tbuckley/cabot-search huggingface dataset:
Progressive Telomere Shortening Is Part of the Natural History of Chronic Lymphocytic Leukemia (CLL) and Impacts Clinical Outcome
Authors: Elisa Bernocco, Davide Rossi, Elisa Genuardi, Chiara Lobetti-Bodoni, Roberto Passera, Daniela Drandi, Marta Coscia, Marina Ruggeri, Marco Fangazio, Paola Ghione, Daniela Barbero, Barbara Mantoan, Sara Barbiero, Manuela Zanni, Valter Gattei, Luciana Bergui, Paola Omedè, Massimo Massaia, Mario Boccadoro, Gianluca Gaidano, Marco Ladetto
Journal: Blood (2011)
The Proteasome Inhibitor, Ixazomib, Combined with Novel Drug Combinations in T-Cell Lymphoma (TCL) and Hodgkin Lymphoma (HL): Identification of Key Genes and Signaling Pathways Via a Novel Systems Biology Approach
Authors: Frank C. Passero, Ravi Dashnamoorthy, Afshin Beheshti, Lynn Hlatky, Nassera Abermil, Michael E Coyle, Jaya Sharma, Andrew M. Evens
Journal: Blood (2015)
Abstract 5487: Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity
Authors: Shikshya Shrestha, Steve Offer, Robert B. Diasio
Journal: Cancer Research (2015)

Abstract 5-Fluorouracil (5-FU) is a cornerstone drug for the treatment of several aggressive tumors; however, adverse 5-FU toxicity contributes to approximately 1,300 deaths annually in the U.S. While three genetic variations in dihydropyrimidine dehydrogenase (DPD; DPYD gene) are well-established predictors of toxicity (i.e., *2A, I560S, D949V), the contributions of additional reported missense DPYD variants (&amp;gt;130) have not been adequately evaluated in clinical studies. Our lab has previously developed methods to study DPYD variants for potential clinical relevance to 5-FU toxicity using in vitro and cellular approaches (see Offer et al. Cancer Research 2013 &amp; 2014). In the current study, we measured the in vitro enzyme activity of 47 uncharacterized missense variants that have been previously reported in dbSNP and NHLBI ESP databases. Additionally, we assessed the impact of these variants on 5-FU sensitivity in multiple transgenic human cellular models using real-time cellular analysis. Approximately one-third of the studied variants showed significantly reduced enzyme activity compared to wild type. Of the DPD-deficient variants identified in this study, 8 were profoundly deficient (&amp;lt;12.5% of “wildtype” activity), with enzyme activities similar to *2A. Two deficient variants showed modest reductions in enzyme activity (12.5-25% activity), similar to I560S. The remaining 5 deleterious variants exhibited mild deficiency (&amp;gt;25% activity, but significantly lower than “wildtype”), similar to D949V. Cellular sensitivity to 5-FU for cells expressing these variants paralleled the in vitro enzyme activity results, with deleterious variants showing reduced tolerance to 5-FU relative to cells transgenic for wildtype DPD. These trends were observed in multiple cell lines derived from various tissues and tumor types. Overall, our results add to the growing database of deleterious DPYD variations. Many of these variants have been observed primarily in non-Caucasian racial groups, consistent with our previous reports. These data suggest that the deleterious variants classified in this study may be important predictors of 5-FU toxicity, particularly in individuals of non-Caucasian ancestry. Additionally, these data suggest that genetic testing for rare variants may improve the success of predictive tests for 5-FU toxicity. Finally, this study suggests that in vitro and cellular models may be important pharmacogenomic methods to rapidly characterize variants of potential relevance in additional drug-gene pathways. Citation Format: Shikshya Shrestha, Steve Offer, Robert B. Diasio. Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2015-5487
The early termination of clinical trials: causes, consequences, and control. With special reference to trials in the field of arrhythmias and sudden death. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology.
Journal: Circulation (1994)

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations because of the inherent difficulty of a prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a Task Force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial.
Impact of microRNA miR-345 in blood on survival and response in 144 patients with metastatic colorectal cancer treated with third-line cetuximab and irinotecan.
