tbuckley/cabot-search huggingface dataset:
Gene-expression profiling of collecting duct carcinoma of the kidney.
Authors: Anna Tessari, Isabella Testa, Elena Verzoni, Giovanni Nigita, Maurizio Colecchia, Dario Palmieri, Paolo Grassi, Claudia Maggi, Antonia Martinetti, Filippo G. De Braud, Carlo M Croce, Giuseppe Procopio
Journal: Journal of Clinical Oncology (2016)

540 Background: Collecting duct carcinoma (CDC) of the kidney is a rare tumor, originating from renal medulla, characterized by younger age at diagnosis and poor prognosis. Since targeted therapies are currently not available for CDC, we aimed to identify the most deregulated pathways in this type of cancer to gain insights into new molecular targets. Methods: Total RNA was extracted from FFPE samples of primary CDC (n=9), clear cell carcinoma (CCC, n=7) and healthy normal (n=7) adjacent renal tissues (23 total samples). Gene expression profile was performed by GeneChip Human Transcriptome Array 2.0 (HTA 2.0 -Affymetrix). The One-Way between-subject ANOVA algorithm was used to calculate statistical significances of pairwise comparisons. Transcripts with a linear fold change (f.c.) of &lt;-2/&gt;2 (p-value&lt;0.05) were included in the study. Functional enrichment analysis identified the most deregulated pathways in CDC. Results: A total of 1,079 genes (827 coding, 252 non-coding) were significantly deregulated comparing CDC, CCC and normal kidney (p&lt;0.05). In CDC vs normal tissue comparison, 484 genes (339 coding, 145 non-coding) are significantly up-regulated, and 49 (40 coding, 9 non-coding) down regulated in tumors (p&lt;0.05). The 4 most highly expressed transcripts in CDC are currently unknown, requiring further studies. Among the most altered known transcripts, we identified FN1 (f.c. 6.33), miR-21 (f.c. 4.01), KNG1 (f.c. -9.4) and AQP2 (f.c. -6.03), whose deregulation was previously associated with advanced disease and lower survival in renal cancer, supporting the quality of our analysis. Functional enrichment analysis indicated a strong downregulation of transcripts associated with histone modifications, function of cytoplasmic ribosomal proteins, senescence, autophagy and focal adhesion in CDC vs both CCC and normal tissues. Conclusions: Our analysis identifies several coding and non-coding transcripts differentially expressed in CDC vs CCC and normal kidney, resulting in alteration of a number of cellular pathways associated with cancer pathogenesis, progression and prognosis. These results pave the way to a deeper understanding of a rare tumor as CDC, driving the development of new, targeted therapies for this aggressive disease.
Discovery of molecular biomarker signatures for the detection of bladder cancer.
Authors: Evan Gomes, Virginia Urquidi, Yunpeng Cai, Yijun Sun, Charles Joel Rosser, Steve Goodison
Journal: Journal of Clinical Oncology (2013)

302 Background: Bladder cancer (BCa) is among the five most common malignancies world-wide, and due to high rates of recurrence, one of the most prevalent. Improvements in non-invasive urine-based assays to detect BCa would benefit both patients and healthcare systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with BCa. Methods: Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of BCa and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR). Results: Data analysis identified 52 genes associated with BCa (p≤0.001), and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of BCa with a specificity of 100% at 90% sensitivity. Conclusions: Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected BCa. The refinement and validation of the multi-gene urothelial cell signatures identified in this preliminary study may lead to accurate, non-invasive assays for the detection of BCa. The development of an accurate, non-invasive BCa detection assay would benefit both the patient and healthcare systems through better detection, monitoring and control of disease.
Is Heparin-Induced Thrombocytopenia (HIT) Overdiagnosed by the Conventional EIA Detecting IgG/M/A Antibodies Against Heparin-Platelet Factor 4-Complex? First Experience with the New EIA Detecting Only IgG-Class Antibodies.
Authors: Frauke Bergmann, Bruns Christiane, Groening Arndt
Journal: Blood (2007)
Inter- and intra-observer variation in gross tumor delineation on MVCT images in patients undergoing tomotherapy based IGRT for postoperative vault recurrences: Updated result.
Authors: M. N. Upasani, S. Chopra, R. Engineer, Z. Master, R. Ph, U. Mahantshetty, S. K. Shrivastava
Journal: Journal of Clinical Oncology (2011)

