tbuckley/cabot-search huggingface dataset:
Combination therapy with enzalutamide and the poly (ADP-ribose) polymerase-1 (PARP1) inhibitor niraparib in castration-resistant prostate cancer (CRPC): HCRN GU 14-202.
Authors: John Paul Flores, Paul Mathew
Journal: Journal of Clinical Oncology (2016)

TPS5095 Background: PARP1 is a multi-functional enzyme implicated in DNA repair and transcription factor regulation. It regulates AR association with chromatin required for transcription, and in preclinical models, PARP1 inhibition delays castration-resistance. Germline and acquired defects of homologous DNA repair predict for sensitivity to PARP1-inhibitors in CRPC, and long-term responses have been observed. Enzalutamide is an AR antagonist that prolongs survival in metastatic CRPC. Goal: Combined targeting of AR by enzalutamide and the PARP-inhibitor niraparib may lead to synergistic benefit in CRPC. This study aims to assess the feasibility of this combination. Methods: Eligible participants must have progressive metastatic CRPC and ECOG PS 0-1. Prior docetaxel, Ra-223, or Sipileucel-T are permitted, but previous enzalutamide or other next-generation AR antagonists are not. A limited number of participants are allowed prior abiraterone. The study features a modular Phase I design beginning with a 4 week lead-in of standard dose enzalutamide 160mg daily. Participants who tolerate enzalutamide without dose-limiting toxicity (DLT) during lead-in then proceed to combination with niraparib. Up to 3 cohorts of 6 patients are planned with niraparib doses of 100 (dose level 0), 200 (+1), and 300 mg (+2). Dose escalation is permitted if the DLT rate during the first cycle (4 weeks) of combination therapy is < 33%. The primary objective is to determine the maximum tolerated dose of the combination. Secondary objectives include PSA kinetics, objective response, progression free survival, description of toxicity, and quality of life. Exploratory biomarker studies will be conducted to correlate with outcomes. Circulating tumor cells (CTCs) and plasma will be archived at baseline, post- enzalutamide, post-combination therapy with niraparib, and progression (Epic Sciences). Assays include CTC quantitation and morphology, nuclear AR expression, AR N:C terminal ratio to assess AR splice variants, and pilot studies assessing homologous repair deficiency phenotype. Enrollment opened February 2016. Clinical trial information: NCT02500901.
Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results
Authors: F. Morschhauser, J. P. Leonard, L. Fayad, B. Coiffier, M. Petillon, M. Coleman, H. Horne, N. Teoh, W. A. Wegener, D. M. Goldenberg
Journal: Journal of Clinical Oncology (2007)

8032 Background: An open-label, multicenter study has shown that the humanized anti-CD20 antibody, IMMU-106 (hA20), which has framework regions of epratuzumab, has a good safety and efficacy profile in NHL pts when administered once-weekly × 4 at different doses. The trial is now focused on confirming the efficacy of lower doses (80–120 mg/m 2 /wk × 4). Methods: A total of 68 pts (35 male, 33 female; age 34–84) received hA20 at 750 (N=3), 375 (N=27), 200 (N=11), 120 (N=21), or 80 mg/m 2 (N=6). They had follicular (FL, N=47) or other (N=21) B-cell NHL, were predominantly stage III/IV (N=47) at study entry, and had received 1–8 prior treatments (median, 2), including 1 (N=40) or more (N=21) rituximab regimens (without progression within 6 months). Results: Sixty- six pts completed all 4 infusions; 1 pt progressed during treatment and withdrew, while another pt with hives and chills after prior rituximab discontinued treatment after a similar episode at 1st infusion. hA20 was generally well tolerated, with shorter infusion times (typically 2 h initially and 1 h subsequently) at lower doses. Drug-related adverse events were transient, Grade 1–2, most occurring only at 1st infusion, and there was no evidence of HAHA in 54 pts now evaluated. Mean antibody serum levels increased with dose and infusions; serum clearance at 375 mg/m 2 appears similar to rituximab. Currently, 48 pts with at least 12 wks follow-up were evaluated by Cheson criteria: 32 FL pts had 15 (47%) OR's with 7 (22%) CR/CRu's, even after 2–4 prior rituximab-regimens, and 17 non-FL pts had 6 (38%) OR's, with 1 CRu in a marginal zone NHL pt. At a median follow-up of 11 mo., 9/21 pts with ORs are continuing responses, including 4 long-lived responses (15–20 mo). The evaluated pts include 17 pts at 120 mg/m 2 who had 5 (29%) ORs with 3 (17%) CR/CRu's. Responses at 80 mg/m 2 remain to be evaluated, but B-cell depletion occurs after the 1st infusion even at this low dose. Conclusions: hA20 appears well-tolerated, with no evidence of significant adverse events other than minor infusion reactions, even at short infusion times. B-cell depletion and responses have occurred at all doses evaluated, with no clear-cut evidence of a dose-response. As such, the study is continuing to confirm the efficacy of lower doses. No significant financial relationships to disclose.
Prognostic Interaction Between ASXL1 and TET2 Mutations in Chronic Myelomonocytic Leukemia
Authors: Mrinal M Patnaik, Terra L. Lasho, Pooja Vijayvargiya, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2015)
Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress
Authors: Jesus Zamora-Pineda, Ashok Kumar, Jung H. Suh, Meng Zhang, Julie D. Saba
Journal: The Journal of Experimental Medicine (2016)

