tbuckley/cabot-search huggingface dataset:
ImmunoPET compared with conventional imaging modalities for the detection of Ewing sarcoma metastases in a preclinical model.
Authors: Allison Frances O'Neill, Jason L.J. Dearling, Tanya Tupper, Rebecca Modiste, Guangping Dai, Quang-dé Nguyen, Andrew L. Kung, Alan Packard
Journal: Journal of Clinical Oncology (2015)

10048 Background: Ewing sarcoma is a solid tumor arising from bone and the soft tissues that affects approximately 250 children and adolescents each year. Localized disease confers a favorable 75% 5-year survival, but the prognosis for metastatic disease remains dismal with only a 20% 5-year survival. The ability to accurately diagnose disease extent is therefore crucial. Conventional imaging modalities provide high-resolution anatomic data but lack specificity. The goal of this preclinical study was to compare the detection of metastatic Ewing sarcoma using a 89Zr-labeled anti-CD99 antibody (Ab) with conventional imaging modalities including MRI and [18F]FDG-PET. Methods: NOD scid gamma mice were injected via tail vein with luciferase-transduced TC32 Ewing sarcoma cells and monitored for tumor growth by bioluminescence imaging until development of 2-3 mm liver metastases at 4 weeks. Disease burden and lesion distribution were assessed by MRI and [18F]FDG-PET. Mice were then injected with the 89Zr-labeled anti-CD99 Ab and imaged from 16 to 144 h post-injection. Results: Liver metastases were detected by immunoPET from 16 h to 144 h post-injection with the maximum tumor-to-background ratio observed at 72 h (SUVmax = 12.5 for tumor and 4 for local normal tissues). Liver metastases of 2-3 mm diameter were identified on MR images guided by immunoPET data, but were not detected using [18F]FDG. Autoradiography data demonstrated a 89Zr-Ab metastases-to-liver uptake ratio of 13:1. Conclusions: The 89Zr-labeled anti-CD99 Ab PET probe out-performed [18F]FDG and MRI in the detection of Ewing sarcoma metastases, validating our prior work with a 64Cu-labeled anti-CD99 probe. The longer half-life of 89Zr allowed imaging at later time points (72 h) than 64Cu yielding a tumor-to-background ratio that was two-fold higher. The more sensitive and specific detection and monitoring of metastatic disease may have tremendous implications for the clinical care of patients with Ewing sarcoma. In light of existing safety data for the imaging of adult solid tumors with 89Zr-labeled Abs, this study supports next steps for translation to pediatrics.
FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (GDC-0068) in combination with paclitaxel as neoadjuvant treatment for early stage triple-negative breast cancer.
Authors: Steven J. Isakoff, Cristina Saura, Isabel Calvo, Miguel J. Gil Gil, Debra A. Patt, Serafin Morales Murillo, Jay C. Andersen, EVA Ciruelos, Julie Gottlieb Fisher, Jose Passos-Coelho, Lorena de La Pena, Amy V. Kapp, Steven Gendreau, Wai Y. Chan, Stina Mui Singel, Daniel J. Maslyar, Jose Baselga, Mafalda Oliveira
Journal: Journal of Clinical Oncology (2016)

TPS1105 Background: TNBC often exhibits activation of PI3K/Akt signaling, associated with loss of PTEN expression, low INPP4B expression, PI3K/Akt mutations, or PI3K/AKT3 amplification. Inhibition of the PI3K/Akt pathway may lead to radiosensitization and/or chemosensitization. Ipatasertib (ipat) is an oral, potent ATP-competitive small molecule inhibitor of all three isoforms of Akt. The combination of ipat with taxanes in preclinical models resulted in enhanced efficacy relative to either ipat or chemotherapy alone. In a Phase Ib clinical study, the combination of ipat with either paclitaxel (pac) or docetaxel was well-tolerated and resulted in RECIST responses, particularly pts with tumors having PI3K/Akt activation. Methods: FAIRLANE is a randomized, double-blind, placebo-controlled, multicenter, neoadjuvant Phase II study designed to estimate the efficacy of ipat combined with pac versus placebo combined with pac in women with Stage Ia-IIIa triple-negative breast cancer (TNBC). Approximately 150 patients (pts) will be enrolled, randomized in a 1:1 ratio, and stratified by PTEN status, node involvement, and tumor size. Pts will receive 3 cycles (each cycle is 28 days) of ipat 400 mg or placebo orally once daily on Days 1 to 21 along with pac 80 mg/m2 on Days 1, 8, 15, and 22. All pts will undergo pretreatment and Cycle 1 Day 8 tumor tissue biopsies to evaluate pathway biomarkers. Following three cycles of treatment, pts will undergo surgery. The primary efficacy endpoint is pCR within the breast and axilla (ypT0/Tis ypN0) in all pts and in pts with PTEN-low tumors, and will be assessed by local pathologic assessment. Additional endpoints include objective response rate, safety, BCS rate, pharmacokinetics, and pathway biomarkers. Following surgical resection of primary tumor, pts may continue post-operative treatment with a standard adjuvant chemotherapy regimen at the treating physician’s discretion. As of 14 Jan 2016, 61 patients have been enrolled, and global enrollment is ongoing. Clinical trial information: NCT02301988.
Treatment of liver cancer by nanomedicine.
Authors: Wolfgang Wagner, Manfred Georg Krukemeyer
Journal: Journal of Clinical Oncology (2012)