e15587 Background: This study was designed to evaluate inter and intra-observer concordance in gross tumor volume (GTV) delineation on megavoltage CT (MVCT) images. Methods: Three observers delineated GTV on MVCT and CECT and two observers recontoured on MVCT images. Tumor volumes were calculated and correlated using spearman correlation. The standard deviation of centre of mass was averaged on per patient basis. The ratio of common volume and encompassing volume was used to determine intra and inter-observer spatial concordance for observer variability on MVCT & CECT image datasets of same patients. Lack of difference in spatial concordance ratio between MVCT and CECT images was used as an index of usability of MVCT images. Forty-five image datasets were available for 8 patients. Results: High intra-observer GTV correlation was recorded for observer 1 and 2 (r=0.93 & r = 0.98; p= 0.03 and 0.0001). The average intra observer spatial concordance ratio was 0.57 and 0.62 respectively. The mean GTV of observers 1, 2 and 3 were 30.9cc (17.9-52.2); 29.8cc (15-51.8) and 40.8cc (16.7-104.1) respectively. Average standard deviation of centre of mass of all observers was less than 5mm in either direction. Largest inter-observer discordance was observed in anterior, inferior and lateral direction. The inter-observer spatial concordance of GTV on MVCT and CECT images was 0.35 and 0.36 (p = 0.24) respectively. The intra-observer spatial concordance of GTV on MVCT and CECT images was 0.56 and 0.63 (p value not significant) respectively. Conclusions: Moderate to good inter and intra-observer GTV correlation was observed on MVCT images however was associated with low inter-observer spatial concordance on both MVCT and CECT images. Strategies to improve contouring reproducibility on MVCT and KVCT images are desirable.
Use of tumoral expression TXR1 and TSP1 to predict overall survival of patients with non-small-cell-lung-cancer (NSCLC) treated with first line chemotherapy
Authors: J. Souglakos, C. Papadaki, M. Trypaki, A. Koutsopoulos, E. Stathopoulos, D. Mavroudis, M. Sfakianaki, V. Georgoulias
Journal: Journal of Clinical Oncology (2008)

19011 Background: In vitro data suggestthat overexpression of TXR1 gene is associated with resistance to taxane-based chemotherapy, through downregulation of the thrombospondin 1 (TSP1) expression. The prognostic and predictive value of tumoral expression both genes were evaluated. Methods: Tumor samples from 80 chemotherapy-naïve patients, with stage IIIb (with pleural effusion) or IV NSCLC were prospectively collected. TXR1 and TSP1 mRNA levels were determined using quantitative real-time PCR from microdissected tumor cells derived from patients’ primary tumors. Results: Patients’ characteristics included median age 61 years, performance status 0–1(WHO) 95%, male 91%. Successful amplification could be performed in 78 (97%) patients. The tumoral mRNA levels of the two genes were inversely correlated (Spearman’s test: -0.54; p<0.001). Patients with low mRNA tumoral levels of TXR1 mRNA (n=39) had a significantly increased TTP (8.2 vs 2.5 months; p=0.04) and OS (19.4 vs 6.6 months; p=0.004) but there was no difference in response to treatment (RR) (42 vs 22%; p<0.09) in comparison with patients with high tumoral levels of TXR1 mRNA (n=39). Patients with tumoral TXR1 mRNA levels in the lower quartile (n=19) presented higher RR (42 vs 11%; p=0.034) in comparison with patients in the higher quartile (n=18). TSP1 overexpression was significantly correlated with increased OS (17.9 vs 9.2 months; p=0.02), but not with RR (33 vs 30%; p=0.8) and TTP (6.2 vs 2.7 months; p=0.154). Patients with high TSP1 and low TXR1 mRNA expression (n=31) presented prolonged OS (20.6 vs 7.5 months; p=0.006) and a trend for prolonged TTP (8.5 vs 2.5 months; p=0.06) when compared with patients with low TSP1 and high TTP1 mRNA expression (n=32). Conclusions: The tumoral mRNA expression of TXR1 merits further evaluation as a marker of resistance to taxanes treatment of NSCLC whereas the tumoral expression of TSP1 merits further evaluation as a prognostic marker for OS. No significant financial relationships to disclose.
AR-67, a DNA Topo-Isomerase I Inhibitor, Demonstrates Acceptable Tolerability and Preliminary Activity in a Phase II Trial of Patients with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML),
Authors: Naval Daver, Hagop M. Kantarjian, Guillermo Garcia-Manero, Gautam Borthakur, Farhad Ravandi, Tapan Kadia, Zeev Estrov, Marina Konopleva, Stefan Faderl, Jorge E. Cortes
Journal: Blood (2011)
Dna Methylation Is Linked to a Specific Cell-Adhesion Program in Relapsed Pediatric t(8;21)(q22;q22)RUNX1-RUNX1T1 Patients
Authors: Matteo Zampini, Claudia Tregnago, Valeria Bisio, Benedetta Accordi, Valentina Serafin, Paolo Pierani, Nicola Santoro, Marco Zecca, Concetta Micalizzi, Maria Caterina Putti, Franco Locatelli, Giuseppe Basso, Martina Pigazzi
Journal: Blood (2016)
Antitumor activity of MLN4924, an investigational inhibitor of NEDD8-activating enzyme (NAE), in preclinical models of melanoma.
Authors: T. Traore, M. Mihollen, J. Garnsey, A. Berger, M. Manfredi, K. Cosmopolous, J. Donelan, P. G. Smith
Journal: Journal of Clinical Oncology (2011)