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)-mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.
Long-term effects of cilengitide, a novel integrin inhibitor, in recurrent glioblastoma: A randomized phase IIa study.
Authors: K. Fink, T. Mikkelsen, L. B. Nabors, P. Ravin, S. R. Plotkin, D. Schiff, C. Hicking, M. Picard, D. A. Reardon
Journal: Journal of Clinical Oncology (2010)

2010 Background: Prognosis of patients with recurrent glioblastoma multiforme (GBM) is poor. Cilengitide is an investigational selective αvβ3/5 integrin inhibitor with multiple anti-tumor effects. In a randomized phase IIa trial of cilengitide in patients with recurrent GBM, median overall survival (OS) was 9.9 months (2,000 mg arm) vs. 6.5 months (500 mg arm) [Reardon et al, JCO 2008]. Long-term follow up data are reported here. Methods: A phase IIa randomized, multicenter, open-label trial examined effects of 2 monotherapy cilengitide regimens: 500 mg (n = 41) and 2,000 mg (n = 40). Prior to inclusion, patients had surgery or biopsy, chemoradiation (temozolomide) and measurable contrast enhanced tumor size (1 cm2). Cilengitide was infused over 1 hour twice-weekly during a 4-week cycle until disease progression or unacceptable adverse events. Eligible subjects were ≥ 18 years with histologically-confirmed recurrent GBM, stable corticosteroid dose, satisfactory hematologic and biochemical results, and Karnofsky performance score ≥ 70. Results: Mean treatment duration was 139 days (range 11–1390). Median follow-up was 53.3 and 48.3 months for cilengitide 500 and 2,000 mg, respectively. OS rates were consistently greater with cilengitide 2,000 mg (37.3, 22.5, 15.0, 10.0 and 10.0% at 12, 24, 36, 48 and 54 months, respectively) vs cilengitide 500 mg (22.0, 12.2, 4.9, 2.4 and 0% at 12, 24, 36, 48 and 54 months, respectively): hazard ratio 0.635 with 95% confidence interval 0.402–1.003. Fifteen patients received cilengitide treatment for > 6 months, 6 patients for > 1 year. Treatment-related AEs (AEs) tended to occur within 6 months of receiving the first dose of cilengitide and the most common (> 1 subject) was fatigue (n = 3), while the most common grade 3/4 serious AE was convulsion (n = 2). No study drug-related grade 3/4 AEs occurred > 6 months from the first cilengitide dose and only 2 patients reported serious AEs during that time. Conclusions: Cilengitide monotherapy was well tolerated and feasible with a twice weekly regimen for > 4 years of follow-up. Long-term survival rates were consistently greater with the 2,000 mg dose of cilengitide versus the lower-dose group in this randomized phase II study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA EMD Serono, Merck KGaA Merck KGaA EMD Serono, Merck KGaA EMD Serono, Merck KGaA
PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression
Authors: Dai Horiuchi, Roman Camarda, Alicia Y Zhou, Christina Yau, Olga Momcilovic, Sanjeev Balakrishnan, Alexandra N Corella, Henok Eyob, Kai Kessenbrock, Devon A Lawson, Lindsey A Marsh, Brittany N Anderton, Julia Rohrberg, Ratika Kunder, Alexey V Bazarov, Paul Yaswen, Michael T McManus, Hope S Rugo, Zena Werb, Andrei Goga
Journal: Nature Medicine (2016)
Phosphoproteomic assessment of HER2 signaling pathway in HER2 non-amplified patients of the GeparQuattro and GeparQuinto trials
Authors: S. Avril, G. von Minckwitz, K. Malinowsky, P.A. Fasching, T. Karn, A. Hartmann, M. Untch, C. Denkert, K.-F. Becker, S. Loibl
Journal: Annals of Oncology (2015)
Abstract A45: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways in triple-negative breast cancer
Authors: Tony J. Wu, Barzin Y. Nabet, Bihui Xu, Mirjam C. Boelens, Jos Jonkers, Andy J. Minn
Journal: Cancer Research (2016)

