tbuckley/cabot-search huggingface dataset:
Outcomes of first-line treatment for chronic lymphocytic leukemia (CLL) with 17p deletion (del17p).
Authors: Paolo Strati, Michael J. Keating, Susan Mary O'Brien, Alessandra Ferrajoli, Jan Andreas Burger, Stefan Faderl, Nitin Jain, William G. Wierda
Journal: Journal of Clinical Oncology (2013)

7102 Background: Patients (pts) with relapsed CLL bearing del17p are very high-risk for poor clinical outcomes. We summarize outcomes for first-line treatment of del17p CLL. Methods: We identified pts with CLL and del17p by FISH who received first-line treatment at MDACC between 1/04 and 12/12. Log-rank test and Cox regression were used for univariable and multivariable analyses. Results: Baseline characteristics are shown (Table). Median time from diagnosis to first treatment (TTFT) was 15 (11-19) mos; no association between % del17p positive cells at diagnosis and TTFT was noted (p=.45). With first-line therapy (Table), 19 pts (30%) achieved complete remission (CR), 2 (3%) nodular partial remission (nPR), 18 (30%) PR, and 24 (37%) were non-responders. Fourteen CR pts (78%) were minimal residual disease negative by flow cytometry. The median time-to-treatment failure (TTF) was 14 (10-18) mos (43 events); the median follow-up was 33 (1-89) mos. Univariable analyses showed age &gt;65 yrs (p=.04), complex karyotype (p=.02), lack of response to therapy (p&lt;.001) and &gt;50% cells positive for del17p by FISH (p=0.009) associated with shorter TTF. The multivariable model showed karyotype (p=.005) and quality of response (p&lt;.001) independently associated with TTF. Median Overall Survival (OS) was 63 (43-83) mos (48 deaths). Fifteen pts (23%) developed Richter Syndrome (RS) after a median of 12 (1-27) mos; 8 deaths (29%) were related to RS. Univariable analysis showed that only lack of response was associated with a shorter OS (p=.001). Conclusions: Del17p CLL is high-risk for first-line therapy; better response to therapy was observed in young patients with low % del17p positive cells by FISH who received FCR. New strategies and agents must aim at both improving response and maintaining remission, particularly in pts with complex karyotype. [Table: see text]
Immunohistochemistry (IHC) to enhance the prognostic allocation of locally advanced and metastatic urothelial cancer (UC) undergoing first-line chemotherapy (CT).
Authors: Patrizia Giannatempo, Biagio Paolini, Salvatore Lo Vullo, Manuela Marongiu, Elena Farè, Daniele Raggi, Nicola Nicolai, Luigi Piva, Mario Catanzaro, Davide Biasoni, Tullio Torelli, Silvia Stagni, Massimo Maffezzini, Alessandro M. Gianni, Guru Sonpavde, Roberto Salvioni, Luigi Mariani, Maurizio Colecchia, Andrea Necchi
Journal: Journal of Clinical Oncology (2014)

4547 Background: Knowledge of the expression of molecular drivers and potentially druggable targets may enhance prognostic classification of metastatic UC. We aimed at assessing the expression of multiple key molecular biomarkers (BMK) by IHC and their potential to enhance prognostic allocation of patients (pts) with UC. Methods: We analyzed formalin-fixed paraffin embedded tumor from pts with UC undergoing first-line CT with MVAC for locally-advanced unresectable (LA, T3-4±N+) and metastatic (M) disease between the years 2000 and 2013. The expression of the following panel of BMKs by IHC were evaluated using conventional protocols: ERCC1, EGFR, HER2, VEGFR-3, PDGFRα, p53, p63. Expression levels were dichotomized as positive (2+,3+) or negative (≤1+). Fisher exact test was used to evaluate the association with response and setting (LA vs M). Cox regression multivariate (MVA) models evaluated the association with PFS and OS of each biomarker, adjusted for recognized prognostic variables (setting [LA vs M], Bajorin score [0 vs 1-2], primary site). Results: Since 06/2009, tissues of 88 pts (27 LA, 61 M) underwent IHC. Samples were from primary tumor (N=67) or metastases (N=21). Rates of positive IHC/number evaluable were as follows: ERCC1: 30/66 (45%); HER2: 24/52 (46%); EGFR: 31/54 (57%); VEGFR-3: 50/66 (76%); PDGFRα: 10/63 (16%); p53: 25/56 (45%); p63: 46/53 (87%). HER2 trended for a significant association with higher stage (p=0.079). Median follow up was 41 months (IQR, 15-64). On MVA, significant results were obtained for VEGFR-3 and PDGFRα, in addition to Bajorin score (Table). The c-index was 0.68 for both PFS and OS. Conclusions: VEGFR-3 and PDGFRα expression appears to confer a divergent prognostic impact in pts receiving first-line cisplatin-based CT for advanced UC. These data warrant external validation and underline the difficulties in defining the role of angiogenesis as a molecular driver and therapeutic target. PFS OS Variable HR 95% CI p HR 95% CI p VEFGR-3 Pos vs Neg 0.45 0.21-1.01 0.054 0.36 0.15-0.85 0.019 PDGFRα Pos vs Neg 3.32 1.28-8.58 0.013 2.66 0.96-7.42 0.060 Bajorin score 1-2 vs 0 4.24 1.94-9.26 <0.001 4.49 1.91-10.56 <0.001
B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy
Authors: Leo Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Hui Guo, Zhihong Chen, Wenjing Tao, Carrie Li, Jack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y. Huang, Yiping Shao, Laura Lam, Qing Yi, Y. Lynn Wang, Michael Wang
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. Results: The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient's peripheral blood. Conclusions: Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients. Clin Cancer Res; 23(15); 4212–23. ©2017 AACR.
Developing and evaluation of a new clinicopathologic response index after neoadjuvant chemotherapy as a predictor of clinical outcomes in locally advanced breast cancers.
Authors: Tarek M. A. Abdel-Fatah, Graham Ball, Andrew HS Lee, Sarah Pinder, R Douglas MacMilan, Eleanor Cornford, Paul Moseley, Rafael Silverman, Bruce Latham, David Palmer, Arlene Chan, Ian O. Ellis, Stephen Chan
Journal: Journal of Clinical Oncology (2014)