8594 Background: MLN4924 is a novel, small molecule inhibitor of Nedd8-activating enzyme (NAE) currently in Phase I clinical trials. Conjugation of NEDD8 to cullin scaffold proteins is required for E3 ubiquitin ligase activity that enables polyubiquitination and proteasomal destruction of proteins. Many of the proteins that are substrates for cullin-RING E3 ligases (CRLs) have key roles in cell cycle progression, signal transduction and cancer cell growth and survival. Methods: Cell and xenograft models of melanoma were used to explore the activity of MLN4924 in pre-clinical models. Results: We show that both wt and mt BRAF melanoma cell lines are sensitive to MLN4924. BRAF mt A375 cells treated with MLN4924 show an accumulation of Cdt-1, induction of DNA re-replication, a DNA damage response and undergo apoptosis. The DNA re-replication phenotype was confirmed by demonstrating that A375 cells actively incorporate BrdU in the presence of MLN4924. MLN4924 inhibition of CRL activity results in stabilization of BIM in A375 cells that may contribute to the apoptotic signal induced by MLN4924. In vivo studies demonstrate a significant decrease of NEDD8-cullin levels with an elevation in CRL substrates (NRF-2, pIKBa) in A375M xenografts grown in nude rats following a single dose of MLN4924. In antitumor activity studies tumor regressions are observed on a dosing regimen being evaluated in Phase I clinical trials in melanoma patients. We developed a xenograft explant model (PHTX-50M) in nude mice using a tumor biopsy obtained from a patient with V600E mutant BRAF malignant melanoma. Dose dependent inhibition of NAE pathway activity and antitumor activity is observed in the PHTX-50M model with MLN4924. Pre-clinical combination studies were performed with DTIC (Dacarbazine) in the primary tumor explant model where MLN4294 was shown to have additive antitumor activity. Conclusions:These data demonstrate the activity of MLN4924 in preclinical melanoma models, including a primary tumor explant model and supports the continued clinical evaluation of MLN4924 in patients with melanoma in which a confirmed Partial Response has been reported.
Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Preliminary Results of an IFM Phase II Study
Authors: J.-L. Harousseau, M. Attal, V. Coiteux, A.-M. Stoppa, C. Hulin, L. Benboubker, J.-G. Fuzibet, M. Renaud
Journal: Journal of Clinical Oncology (2005)