Abstract Breast cancer cells can achieve protection from DNA damage both through cell-autonomous mechanisms and intercellular communication with the tumor microenvironment. Previously, we described an Interferon-Related DNA Damage Resistance Signature comprising of a network of interferon-stimulated genes (ISGs) that promotes and clinically predicts chemotherapy and radiation resistance in breast cancer. Here, we examine the heterotypic tumor-stroma interactions that regulate ISGs. We show that STAT1 and other ISGs are induced in breast cancer cells following interaction with stroma. STAT1 induces NOTCH3 expression, explaining a requirement for juxtacrine signaling. Moreover, we report that stroma upregulates ISG expression in breast cancer cells through exosomes. Exosomes transferred from the stroma and ISG induction are both dependent on RAB27B. In mice, targeting these pathways abrogate stroma-mediated resistance and results in long-term tumor-free survival. Analysis of primary human tumors supports the role of anti-viral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance. To determine whether these observations can further predict clinical efficacy, cell lines derived from a genetically engineered mouse model for p53-induced breast cancer, K14cre;Brca1F/F;p53F/F, were tested. We show that stroma induces breast cancer ISGs through exosomes, which in turn can induce signaling to activate NOTCH3 and regulate DNA damage resistance. Citation Format: Tony J. Wu, Barzin Y. Nabet, Bihui Xu, Mirjam C. Boelens, Jos Jonkers, Andy J. Minn. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A45.
Microsphere-Based Scaffolds in Regenerative Engineering
Authors: Vineet Gupta, Yusuf Khan, Cory J. Berkland, Cato T. Laurencin, Michael S. Detamore
Journal: Annual Review of Biomedical Engineering (2017)

Microspheres have long been used in drug delivery applications because of their controlled release capabilities. They have increasingly served as the fundamental building block for fabricating scaffolds for regenerative engineering because of their ability to provide a porous network, offer high-resolution control over spatial organization, and deliver growth factors/drugs and/or nanophase materials. Because they provide physicochemical gradients via spatiotemporal release of bioactive factors and nanophase ceramics, microspheres are a desirable tool for engineering complex tissues and biological interfaces. In this review we describe various methods for microsphere fabrication and sintering, and elucidate how these methods influence both micro- and macroscopic scaffold properties, with a special focus on the nature of sintering. Furthermore, we review key applications of microsphere-based scaffolds in regenerating various tissues. We hope to inspire researchers to join a growing community of investigators using microspheres as tissue engineering scaffolds so that their full potential in regenerative engineering may be realized.
T/NK Lymphocytosis in CML Ph+ Patients During Dasatinib Therapy.
Authors: Antonella Russo Rossi, Alessandra Ricco, Paola Carluccio, Mario Delia, Manuela Leo, Paola Casieri, Fabio Stagno, Angela Minervini, Vincenzo Liso, Giorgina Specchia
Journal: Blood (2009)
Pilot study of VHL mutation analysis to predict response to interleukin-2 in patients with metastatic renal cell carcinoma
Authors: A. J. Pantuck, P. Fergelot, J. Patard, J. Lam, A. S. Belldegrun, R. A. Figlin
Journal: Journal of Clinical Oncology (2006)