Authors: Jakob Vasehus Schou, Klaus Kaae Andersen, Benny Vittrup Jensen, Dorte Lisbet Nielsen, Estrid V. Høgdall, Julia S. Johansen
Journal: Journal of Clinical Oncology (2012)

451 Background: MicroRNAs (miR) are small non-coding RNAs regulating gene expression at a posttranscriptional level. A prognostic potential of miRs in cancer tissue, whole blood or serum/plasma has been proposed in a small subset of cancers. MiR-345 has been reported up-regulated in cancer tissue and involved in malignant transformation in cancer cells. The aim of the study was to describe the ability of miR-345 to predict OS and response in patients with metastatic colorectal cancer (mCRC) treated with 3. line cetuximab and irinotecan independent of their KRAS status. Methods: A total of 144 patients with mCRC were included in a prospective phase II study of 3. line treatment with cetuximab and irinotecan. All patients had progressed on 5-FU, oxaliplatin and irinotecan prior to the protocol. MiRs were isolated from whole blood collected in PAXgene Blood RNA tubes (Qiagen), and miRNA profiling was performed using TaqMan MicroRNA Array v2.0 (Applied Biosystems). Cox proportional hazard model was applied to study the correlation between baseline miR-345 expression and OS. Logistic regression analysis was applied to study response (PR (n=25) vs. PD (n=38)) and clinical benefit (PR+SD &gt; 9 months (n=32)) vs. no clinical benefit (PD+SD &lt; 4 months (n=87)). Hazard ratios (HR) and odds ratios are per inter quartile range. Results: High expression of miR-345 was associated with poor treatment response with an odds ratio of 1.43 (p= 0.002) for progressive disease as best overall response and 2.04 (p=0.01) for no clinical benefit. High expression of miR-345 was significantly associated with short OS (HR =5.01, 95% Confidence Interval (CI): 2.39-10.50) when adjusted for KRAS status and performance status. This finding was confirmed in the subgroup of patients with KRAS wild type (n=87) (HR=3.02, 95% CI: 1.00-9.07). Conclusions: High expression of miR-345 in whole blood is correlated to lack of response and short OS in mCRC patients treated with cetuximab and irinotecan. This suggests that miR-345 may be a new predictive and prognostic biomarker for treatment with cetuximab and irinotecan.
A phase II study of concurrent cetuximab-cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with correlation using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)
Authors: B. B. Ma, S. F. Leung, M. K. Kam, E. P. Hui, A. D. King, S. L. Chan, B. K. Yu, S. K. Chiu, F. H. Lee, A. T. Chan
Journal: Journal of Clinical Oncology (2008)

6055 Background: Based on the activity of cetuximab + platinum in recurrent NPC (Chan AT et al J Clin Oncol 2005;23: 3568–76), we evaluated the feasibility of adding cetuximab to concurrent cisplatin-IMRT in the curative setting. The effect of cetuximab on DCE-MRI parameters in primary NPC was also studied. Methods: Patients (pts) with untreated, non-metastatic advanced NPC were given an initial dose of i.v. cetuximab (400mg/m2) followed by IMRT (74Gy) 7–10 days later. RT was delivered concurrently with weekly i.v. cetuximab (250mg/m2) and i.v. cisplatin (30mg/m2) over 6–7 weeks. DCE-MRI was conducted before RT at baseline and 1 week after the first cetuximab dose. Results: Twenty pts (mean age 42 years, range 24–59, 17 males) were enrolled and evaluated for acute toxicity (NCI CTCAE v3.0) (n=20) and response (n=12). Stage distribution at baseline was: T1–2b = 6 pts (30%); T3–4 = 14 pts (70%); N0–1 = 11 pts (55%); N2–3 = 9 pts (45%); AJCC stage III = 12 pts (60%), IVa = 7 pts (35%), IVb = 1pt (5%). All pts completed IMRT without major interruptions. Drug compliance was good with 90% of pts completing ≥5 doses of cetuximab, and 80% completing >5 doses of cisplatin. The most common non-hematological grade 3–4 toxicities were RT-mucositis (85%), mouth pain (85%) and dysphagia (45%). Rash was grade 1–2 in 14 pts, grade 3 in 3 pts. Seven pts (35%) required nasogastric tube feeding and 4 pts had grade 3 RT-dermatitis. Grade 3–4 lymphopenia was the commonest hematological toxicity (85%). 6 SAEs were reported due to grade 3 mucositis or dysphagia. At 3 months post-RT, there were 10 (83%) complete responses and 2 partial responses at nasopharynx. All pts were alive at analysis. DCE-MRI performed in 11 pts showed a non-significant rising trend in mean Ktrans (volume transfer coefficient) and initial area under the contrast agent concentration-time curve (AUC). Conclusions: This is the first report on the feasibility of combining cetuximab-cisplatin and IMRT in NPC. Grade 3 mucosal toxicities were common but manageable. Accrual is ongoing and updated DCE-MRI data will be presented. No significant financial relationships to disclose.