6653 Background: Standard induction therapy for patients (pts) with newly diagnosed Multiple Myeloma (MM) is based on Dexamethasone (Dex). Currently, the use of VAD or Dex alone results in a complete remission (CR) rate of < 10%. Both in vitro studies and preliminary clinical experience have suggested that bortezomib and Dex could be synergistic. Methods: The IFM group initiated a Phase II open trial evaluating the combination of bortezomib and Dex in pts with previously untreated MM and candidates for ASCT. The regimen consisted of bortezomib 1.3mg/m2 iv on days 1, 4, 8, 11 and Dex 40 mg per os days 1–4, 9–12 (for the first 2 cycles, days 1–4 only for the last 2 cycles), administered on 4 consecutive 21 days cycles. Stem cell collection was performed just before cycle 4 after G-CSF priming. The primary objective of the study was CR rate after 4 cycles. 53 pts have been recruited and data are available for the first 36 pts. The median age is 54 years (38–71). Toxicity: Twenty seven/36 (75%) pts received the whole treatment (16 injections). The treatment was withdrawn in 1 pt after 13 injections for grade 3 peripheral neuropathy and in 1 pt after 14 injections for grade 4 GI toxicity. Five pts received only 3 cycles (4 progression, 1 GI toxicity). The most frequent side effects were GI symptoms (49%), fatigue (34%), peripheral neuropathy (29%), skin toxicity (26%), thrombocytopenia (17%). However side effects were usually mild (grade 1/2), no grade 3 thrombocytopenia, 9% grade 3 neuropathy, 9% grade 3/4 GI toxicity. Efficacy: Efficacy results are available in 30 pts the following: CR 5; very good partial remission 4; PR 13; minimal response 2; failure 5; death 1. The overall response rate was 80% and the CR rate was 17%. In 29 evaluable cases stem cells could be adequately collected: median CD34+ cell yield 7.1 x E6/kg (2.9–33.8). These preliminary results appear to be very encouraging and the bortezomib/Dex combination appears effective and well tolerated in pts with newly diagnosed MM. The results will be updated at time of presentation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmion Amgen Millennium, Ortho-Biotech, Roche
Preferences of patients with metastatic breast cancer.
Authors: M. L. Smith, C. B. White, E. Railey, A. M. Storniolo, G. W. Sledge
Journal: Journal of Clinical Oncology (2011)

6044 Background: Patients with metastatic breast cancer face difficult trade-offs between toxicity and efficacy. Techniques from other fields can help analyze trade-off preferences. Methods: The Research Advocacy Network and CBWhite conducted research using conjoint analysis (CA) as part of the DOD Center of Excellence for Individualization of Therapy in Breast Cancer. An online survey was released via three organizations: Living Beyond Breast Cancer, Metastatic Breast Cancer Network, and BCMets listserv. Over 400 women answered questions about biomarker tests and questions designed to elicit views on the trade-off between benefit and side effect. CA questions present pairs of hypothetical treatments, each defined by benefit and side effect likelihoods. In each question, respondents select a preferred treatment or no treatment. Analysis of patterns provides results allowing prediction of selecting treatment for any combination of benefit and side effect. Results: Preference curves show greater preference for higher benefit and lower side effect likelihoods. Range is from 92% for “best” combination (60% benefit/20% side effect) to 12% for “worst” combination (10% benefit/90% side effect). Benefit appears more influential than side effect; selecting treatment drops more quickly as benefit diminishes and more slowly as side effect increases. Subgroup analysis shows differences depending on age, side effect, and presence of children. Using CA to predict impact of biomarkers shows: 19% to 27% may change treatment decision if biomarker predicts 30% vs 50% benefit likelihood;10% to 18% may change treatment decision if biomarker predicts 30% vs 50% side effect likelihood. Conclusions: Conjoint analysis can be used to quantify patient preference with respect to benefit and side effect trade-offs. Predictions and usefulness will be improved by designing CA based on specific treatment research questions that have particular side effect profiles. Biomarker influence can be modeled using conjoint data. Prediction of % selecting treatment for each combination of benefit and side effect likelihood. Side effect likelihood Benefit likelihood 20% 40% 60% 75% 90% 60% 92 88 76 65 49 40% 87 75 54 47 39 20% 53 42 33 26 23 10% 36 35 25 14 12
Selinexor, ARA-C and Idarubicin: An Effective and Tolerable Combination in Patients with Relapsed/Refractory AML: A Multicenter Phase II Study
Authors: Walter Fiedler, Jörg Chromik, Maxim Kebenko, Felicitas Thol, Arne Trummer, Chirstoph Schünemann, Christian H. Brandts, Anne Köhler, Vera Schlipfenbacher, Carsten Bokemeyer, Susann Theile, Anne L. Kranich, Michael Heuser
Journal: Blood (2015)
Adjuvant colon cancer care quality, risk, value, and level one data and guideline compliance among the elderly privately insured in southeastern USA.
Authors: William J. Hrushesky, Anmol Baranwal, Dinah Faith Q. Huff, William S. Shimp, Avinash Mamgain, Marc L. Fishman, Anna E. Schorer, Laura Rose Bobolts, Sharon Davis, Jurgen Kogler, Melissa Armitage, Charles L. Bennett
Journal: Journal of Clinical Oncology (2014)