14539 Background: More than 300 different mutations have been described in von Hippel-Lindau (VHL) families and nearly 100 in sporadic RCC. In familial cases, there is an excess of mutations in exon 3 and exon 1, whereas mutations are evenly distributed in sporadic cases. Recent evidence suggests the importance of genotype/phenotype correlations with different VHL gene mutations contributing to a tumor’s unique biological behavior. We performed a pilot study to compare the incidence and type of VHL mutation in IL-2 complete responders (CR) and non-responders (NR). Methods: Genomic DNA was extracted from 20 frozen clear cell tumour samples (10 CR and 10 NR) using Qiamp DNA mini kits (Qiagen). Four amplimers covering the entire coding sequence and three exon/intron junctions of the VHL gene were synthesized by PCR. PCR products were subsequently purified and were sequenced using Big Dye Primer Cycle Sequencing kit (Perkin-Elmer Applied Biosystems) and an automated DNA sequencer (Perkin-Elmer Applied Biosystems). Point mutation detection was performed on DNA sequencing gels from colored peak chromatograms. Mutation bearing sequences were confirmed by a second round of PCR and sequencing. Results: In the CR patients, only 2 out of 10 samples (20%) had evidence of a VHL mutation. These VHL mutations included a false sense mutations in exon 2, comprised of a C to T transition at position 646 in the cDNA, creating a stop codon, and a frameshift mutation in exon 1 introducing in one allele an abnormal stop codon at the beginning of exon 3 potentially leading to a shorter protein product. In the 10 non-responder samples, there was also a 2 out of 10 (20%) incidence of VHL mutations. These mutations included a complex 12 nucleotide deletion in the third exon in the a domain of the protein, and a G deletion in the first exon introducing a premature stop codon. Conclusions: In this small pilot study of metastatic RCC patients, there were relatively few VHL gene mutations, and VHL mutations did not appear to correlate with response to IL-2 therapy. This study, however, does not assess inactivation of VHL genes due to hypermethylation. An expanded genetic profile to evaluate IL-2 responders versus non-responders using 500k SNP Chips is underway. No significant financial relationships to disclose.
Which is more recommendable as the second line chemotherapy to S-1 for advanced gastric cancer; combination of CPT-11 plus CDDP or weekly paclitaxel?
Authors: H. Imamura, H. Furukawa, K. Kishi, M. Tatsuta, S. Masutani, M. Fukunaga, T. Nakayama, J. Shimizu, H. Takemoto, T. Kishimoto
Journal: Journal of Clinical Oncology (2004)

4136 Background: Since S-1 has the highest response rate as a single-agent for advanced gastric cancer (AGC) is usually used as the first line chemotherapy in Japan. Imamura et al. reported that combination of CPT-11 plus CDDP treatment for AGC showed a good response rate (52%) and its adverse reactions were mild (ASCO 2002; 622 abstr.). On the other hand Arai et al. reported that Paclitaxel was active in AGC with a good safety profile, feasibility and activity as salvage treatment (ASCO 2003; 1040 abstr.). The aim of this study is to evaluate which is recommendable as a subsequent second line chemotherapy to S-1;depends on document reviewcombination of CPT-11 plus CDDP (group A) ordepends on document reviewPaclitaxel (group B). Methods: The eligibility criteria included microscopically proven advanced and/or recurrent gastric cancer with measurable metastatic lesions; adequate organ functions; oral intake is possible; ECOG PS of 0, 1 or 2; an age of <= 75; no prior chemotherapy; and provision of written informed consent. S-1 was administered orally 40mg/m2 twice a day for 28 consecutive days followed by a 14-day rest period. When tumor progression is observed, the second line treatment followed after 2 weeks rest. The treatment regimen consisting of CPT-11 (60mg/m2) on days 1 and 15 and CDDP (10mg/m2) on days 1, 2, 3, 15, 16, and 17 (group A; 14 patients) or Paclitaxel (70mg/m2) by on days 1, 8, 15 (group B; 11 patients) was repeated every 4 weeks. Results: The overall response rate (RR) of S-1 as the first line chemotherapy was 36% (2 CRs, 7 PRs, 10 SDs and 6 PDs). Neither grade 4 hematological toxicities nor grade 3 or 4 febrile neutropenia occurred. RRs of second line therapy in group A and B were 36% (5 PRs, 6 SDs and 3 PDs) and 36% (1 CR, 3 PRs, 4 SDs and 3 PDs), respectively (P=0.6784). There were no treatment-related deaths. After median follow up periods from the first line chemotherapy of 875 (488–1171) and 319 (163–1027) days, 1-year survival rats were 30% (MST; 355 days) and 89% in group A and B, respectively (P=0.026). Conclusion: Both regimens showed similar RR and Paclitaxel as the second line showed a better one-year survival rate than a combination of CPT-11 plus CDDP. No significant financial relationships to disclose.
Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders
Authors: Payal P. Khincha, Alison A. Bertuch, Suneet Agarwal, Danielle M. Townsley, Neal S. Young, Siobán Keel, Akiko Shimamura, Farid Boulad, Tregony Simoneau, Henri Justino, Christin Kuo, Steven Artandi, Charles McCaslin, Des W. Cox, Sara Chaffee, Bridget F. Collins, Neelam Giri, Blanche P. Alter, Ganesh Raghu, Sharon A. Savage
Journal: European Respiratory Journal (2016)

