-214 inhibitor perturbs this circuit in colonic biopsies from UC patients ex vivo while intracolonic delivery suppresses CAC growth in mice. Conclusions: Our findings demonstrate a gene controlling the inflammatory response specifically in UC and CAC. The miR-214 molecular circuit activity correlates with UC disease activity and duration. Activation of this circuit contributes to colitis-associated colon carcinogenesis, and its suppression has therapeutic potential for patients with UC-related dysplasia.
A double blind randomised placebo controlled trial of the PPAR-gamma agonist pioglitazone in mild asthma
Authors: John Anderson, Kevin Mortimer, Linhua Pang, Katherine Smith, Helen Bailey, Alan Knox, Tim Harrison
Journal: European Respiratory Journal (2013)

Introduction   Activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) modulates inflammatory gene transcription, and may be a novel therapeutic target for asthma (Nie et al. J Biol Chem 2005; 280(4):2550-61). To determine whether activating PPAR-γ results in measurable clinical effects in asthma, we performed a single centre randomised, parallel group, double blind, placebo controlled trial using the PPAR-γ agonist, pioglitazone (PIO).   Methods   68 non-smokers with asthma (taking as-required short-acting bronchodilators & 0-800mcg beclometasone) were randomised to PIO (n=34) or placebo (n=34). The primary outcome was the adjusted mean FEV 1  at 12 weeks. Secondary outcomes were adjusted mean morning and evening peak expiratory flow (PEF), asthma control & quality of life questionnaires, exhaled nitric oxide, bronchial hyper-responsiveness, induced sputum cell counts & adverse events (AE) at 12 weeks. Outcomes were adjusted for baseline value and other covariates and compared with ANCOVA. The full analysis (FA) included 55 completed cases & the per-protocol analysis (PPA) 52.   Results   There was no significant difference in the adjusted mean FEV 1  (-0.014 L, 95 % CI -0.15 to 0.12, p=0.84) or any of the secondary outcomes at 12 weeks in the FA. The PPA replicated the FA, except for a significantly lowered adjusted evening PEF in the PIO group at 12 weeks (-21.33 L/min 95% CI -39.15 to -3.51 p=0.02). There were more reported AEs (40% vs. 32%) & a lower adjusted haemoglobin in the PIO group at 12 weeks (-0.53 g/dL 95% CI -0.96, -0.11, p=0.015).   Conclusion  PPAR-γ agonists are not promising treatments for mild asthma.
COPD as an independent risk factor for lung cancer in patients with bronchial squamous dysplasia
Authors: Alaa Mohamed, Kiyoshi Shibuya, Ichiro Yoshino, Tarek Mahfouz, Aliae Abdrabou, Maha Elkholy
Journal: European Respiratory Journal (2011)

Background: We evaluated airflow obstruction as a possible independent risk factor for lung cancer (LC) in patients with bronchial squamous dysplasia (SD).

Methods: A total of 114 patients (111 men and 3 women) with at least 1 bronchial SD, at least 1 follow-up evaluation and normal baseline chest computed tomography (CT) were evaluated; 58 (51%) were COPD and 56 (49%) were non-COPD patients. Median age was 68 years (range,44–84 yr) and median follow-up duration was 21 months (range,4-98 months). Follow-up included periodic white light and autofluorescence bronchoscopy and chest CT. Expression of iNOS (inducible nitric oxide synthase) and EGFR (epidermal growth factor receptor) in bronchial epithelium biopsy specimens was evaluated by immunohistochemistry (IHC). Diagnosis of carcinoma in situ (CIS) and/or LC were follow-up endpoints.

Results: Expression of iNOS and EGFR was closely related to patient COPD status (p=0.007 and p=0.018, respectively). COPD patients were more likely to have baseline high grade dysplasia (p=0.017), multiple dysplasias (p=0.045) and to develop a new dysplasia during follow-up (p=0.003). Progression to CIS or LC occurred more frequently in patients with COPD (p=0.012), positive EGFR (p=0.019), positive iNOS (p<0.001) and baseline high grade SD (p=0.035). Multivariate analysis showed that risk for progression was closely related to airflow obstruction (RR=0.959; 95% CI=0.923-0.997; p=0.044) and iNOS expression (RR=10.521; 95% CI=2.75-40.3; p=0.001).