1083 Background: There is an urgent need to identify a set of clinico-pathological criteria which is more sensitive than pathological complete response (pCR) to assess the response to neo-adjuvant chemotherapy (Neo-ACT) and to guide the subsequent adjuvant therapy (AT). Methods: We performed a clinico-pathological assessment of 427 patients who had completed Neo-ACT with a median follow-up of 5-years. The patients were divided into: 1) Training set (n=172) treated with anthracycline combination (AC); 2) Internal validation set (n=130) treated with AC+Taxane; and 3) external validation set (n=125) treated with AC-/+Taxane. Results: Among the clinico-pathological factors associated with higher risk of relapse and death after Neo-ACT in univariate analysis: absence of fibrosis in both primary tumour site and lymph node (LN), presence of lymphovascular invasion, and increasing number of LN metastases, maintained significance as independent predictors for both disease free survival (DFS) and breast cancer specific survival (BCSS) after controlling for AT and other covariates by using multivariate Cox proportional hazards models with backward stepwise exclusion (p<0.01); whilst the percentage of reduction in primary tumour size was associated with DFS only (p=0.022). New pathological response indecies (NPRIs) for DFS and BCSS were calculated and four prognostic-groups (NPRI-PGs) were identified. Patients with NPRI-PG2 for DFS (n=63/172; 36.6%) and BCSS (66/172; 38.4%) has the same prognosis as those who achieved pCR (NPRI-PG1; 15%). The receiver operating characteristic (ROC) curves indicated that the NPRI outperformed the currently used prognostic factors [area under the curve (AUC) >0.85] and adding NPRI has improved their performance as a predictor for DSF (AUC>0.87) and BCSS (AUC> 0.88). Conclusions: The NPRI accurately predicts DFS and BCSS, with a higher sensitivity than pCR . The NPRI can improve the sensitivity and specificity of clinico-pathological response as a study end-point, for assessing response to a Neo-ACT regimen, and can serve as a valuable tool for the discovery of future predictive molecular markers.
Phase I trial of intratumoral therapy using HF10, an oncolytic HSV-1, demonstrates safety in HSV+/HSV- patients with refractory and superficial cancers.
Authors: Robert L. Ferris, Neil D. Gross, John J. Nemunaitis, Robert Hans Ingemar Andtbacka, Athanassios Argiris, James Ohr, John T. Vetto, Neil N. Senzer, Cindi Bedell, Richard S. Ungerleider, Maki Tanaka, Yukihiro Nishiyama
Journal: Journal of Clinical Oncology (2014)