The telomere biology disorder (TBD) dyskeratosis congenita (DC) is a multisystem inherited bone marrow failure syndrome and cancer predisposition syndrome caused by germline mutations in telomere biology genes ( DKC1 , TINF2 , TERC , TERT , NOP10 , NHP2 , CTC1 , WRAP53 , ACD , RTEL1 and PARN ). The classic triad of reticular skin pigmentation, dysplastic nails and oral leukoplakia is diagnostic of DC [1, 2]. Leukocyte telomere lengths less than the first percentile for age measured by flow cytometry with fluorescence in situ hybridisation are consistent with DC in the presence of other phenotypic features [3]. Pulmonary fibrosis, a known complication of DC/TBD, occurs in ≥20% of patients [1]. Pulmonary arteriovenous malformations (PAVMs) in DC have been previously described in case reports or small case series in the context of hepatopulmonary syndrome (HPS) [4–9]. Presenting features of PAVMs may overlap with those of pulmonary fibrosis, including dyspnoea, orthopnoea, platypnoea, cyanosis and digital clubbing. HPS is described as pulmonary vascular dilatation due to liver disease of any cause (cirrhotic/noncirrhotic with/without portal hypertension), leading to deficient arterial oxygenation [10]. PAVMs are underrecognised in telomere biology disorders and present diagnostic and therapeutic challenges <http://ow.ly/2lPc304eu0t> This case series is the first completed research effort of the Clinical Care Consortium for Telomere Associated Ailments (CCCTAA), formed in 2013. We thank the patients, their families and the referring clinicians for their valuable contributions to this study.
Combination of ECG and Echocardiography for Identification of Arrhythmic Events in Early ARVC
Authors: Ida S. Leren, Jørg Saberniak, Trine F. Haland, Thor Edvardsen, Kristina H. Haugaa
Journal: JACC. Cardiovascular imaging (2016)

The aim of this study was to investigate early markers of arrhythmic events (AEs) and improve risk stratification in early arrhythmogenic right ventricular cardiomyopathy (ARVC). AEs are frequent in patients with ARVC, but risk stratification in subjects with early ARVC is challenging. Early ARVC disease was defined as possible or borderline ARVC diagnosis according to the ARVC Task Force Criteria 2010. We performed resting and signal averaged electrocardiogram (ECG). Using echocardiography, we assessed right ventricular (RV) outflow tract diameter and right ventricular basal diameter (RV diameter). Global longitudinal strain and mechanical dispersion (MD) from strain echocardiography were assessed in both the right and left ventricle. AEs were defined as documented ventricular tachycardia, cardiac syncope, or aborted cardiac arrest. Of 162 included subjects with ARVC (41 ± 16 years of age, 47% female), 73 had early ARVC, including mutation positive family members not fulfilling definite ARVC diagnosis. AEs occurred in 15 (21%) subjects with early ARVC. Those with AEs in early disease had larger RV diameter (40 ± 4 mm vs. 37 ± 5 mm), more pronounced RVMD (39 ± 15 ms vs. 26 ± 11 ms), and more pathological signal averaged ECGs compared with those without AEs (all p ≤ 0.05). Adding measurements of RV diameter and RVMD to electrical parameters improved identification of subjects with AEs compared with electrical parameters alone (p = 0.05). ECG parameters, RV diameter, and RVMD were markers of previous arrhythmic events in patients with early ARVC. A combination of electrical and echocardiographic parameters improved identification of subjects with AEs in early ARVC disease.
A Phase 2 Study of Bortezomib Combined with Reinduction Chemotherapy in Children and Young Adults with Recurrent, Refractory or Secondary Acute Myeloid Leukemia: A Children's Oncology Group (COG) Study
Authors: Terzah M. Horton, John Perentesis, Alan S. Gamis, Todd A. Alonzo, Robert B. Gerbing, Jennifer Ballard, Kathleen Adlard, Dianna Howard, Franklin O. Smith, Jeffrey A. Moscow
Journal: Blood (2012)