Conclusion: In patients with bronchial SD, COPD is closely related to risk of progression to CIS or LC. This study supports the hypothesis that inflammation and oxidative stress promote lung carcinogenesis.
Economic implications of the first-line treatment of advanced renal cell carcinoma in Thailand: A cost-effectiveness analysis.
Authors: N. Topibulpong, S. Tanasanvimon, N. Parinyanitikul, C. Vinayanuwattikun, V. Sriuranpong
Journal: Journal of Clinical Oncology (2010)

e15136 Background: Currently, there are several agents used to treat metastatic renal cell carcinoma (mRCC). However, limited studies comparing cost analysis among these available agents. Here we conducted a cost analysis of mRCC treatments in Thailand to determine the economic implications of these agents. Methods: A life-time Markov model was developed to simulate the patterns of disease progression and to determine the outcomes under treatment of available medicines including interferon-alpha (IFNa), sunitinib, sorafenib, and bevacizumab. Costs were measured based on the perspective of a healthcare provider. Resource utilization derived from retrospective chart reviews of 14 mRCC patients treated at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Costs and survival benefits were discounted annually at 3%. Results: The major assumption of the study was that the projected PFS and overall survival were longer for sunitinib than the other comparative treatments based on results of published studies. Cost-effectiveness analyses demonstrated that IFNa had the most favourable cost-effectiveness ratio at 1.3 Million Baht/QALYs followed by sunitinib, sorafenib, and bevacizumab at 1.7, 1.9, 9.3 Million Baht/QALYs respectively. However, sunitinib had a better incremental cost-effectiveness ratios (ICERs) over IFNa at 2.0 million Baht/PFY, 2.7 million Baht/LYG, and 3.6 million Baht/QALY gained. Both of sorafenib and bevacizumab plus IFNa cost-effectiveness were outperformed by sunitinib. Sensitivity analysis showed that the most sensitive parameters for sunitinib were the overall survivalefficacy and costs. Conclusions: Our study reveals that sunitinib has the good cost-effectiveness profiles as one of the first line treatment of mRCC. With current study model, it may be applicable to the situation in developing country with limit availability of TKIs in the treatment of mRCC. However, sunitinib's ICER comparing to IFNa is still beyond the ICER threshold for a developing country. This cost-effectiveness evidence should be taken into account in conjunction with other clinical, societal, and ethical considerations in the treatment of mRCC. No significant financial relationships to disclose.
CHOP/CHOEP-14 followed by consolidation with alemtuzumab in untreated aggressive T-cell lymphomas (DSHNHL 2003–1): Feasibility and toxicity of a phase II trial of the German High Grade Non-Hodgkin’s Lymphoma Group DSHNHL
Authors: L. H. Trumper, K. Hohloch, M. Kloess, U. Dührsen, H. Eimermacher, A. Haas, A. Aldaoud, M. Loeffler, N. Schmitz, M. Pfreundschuh, C. Binder
Journal: Journal of Clinical Oncology (2006)