Rates of Infection and Bleeding Are Not Increased in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine Compared with Supportive Care.
Authors: Lewis R. Silverman, David R. McKenzie, Bercedis L. Peterson, Rosalie Odchimar-Reissig, Randy Hinkle, Jay T. Backstrom, Richard A. Larson
Journal: Blood (2005)
Abstract 445: Tumor microenvironment influences survival of mantle cell lymphoma-initiating cells through FGF/FGFR1 signaling
Authors: Lalit Sehgal, Rohit Mathur, Zuzana Berkova, Tamer Khashab, Xin Wang, Jorge E. Romaguera, Alma E. Rodriguez, Sattva Neelapu, Felipe Samaniego
Journal: Cancer Research (2015)

Abstract Introduction Mantle cell lymphoma (MCL) represents an aggressive, incurable form of non-Hodgkin's lymphoma (NHL). The health complications associated with advanced age of MCL patients restrict treatment with intense chemotherapy. Translocation t(11;14), responsible for overexpression of cyclin-D1, is the hallmark of MCL. More detailed insight into MCL pathogenesis has been delayed until the recent development of a tissue culture system, using human mesenchymal stromal cells (hMSC), suitable for propagating primary MCL cells. We hypothesized that tumor-initiating cells are responsible for MCL relapse and chemoresistance and thus, identification of signals responsible for survival and maintenance of MCL-initiating cells (MCL-ICs) is essential for design of curative treatment strategies. Methods Isolates of primary MCL cells (n = 24) were co-cultured with human mesenchymal stem cells (hMSCs) and the content of MCL-ICs was analyzed by flow-cytometry based on marker expression profile; CD34-CD3-CD45+CD19-. Cytokine array was used to identify the soluble factors enriched in the co-cultures and the expression of these factors was confirmed by RT-PCR analysis. The signaling pathways employed by the newly-identified factors were blocked in 3 MCL cell lines (JVM2, Mino, Z138) to confirm their essential role in survival of MCL cells and, more importantly, for MCL-ICs. Results Co-cultures of primary MCL isolates with hMSCs supported the growth of MCL cells for over 4 weeks with continued presence of MCL-ICs (CD34-CD3-CD45+CD19-) representing about 1% of MCL cells. We found that IL-6 produced by hMSCs triggered an FGF/FGFR autocrine loop in MCL-ICs. The extent of FGFR expression correlated tightly with expression of SOX11, a pathology related negative prognostic marker in MCL. MCL cell survival and growth was regulated via the FGFR/mir101/ EZH2/ NF-κB/XIAP axis. Blocking of this signaling pathway with FGFR1 inhibitors consistently induced early reduction in XIAP levels and subsequently MCL cell death. Conclusion We established that propagation of primary MCL in co-cultures with hMSCs depends on an FGF/FGFR autocrine loop that enhances XIAP protein expression and thus, supports survival of MCL cells. We identified the factors essential for survival of MCL and MCL-ICs that present new targets for improved MCL treatment strategies. Citation Format: Lalit Sehgal, Rohit Mathur, Zuzana Berkova, Tamer Khashab, Xin Wang, Jorge E. Romaguera, Alma E. Rodriguez, Sattva Neelapu, Felipe Samaniego. Tumor microenvironment influences survival of mantle cell lymphoma-initiating cells through FGF/FGFR1 signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 445. doi:10.1158/1538-7445.AM2015-445
A Phase I/II Study of Bendamustine, Low-Dose Dexamethasone, and Lenalidomide (BdL) for the Treatment of Patients with Relapsed Multiple Myeloma
Authors: Stefano Sacchi, Samantha Pozzi, Stefania Badiali, Attilio Guarini, Carla Mazzone, Alessandro Corso, Donatella Vincelli, Luciano Masini, Pellegrino Musto, Roberto Ria, Giovanni Quarta, Antonio Lazzaro, Antonio Palumbo, Fortunato Morabito
Journal: Blood (2012)
Quantitative PCR Predicts Early Relapse in Patients with Chronic Lymphocytic Leukemia (CLL) Submitted to Autologous Stem Cell Transplantation. The Case for Early Clinical Intervention.