249 Background: Oxaliplatin-containing regimens are among the most efficacious adjuvant treatments for locally-advanced colon cancer, although significant toxicity can occur. Because of relevant level I data, the NCCN revised its guidelines in 2012, recommending omission of oxaliplatin from combination adjuvant chemotherapy regimens for older patients (&gt;70yo) with colon cancer. We examined prescribing behavior of oncologists between 2009 and 2014 to evaluate how rapidly NCCN guidelines were adopted into practice. Methods: This is a retrospective observational study of chemotherapy request data from more than 2,000 community oncologists in the southeastern United States. We examined 57 consecutive months of chemotherapy requests for stage II and III colon cancer patients 70 years and older, based on three epochs. During the middle epoch, one phase III trial evaluating oxaliplatin-containing regimens as adjuvant chemotherapy (NSABP C-07), and a revised 2012 NCCN guidelines, each supported omission of oxaliplatin from adjuvant chemotherapy regimens for older persons with colon cancer. Multivariate analyses evaluated associations among patient characteristics (age, gender, and performance status), disease stage, and time-period, with the odds of receiving oxaliplatin-containing regimens as adjuvant chemotherapy. Results: Among 266 persons with stage II or III colon cancer 70 years of age and older, over the six-year span, most adjuvant chemotherapy requests (184/266, 69.2%) contained oxaliplatin. Older age, male gender, and poor performance status were associated with significantly lower odds of receiving oxaliplatin-containing adjuvant chemotherapy regimens (p&lt;0.05), while time period (epoch) was not significantly associated with temporal changes in patterns of use. Conclusions: Use of oxaliplatin containing adjuvant chemotherapy regimens among older persons with colon cancer did not decrease following publication of phase III clinical trial data and revised NCCN guidelines recommending against oxaliplatin use in this setting. Focused quality improvement initiatives for this population of cancer patients may be helpful.
Perspective of young breast cancer survivors (BCS) on fertility preservation (FP) referral.
Authors: Maureen Seminsky, Samantha Yee, Karen Glass, Shu Foong, Erin Diane Kennedy, Ellen Warner
Journal: Journal of Clinical Oncology (2016)

113 Background: Despite ASCO recommendations (2006, 2013), young cancer patients are frequently not spoken to about the potential effects of treatment on future fertility and are denied the option of FP. Last year we began a 5 year study (SPOKE: Surgeon and Patient Oncofertility Knowledge Enhancement) to increase FP discussion and referral rates of Canadian breast surgeons. To design effective interventions, in addition to interviewing and surveying surgeons we conducted in-depth interviews with young BCS. Methods: Thirty minute semi-structured telephone interviews were conducted with BCS diagnosed &lt; age 40 to explore their oncofertility experiences and their recommendations for future patients. Eligible BCS were recruited by oncologists and fertility specialists. A patient sample was deliberately chosen to reflect diversity of tumor stage, patient demographics and fertility experiences. A $20 incentive was given to each interviewee. Interviews were audio-recorded, transcribed verbatim and the data analyzed using qualitative methods. Subject recruitment was terminated when saturation of themes was obtained. Results: Fifteen BCS from 5 provinces, mean age 32 were interviewed. At diagnosis mean age was 29 with 8 (53%) single, 13 (87%) nulliparous, and 87% receiving adjuvant chemotherapy. At diagnosis all but 1 BCS had either definitely (60%) or possibly (33%) wanted (additional) children but only 8 of the 14 (57%) had been referred for a FP consult. Common recommendations were: discussing fertility as soon as possible after diagnosis to optimize time for decision-making; providing up-to-date information about the various FP options prior to the consult; and encouraging patients ambivalent about future childbearing to pursue FP. Conclusions: Despite the perception by many surgeons that patients are not psychologically able to handle information about fertility and FP at the time of their diagnosis, the majority of BCS interviewed thought that early fertility discussion by the surgical team was essential. SPOKE will include knowledge translations interventions for surgeons, and the creation of a FP information ‘toolbox’ with separate versions for surgeons and patients. Funded by the CBCF and CIHR.