7538 Background: The clinical course of peripheral T-cell lymphomas (PTCL) is unfavourable. Treatment protocols developed for aggressive B-NHL are employed, with significantly worse outcomes. The MoAb alemtuzumab (CAM) has shown promising activity in T-NHL, although its use may be complicated by severe infections. Methods: In 2003, the DSHNHL group initiated a prospective multicenter phase II trial for previously untreated PTCL. Six cycles of either CHOEP-14 (&lt; 60 y) or CHOP-14 (&gt; 60 y) with G-CSF support are followed by a short consolidation course with CAM, when either a CR or a good PR has been achieved. Inclusion criteria: PTCL-NOS, AILD, intestinal T-NHL, anaplastic large cell T-NHL (ALK negative); age 18–70 y; all IPIs; ECOG PS 0–3. The primary endpoint is feasibility, measured by occurrence SAE and protocol adherence. Secondary endpoints are remission rate, TTF, OS, DFS, tumor control and TRM. CAM is given at a total dose of 133 mg over 4 weeks. Prophylaxis against PCP and herpes infections is mandatory during CAM therapy and is continued until CD 4 cells are &gt; 200/μl. CMV-positive patients are monitored weekly. Results: 35 (of the planned 37) pts have been enrolled, 31 are evaluable. 5/31 pts are still undergoing chemotherapy. 7/31 pts had progressive disease or NC under/after chemotherapy and did not receive CAM. 18 of the 19 pts who achieved a CR/PR (15/4) received CAM. 12 of the CAM pts are in continuous CR, 7 had progressive disease or relapsed. There was no treatment-related death. Of 7 registered SAEs, 3 were related to chemotherapy, 4 to CAM (1 fungal pneumonia, 2 CMV pneumonias, 1 bacterial sepsis after dental procedure). Other CAM side effects were: Herpes Zoster (1), CMV-reactivation (1), grade III-IV neutropenias (2). All pts recovered with appropriate treatment. Conclusion: Preliminary analysis demonstrates that the combination of CHO/E/P-14 followed by a short course of CAM consolidation therapy is feasible without TRM. The adverse effects related to infections can be severe but manageable upon careful monitoring and close follow-up. The phase II trial will close in 4/2006, to be followed by a randomized phase III trial of A-CHOP-14 vs CHOP-14. No significant financial relationships to disclose.
A phase II study of tumor-treating fields (TTF) in combination with pemetrexed for advanced non-small cell lung cancer (NSCLC: Updated survival results.
Authors: M. Pless, D. C. Betticher, C. Droege, R. Cathomas, U. Weinberg
Journal: Journal of Clinical Oncology (2011)

e18030 Background: Low intensity, intermediate frequency, alternating electric fields have anti-mitotic activity in cancer cells. In recurrent glioblastoma patients, these Tumor Treating Fields (TTF) were found to effectively inhibit tumor growth and prolong progression free survival. Promising preclinical data has led to a clinical phase II trial in NSCLC patients (pts). Methods: A single arm, multi-center phase II trial was performed in 41 inoperable stage IIIB and IV NSCLC pts who had had tumor progression after at least one line of prior chemotherapy. All pts received pemetrexed 500mg/m2 IV q3w together with daily TTFields (12 h/day) applied to the chest and upper abdomen, using a portable medical device (NovoTTF-100L), until disease progression. The primary endpoint was “in-field” progression free survival (PFS). Results: Median age was 63 years, 73% had stage IV disease and 17% a performance status of 2. Squamous cell histology was included (17%). The average use of the device was 11.2 hours/day. With a median follow-up of 13.5 months (as of January 2011) the median PFS within the effective TTF area was 28 weeks, and the median overall PFS was 22 weeks. Six patients (14.6%) had a radiological PR and 16 SD (39%). The median overall survival was 13.4 months, the 1 and 2 year survival rate was 57% and 26%, respectively. There were no TTF -related serious adverse events, specifically there were no cardiac or neurogical events. The only device-related adverse event was mild to moderate contact dermatitis under the electrodes in 14 patients, which was easily manageable using steroid creams. Pemetrexed combined with TTF was also well tolerated. Conclusions: The combination of TTF and pemetrexed as a second line therapy for NSCLC has an excellent outcome compared to historical controls with pemetrexed alone. As a novel therapeutic modality TTF has the potential to become an effective non-toxic treatment option for advanced NSCLC and should be tested in a phase III trial in combination with chemotherapy.
Is neoadjuvant (neoadj) treatment necessary prior to liver resection in patients with resectable liver metastases (mets) from colorectal carcinoma (CRC) treated with post-resection hepatic arterial infusion (HAI) plus systemic (SYS) chemotherapy
Authors: N. E. Kemeny, M. Capanu, F. Huitzil-Melendez, D. Haviland, Y. Fong, W. Jarnagin, L. Blumgart, R. DeMatteo, M. D’Angelica
Journal: Journal of Clinical Oncology (2007)