Authors: Carol Moreno, Neus Villamor, Dolors Colomer, Jordi Esteve, Francesc Bosch, Armando Lopez-Guillermo, Elias Campo, Emili Montserrat
Journal: Blood (2004)
Hereditary Lysozyme Amyloidosis Variant p.Leu102Ser Associates with Unique Phenotype
Authors: Samih H. Nasr, Surendra Dasari, John R. Mills, Jason D. Theis, Michael T. Zimmermann, Rafael Fonseca, Julie A. Vrana, Steven J. Lester, Brooke M. McLaughlin, Robert Gillespie, W. Edward Highsmith, John J. Lee, Angela Dispenzieri, Paul J. Kurtin
Journal: Journal of the American Society of Nephrology (2017)

Lysozyme amyloidosis (ALys) is a rare form of hereditary amyloidosis that typically manifests with renal impairment, gastrointestinal (GI) symptoms, and sicca syndrome, whereas cardiac involvement is exceedingly rare and neuropathy has not been reported. Here, we describe a 40-year-old man with renal impairment, cardiac and GI symptoms, and peripheral neuropathy. Renal biopsy specimen analysis revealed amyloidosis with extensive involvement of glomeruli, vessels, and medulla. Amyloid was also detected in the GI tract. Echocardiographic and electrocardiographic findings were consistent with cardiac involvement. Proteomic analysis of Congo red-positive renal and GI amyloid deposits detected abundant lysozyme C protein. DNA sequencing of the lysozyme gene in the patient and his mother detected a heterozygous c.305T>C alteration in exon 3, which causes a leucine to serine substitution at codon 102 (Human Genome Variation Society nomenclature: p.Leu102Ser; legacy designation: L84S). We also detected the mutant peptide in the proband's renal and GI amyloid deposits. PolyPhen analysis predicted that the mutation damages the encoded protein. Molecular dynamics simulations suggested that the pathogenesis of ALys p.Leu102Ser is mediated by shifting the position of the central β-hairpin coordinated with an antiparallel motion of the C-terminal helix, which may alter the native-state structural ensemble of the molecule, leading to aggregation-prone intermediates.
Abstract 3304: Role of Vascular Endothelial Growth Factor C in promoting radioresistance of prostate cancer
Authors: Steffi Haberlau, Pia Hönscheid, Rafael E. Jimenez, Gustavo B. Baretton, Donald J. Tindall, Mechthild Krause, Kaustubh Datta, Michael H. Muders
Journal: Cancer Research (2015)

Abstract Radiotherapy is an important treatment regimen for prostate cancer. We have shown that the lymphangiogenic growth factor, Vascular Endothelial Growth Factor C (VEGF-C), induces docetaxel resistance and autophagy in prostate cancer (Muders et al., Cancer Res 2009 and Stanton et al., Cancer Res 2013). In this study we have evaluated the role of VEGF-C and VEGF-C induced autophagy in radioresistance of prostate cancer using cell culture experiments and human tissue samples. The human prostate carcinoma cell lines PC-3, LNCaP and DU145 were used in these cell culture experiments. Clonogenic survival of prostate cancer cells, after RNA interference (RNAi) of VEGF-C, autophagy related gene 5 (ATG5), and after addition of recombinant human VEGF-C following irradiation therapy, was evaluated. Autophagic flux was tested after ionizing irradiation using a Light-Chain-3 II immunoblot. To confirm our in vitro findings, human tissues of patients who underwent radical prostatectomy and adjuvant radiotherapy at Mayo Clinic were evaluated for VEGF-C expression. The quantity and intensity of VEGF-C staining was evaluated by two pathologists independently and correlated with biochemical relapse free survival (BRFS). The follow-up time is up to 23 years after radiotherapy. Multivariate Cox analysis was performed. VEGF-C levels correlated with a significantly higher radioresistance in colony formation assays and human tissue samples by multivariate analysis. The risk of biochemical recurrence increased 2.8 