6082 Background: HF10 is an oncolytic herpes simplex virus 1 (HSV-1) which can replicate in and destroy cancer cells by direct oncolysis and enhanced anti-tumor immunity. This Phase I dose escalation trial is investigating intratumoral HF10 injections in patients with refractory and superficial cancers. Objectives are to evaluate the safety, tolerability, recommended HF10 dose; viral replication in blood, urine, saliva and tumor biopsies; overall and local (injected lesion) antitumor activity; anti-HSV antibodies; and anti-tumor T cell reactivity, serum cytokines, and proteomics. Methods: InStage 1,1 intratumoral injection of HF10 was administered to a single lesion; in Stage 2, up to 4 injections (≥ 2 weeks apart) are administered per patient. Stage 1 patients were HSV-1 seropositive; Stage 2 patients are HSV-1 seropositive or seronegative. Adverse events (AEs) are evaluated according to NCI CTCAE v3.0. Results: As of 12/10/2013, 26 patients were enrolled and 24 were treated. Stages 1 and 2 have been completed; an expansion cohort (with patients receiving 4 HF10 injections at 1 x 107 TCID50/dose) is ongoing. Total accrual will be 28 patients. 18 patients reported AEs and 6 had HF10-related AE, including: chills (2 patients), and injection site discolorations, edema, and pain, malaise, pruritus, and hypotension (1 patient each). Clearance of HF10 from blood, saliva and urine was rapid. Despite rapid viral clearance, one patient formed ulcers at both the injected and the non-injected lesions after single injection. Importantly, the ulceration occurred only in tumor cells without affecting normal tissue. The observed AEs and viral clearance in HSV-1 seropositive and seronegative patients did not differ. Conclusions: Multiple intratumoral injections of HF10 are safe and well-tolerated in HSV+ and HSV- patients with refractory/superficial cancers. Related AEs include flu-like symptoms and injection site reactions that are also reported for other oncolytic viruses. Despite rapid clearance from blood, urine, and saliva, HF10 has the potential to provide continued viral antitumor activity, suggesting that HF10 could be a promising new oncolytic virus treatment. Clinical trial information: NCT01017185.
Pterostilbene prevents AKT-ERK axis-mediated polymerization of surface fibronectin on suspended lung cancer cells independently of apoptosis and suppresses metastasis
Authors: Ying-Jan Wang, Jing-Fang Lin, Li-Hsin Cheng, Wen-Tsan Chang, Ying-Hsien Kao, Ming-Min Chang, Bour-Jr Wang, Hung-Chi Cheng
Journal: Journal of Hematology & Oncology (2017)

Polymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. Conceivably, drugs that target such polyFN may fight against cancer metastasis. While stilbene analogs trigger pro-apoptotic effect on attached cancer cells, whether they prevent polyFN assembly and metastasis of suspended cancer cells via an apoptosis-independent manner remains unexplored. We depleted suspended Lewis lung carcinoma (LLC) cells of polyFN by silencing the endogenous FN expression or pterostilbene (PS) to examine whether metastasis of lung cancer cells could thus be suppressed. We investigated whether PS regulates AKT-ERK signaling axis to suppress polyFN assembly in suspended LLC cells independently of apoptosis. We tested the therapeutic effects of orally administered PS against cancer metastasis. Both FN-silencing and PS among the three stilbenoids indeed significantly reduced polyFN assembly and lung metastasis of suspended LLC cells in an apoptosis-independent manner. Mechanistically, PS-induced AKT phosphorylation (pAKT) and suppressed ERK phosphorylation (pERK) in suspended LLC cells, whereas pretreatment with a PI3K inhibitor, LY294002, effectively reduced pAKT, rescued pERK, and consequently reversed the PS-suppressed polyFN assembly on LLC cells; these pretreatment effects were then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was further overruled with U0126. Finally, we found that PS, when orally administered in experimental metastasis assays, both significantly prevented lung colonization and metastasis of LLC cells and reduced the already established tumor growth in the mouse lungs. PS suppressed AKT/ERK-regulated polyFN assembly on suspended LLC cells and pulmonary metastasis. PS possesses potency in both preventing and treating lung metastasis of lung cancer cells in apoptosis-independent and apoptosis-dependent manners, respectively.
Utilization of bone densitometry and administration of bisphosphonates to prevent osteoporosis in patients with nonmetastatic prostate cancer receiving anti-androgen therapy.
Authors: Muhammad Atif Khan, Abby E Holt, Swetha Gujja, Rangaswamy Govindarajan
Journal: Journal of Clinical Oncology (2012)