14503 Background: Neoadjuvant therapy in patients (pts) with resectable liver mets has been reported to be associated with improved survival. We evaluated the clinical benefit of neoadj therapy in our pts receiving HAI + SYS after liver resection. Methods: In 4 studies of HAI + SYS after resection of CRC mets, data on neoadj, age, gender, clinical risk score (CRS), number of mets, primary site, resection margin status, presence of synchronous primary and/or bilobar disease were analyzed. Univariate and multivariate Cox proportional hazards models were used to examine differences in overall survival, hepatic or extrahepatic disease-free survival (DFS) between pts who received vs pts who did not receive neoadj. Differences among subgroups were compared using the log-rank test. Results: 234 pts from 4 post-liver resection trials using HAI + SYS were included. Each trial used HAI floxuridine/dexamethasone, with differing SYS regimens: FU/LV (n = 74); CPT11 (n = 98); FOLFOX (n = 31); and FOLFOX or FOLFIRI, ± bevacizumab (n = 31). Neoadj was given to 28% of the pts. Median followup was 4.6 years. No differences in terms of survival, hepatic or extrahepatic DFS were noted between pts who did or did not receive neoadj. Multivariate analyses showed no survival advantage for pts who received neoadj (Y vs N) (HR 0.997, 95% CI, 0.56–1.78). No subsets of pts were identified that showed an improvement in survival from neoadj (table), including pts who responded to neoadj prior to liver resection. Conclusions: Our results do not appear to support the use of neoadj in pts with resectable liver mets from CRC, if they are to be treated with postoperative HAI and SYS chemotherapy. [Table: see text] No significant financial relationships to disclose.
Association of TS and ERCC1 mRNA expressions with overall survival in patients enrolled in CONFIRM 1 and 2.
Authors: P. P. Grimminger, M. Shi, J. C. Barrett, D. E. Lebwohl, K. D. Danenberg, C. L. Vigen, D. Yang, J. Brabender, P. V. Danenberg, H. Lenz
Journal: Journal of Clinical Oncology (2010)

10522 Background: Targeted treatment strategies have been developed to improve survival of patients (pts) with metastatic colorectal cancer. Vatalanib (PTK787/ZK 222584) is an oral angiogenesis inhibitor and was combined with FOLFOX in first- (CONFIRM 1) and in second line (CONFIRM 2) but did not significantly improve progression-free survival or overall survival (OS). There are no molecular prognostic markers for pts with metastatic colon cancer used in the clinic. The goal was to validate our established cut off levels of TS and ERCC1 gene mRNA expressions in these two phase III studies. Methods: 122 mCRC samples of pts (32f /90m; median age 63y; range: 28-83yrs) enrolled in CONFIRM-1 or -2 were included in this study. All pts received either first-line FOLFOX4 (n=29) or FOLFOX4 + PTK/ZK (n=30) chemotherapy or second-line FOLFOX4 (n=37) or FOLFOX4 + PTK/ZK (n=26). After microdissection of the formalin fixed paraffin embedded samples, gene expression was measured using RT-PCR and β-actin as a reference gene. Previously established cut offs were used to determine high or low expressors. Results: TS mRNA expression was associated with OS in first but not second line therapy (9 mo in pts with high TS mRNA expression vs. 27.4 mo in pts with low TS in first line, p<0.001; in second line 10.4 mo with high TS vs. 12 mo in pts with low TS, p=n.s.). The combination of high TS and/or high ERCC1 mRNA expression was also associated with shorter OS (17 vs. 28.4 mo, p=0.043). First line treated pts with high TS and/or ERCC1 levels had a median survival of 17 mo and with both low of 28.4 mo (p=0.043). For second-line FOLFOX4 treated pts only ERCC1, not TS, was associated with OS (8.4 mo in high ERCC1 group vs. 15.8 mo in low ERCC1 group, p=0.032). There was a significant interaction of ERCC1 expression and benefit from PTK. Pts with high ERCC1 did not benefit from FOLFOX chemotherapy, but had benefit from FOLFOX+PTK (p for interaction=0.02). Conclusions: Our data confirmed that high gene expression levels of TS and ERCC1 are markers of poor prognosis. Efficacy of novel drug targets may be dependent on the sensitivity of cytotoxic chemotherapeutic agents. Interactions of molecular pathways need to be explored to allow more effective drug combinations. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Response Genetics Novartis Novartis, Response Genetics Response Genetics Novartis
Needle biopsy in malignant lymphoma.
Authors: G S Pinkus
Journal: Journal of Clinical Oncology (1996)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1996.14.9.2415 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8823318 Needle biopsy in malignant lymphoma. G S PinkusxG S PinkusSearch for articles by this author https://doi.org/10.1200/JCO.1996.14.9.2415 PDF "Needle biopsy in malignant lymphoma.." Journal of Clinical Oncology, 14(9), pp. 2415–2416© 1996 by American Society of Clinical Oncology
&lt;italic&gt;In Vivo&lt;/italic&gt; Effect of Urethan and Hydroxyurea on the Incorporation of Labeled Phosphate Into Nucleic Acids&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C. P. Giri, S. V. Bhide, K. J. Ranadive
Journal: JNCI Journal of the National Cancer Institute (1969)