fold (95% confidence interval: 1.109 to 7.237; p = 0.03) when VEGF-C was highly expressed in prostatectomy patients with adjuvant radiotherapy. In line with our studies on autophagy in VEGF-C mediated docetaxel resistance of prostate cancer, autophagic flux was reduced after VEGF-C depletion during radiation. Interestingly, RNAi for ATG5 showed no effect on radiosensitivity which suggests that the decrease in autophagic flux after VEGF-C depletion is not responsible for the increased radiosensitivity. We conclude that VEGF-C is an important mediator of radiotherapy resistance in prostate cancer. In contrast to our published results on chemotherapy resistance, VEGF-C induced autophagy appears to be less important for resistance against ionizing radiation. Other VEGF-C dependent mechanisms for therapy resistance are under investigation. Citation Format: Steffi Haberlau, Pia Hönscheid, Rafael E. Jimenez, Gustavo B. Baretton, Donald J. Tindall, Mechthild Krause, Kaustubh Datta, Michael H. Muders. Role of Vascular Endothelial Growth Factor C in promoting radioresistance of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2015-3304
ACTR-41. A PHASE II, SINGLE ARM STUDY OF OPTUNE® IN BEVACIZUMAB-NAIVE SUBJECTS WITH RECURRENT WHO GRADE III MALIGNANT GLIOMA
Authors: Daniel O’Connell, Jose Carrillo, Xiao-Tang Kong, Beverly Fu, Daniela Bota
Journal: Neuro-Oncology (2016)

There is an unmet clinical need for the treatment of progressive or recurrent anaplastic glioma (World Health Organization [WHO] grade III) with poor median survival despite available chemotherapy. Published literature indicates that targeting mitosis via tumor treating fields (TTF) in rapidly dividing cancer cells by disrupting both spindle formation and normal cytokinesis selectively kills or arrests growth in glioma cell lines. The Optune® system is a novel anti-mitotic cancer therapy approved by the FDA in 2011 for the treatment of recurrent (supratentorial) glioblastoma (GB) (WHO grade IV) based on the results of a phase 3 clinical trial comparing TTF monotherapy with physician’s choice chemotherapy in patients with recurrent GB demonstrating comparable overall survival and improved quality of life. No data is currently available on the response of WHO grade III malignant glioma to this technology. In addition, no biomarker is yet available in order to predict which patients will have a better response to the Optune® technology. This is a phase 2, single arm study in patients with WHO grade III malignant glioma who have had progressive disease during first-line treatment with radiation, temozolomide (TMZ) and/or procarbazine/lomustine/vincristine (PCV) and who have not previously received bevacizumab (BEV) or any experimental agents. All patients are provided with the Optune® device. Frequency titration experiments are conducted in vitro. This is a prospective, open label study. The primary objective will be to determine the efficacy of Optune® in recurrent malignant glioma patients (6-month progression-free survival). The secondary objectives will be to evaluate the safety and efficacy of Optune® in the subject population and to see if the presence of 1p19q LOH, and/or IDH1 mutation, confers a better response to Optune®.
The Rate of Individual BCR-ABL Decline As an Optimized Predictor of Tyrosine Kinase Inhibitors Treatment Outcome in Chronic Phase CML Patients, Comparison with CML Prognostic Scores and Early Molecular Response Achievement
Authors: Mikhail Fominykh, Vasily Shuvaev, Irina Martynkevich, Grigory Tsaur, Natalya Bederak, Ekaterina Chelysheva, Oleg Shukhov, Adhamjon Abdullaev, Vera Udaleva, Regina Golovchenko, Irina Zotova, Dzhariyat Shikhbabaeva, Lyubov Polushkina, Ekaterina Petrova, Marina Ivanova, Lyudmila Martynenko, Elizaveta Kleina, Natalya Cybakova, Anna Turkina, Kudrat Abdulkadyrov
Journal: Blood (2015)