6099 Background: Prostate cancer subjects with PSA relapse who are treated with androgen deprivation therapy (ADT) are recommended to have baseline and serial bone densitometry (BD) and receive intravenous bisphsphonates (BP). Utilization of BD and BP therapy was evaluated in a retrospective SEER Medicare database analysis. Methods: A cohort study of men aged aged ≥ 65 years with a nonmetastatic incident diagnosis of prostate cancer between 2004 and 2008 was conducted. Data were obtained from the Surveillance, Epidemiology and End Results (SEER) linked Medicare claims. Medicare claims were used to select prostate cancer cases who had ever received ADT and intravenous BP as part of their treatment. ADT was defined as an orchiectomy, goserelin, leuprolide, leuprolide implant, or triptorelin. BD and treatment with pamidronate or zoledronic acid were identified using Medicare HCPCS codes. One-sided exact binomial test of proportion was used to determine if the physician compliance rate is consistent with 80%; meaning equal to or higher than 80%. Results: 157,974 newly diagnosed prostate cancer cases were identified. Of those, 100,865 were age 65 and above and had no bone metastases. Subjects who did not have ADT claims were excluded. 30,846 patients were eligible for analysis. Cases were further stratified by use of BD and BP therapy. Results revealed 86.8% (N=26,774) on ADT did not receive either a BD or intravenous BP therapy. Approximately 2.9% (N=885) of the cases on ADT received BP treatment without ever receiving a BD. 9.3% (N=2,863) of the cases on ADT received a BD without receiving intravenous BP, while only 1.05% (N=324) of the cases on ADT received both a BD and BP. A compliance rate of 1.05%, those patients receiving both bone densitometries to screen for bone loss and preventive therapy, was well below the expected rate of 80%. Conclusions: Contrary to the recommendations, BD assessment and BP use is under utilized in men receiving ADT for non metastatic prostate cancer. Education of practicing physicians regarding better screening and preventative measures for osteoporosis in this population is warranted.
Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus erlotinib.
Authors: Andrew H. Ko, Margaret A. Tempero, Tanios B. Bekaii-Saab, Peter Kuhn, Ryan Courtin, Sharvina Ziyeh, Sanaa Tahiri, Robin Katie Kelley, Elizabeth Dito, Anna Ong, Regina Linetskaya, Olga K. Mirzoeva, Christina Sing-Ying Wu, Alan Paul Venook, Wolfgang Michael Korn
Journal: Journal of Clinical Oncology (2013)

4014 Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1 o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1 st -line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) &gt; 6 weeks, 10 with SD &gt; 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline &gt; 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.
First-in-pediatrics phase I study of crenolanib besylate (CP-868,596-26) administered during and after radiation therapy (RT) in newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent high-grade glioma (HGG).
Authors: Cynthia Wetmore, Alberto Broniscer, David Turner, Karen D. Wright, Atmaram Pai-Panandiker, Larry E. Kun, Abhijit Ramachandran, Arzu Onar-Thomas, Jie Huang, Amar J. Gajjar, Suzanne Baker, Clinton F. Stewart
Journal: Journal of Clinical Oncology (2014)

10064 Background: Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor analyzed from approximately 70 % of pediatric DIPG and 50% of HGG patients, suggesting inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective and potent antagonist of the PDGF pathway with in vitro IC50of 35- and 185- fold lower than observed with dasatanib and imatinib, respectively. Methods: We used a rolling-6 design to study the MTD of once-daily crenolanib administered during and after local RT in children with newly diagnosed DIPG (Stratum A), and in recurrent/progressive HGG, including DIPG (Stratum B). We have completed accrual of 55 patients, 29 and 20 evaluable in Stratum A and B, respectively. Serum pharmacokinetic analyses were performed using non-compartmental techniques on all patients for samples collected on days 1 and 28 of course 1. Pharmacodynamic and mutational analyses of peripheral blood mononuclear cells and tumor tissue are ongoing. Results: Forty-nine evaluable patients have been enrolled to the following dose levels: 100, 130, 170 and 220 mg/m2. Dose limiting toxicities (DLTs) were primarily elevated liver enzymes in both strata, and the most common Grade 3 toxicity seen on Stratum A was leukopenia that resolved with drug interruption. Mild (Grade 2) elevation in liver enzymes was observed in fewer than 15% of patients. The maximum tolerated dose (MTD) of 170 mg/m2 has been established in each stratum. On day 1, median crenolanib non-compartmental AUC0-∞ values for 170 mg/m2dosage on Stratum A was 13,942 nM*hr (6,314-24,369), which was comparable to adult Phase I data at the 280mg flat dose. Conclusions: We have established an MTD in pediatric patients. The PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children at doses slightly higher than the established MTD from Phase I trial in adults (280 mg/day). The spectrum of toxicities observed in children is similar to those observed in adults, though leukopenia is a novel toxicity. Clinical trial information: NCT01393912.
Leukemic CD34+CD38- Cells Display Conserved Differential Expression of Many ATP Binding-Cassette Transporter Genes.
Authors: Marc H.G.P. Raaijmakers, Elke P.L.M. de Grouw, Louis T.F. van de Locht, Bert A. van der Reijden, Theo J.M. de Witte, Joop H. Jansen, Reinier A.P. Raymakers
Journal: Blood (2005)