Effect of urethan (1 mg/g body weight) and hydroxyurea (0.5 mg/g body weight) on the incorporation of labeled phosphate (32P) into nucleic acids in normal adult, newborn, and tumor-bearing mice was studied. Urethan had no effect on DNA and RNA synthesis in liver and lung tissues of adult mice at 6 hours, but it inhibited the DNA synthesis in lung tissue at 96 hours. DNA and RNA synthesis in liver tissue of newborn mice was inhibited by urethan even at 6 and 24 hours. In tumor-bearing mice, urethan decreased the incorporation of32P into DNA and RNA in tumor tissue. Hydroxyurea inhibited only DNA synthesis in liver and lung tissues of adult mice at 6 hours. The inhibitory effect decreased considerably at 96 hours. It decreased the incorporation of32P info DNA and RNA in liver tissue of newborn mice. In tumor-bearing mice, the drug inhibited DNA and RNA synthesis in the tumor, while only DNA synthesis was affected in liver tissue of the host.
Phase I/II study of trimetrexate (TMTX) and capecitabine (CAP) as second and third- line therapy in patients with advanced colorectal cancer (CRC)
Authors: K. Matin, R. K. Ramanathan, S. A. Jacobs, M. K. Wong, M. Earle, T. Evans, M. Troetschel, W. Ferri, D. Friedland, S. Wieand
Journal: Journal of Clinical Oncology (2004)

3673 Background: CAP is an orally administered, tumor selective fluropyrimidine with activity in CRC. The combination of TMTX, a non-classical folate antagonist, and 5-Fluorouracil (5-FU)/Leucovorin (LV) has shown promising activity in Phase II studies. CRC patients who have progressed after first and second line therapy have limited options. We designed a phase I/II study of TMTX and CAP to evaluate the maximal tolerated dose, toxicity, response rate and median survival of patients with advanced CRC. Methods: Eligible patients had received 1 or 2 prior regimens for advanced CRC and no prior therapy with TMTX or CAP. The initial phase I cohort of patients received TMTX 110 mg/m2 weekly x 6 and CAP 750 mg/m2 bid from day 2–15 and 23–36 (one cycle); oral LV 15 mg qid x 4 doses was given after each TMTX dose. Cycles were repeated every 8 weeks. The Phase II dose was determined to be TMTX 110 mg/m2 and CAP 1000 mg/m2 bid. 32 patients (pts) were treated, with 28 treated at the phase II dose. Patient characteristics: Male (n=20): Performance status ECOG 0 (n=22); median age 62 (range 34–78 yrs). All patients had prior 5-FU based therapy, 30 (94%) had prior exposure to irinotecan and 6 (19%) to oxaliplatin. Results: Therapy related Grade 3/4 toxicities included: abdominal pain- 4 patients (12.5%), vomiting- 3 (9.4%); dehydration, diarrhea, constipation and dyspnea- 2 each (6.3%). There was one death due to ileus and sepsis unrelated to therapy. There were no serious episodes of neutropenia or thrombocytopenia. 27 patients were evaluable for response: The overall response rate was 6.3%, with one patient each having had a complete response (CR) and a partial response (PR), while 11(34.4%) had stable disease (SD). The median overall survival (OS) was 5.9 months (95% CI, 5.2 to 10.2 months) and the median time to progression was 3.3 months (95% CI, 1.6 to 3.7 months), when time origin was first study treatment. The mean overall survival was 20.2 months, when time origin was initial diagnosis of metastatic disease. Conclusions: The combination of TMTX and CAP is well tolerated and has moderate activity in the second and third line setting of metastatic CRC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Hoffmann-Roche; MedImmune, Inc.