e13091 Background: Oncological surgery as a therapy branch of general surgery is registering a rapid development in the form of neoadjuvant treatment. Therapies of liver tumors display diverse treatment alternatives. Methods: The administration of cytostatics coupled with and without iron oxides (Fe 3 O 4 ) has been presented in an experimental series with 36 animals with prior implantation of an R 1 H rhabdomyosarcoma in the liver, since iron undergoes selective phagocytosis in the liver. In Group I, mitoxantrone is injected into the lateral tail vein of the animals (n = 12) in a dosage of 1 mg/kg of body weight. Group III (n = 12 animals) received mitoxantrone coupled with iron oxide (Fe 3 O 4 ), and Group II (n = 12 animals) received NaCl, in the same dosage for all groups. In the sonography and in the measurement of the volume, a significantly smaller tumor growth is found in Group II compared with Group I and III. The volume was measured manually postmortally in mm 3 (length x breadth x height). Results: The tumor volume showed the lowest growth in Group II, which was treated with mitoxantrone-coupled iron oxides. 3 animals from Group II died. The autopsy revealed no indication of the cause of death. There were neither thromboses nor allergic reactions in any of the animals. It can be clearly seen that Group I has a smaller mean volume and less scatter than Group II. The mean of Group I is also below that of Group II. Conclusions: It has been possible to demonstrate in animal studies that mitoxantrone-coupled iron oxide (Fe 3 O 4 ) reduces the tumor volume in the liver to a greater extent that administration solely of mitoxantrone. The studies should be verified in a clinical study on humans.
Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout
Authors: N Vazirpanah, L B E Kienhorst, E Van Lochem, C Wichers, M Rossato, P G Shiels, N Dalbeth, L K Stamp, T R Merriman, M Janssen, T R D J Radstake, J CA Broen
Journal: Annals of the Rheumatic Diseases (2017)

Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout.We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity.TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005).Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.
Phase I/II study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor entinostat in patients with metastatic renal cell carcinoma.
Authors: Roberto Pili, Li Shen, Saby George, Hans Hammers, Anita Sandecki, Connie Collins, Igor Espinoza-Delgado, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2012)

TPS4687 Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I specific HDAC inhibitor, entinostat, has synergistic anti-tumor effect in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y et al Clinical Cancer Res 2007). Our group has also recently showed that low dose entinostat induces STAT3 acetylation, down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive function without affecting T effector cells (Shen Li et al PLoSONE 2012). Methods: Based on these preclinical evidences we have initiated a Phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic renal cell carcinoma. The primary objective of the study is to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria are clear cell histology, no prior treatments and being fit to receive high dose IL-2. The Phase I portion consists of two dose levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 (600,000 units/Kg every 8 hrs.) according to a 3+3 design. The sample size of 36 patients in the Phase II portion is powered to detect an increase in objective response rate from 20% to 40% as compared to historical data with high dose IL-2 alone. Correlative studies include assessment of CD4+, CD8+, CD4+/Foxp3, NK cells in tumor and blood samples by immunohistochemistry and FACS analysis, and tumor metabolism by FDG PET. We are also exploring the relationship between entinostat exposure with pharmacodynamic endpoints. To date dose level one has been completed without DLT. Enrollment to dose level two has begun in the Fall 2011. The results from this study may confirm the role of entinostat in enhancing the effect of IL-2 and may be translated into other combination strategies involving immunotherapies. The clinical trial and correlative studies are supported by the National Cancer Institute- R21CA137649.
Phase I study of dalteparin in combination with sunitinib as first-line treatment in patients with metastatic renal cell carcinoma.
Authors: Roberto Pili, Sumanta Kumar Pal, Saby George, Jens Voortman, Pongwut Danchaivijitr, Remi Adelaiye, Nancy Webb, Diane Poslinski, Adrienne Groman, Alan Hutson, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2014)

e15607 Background: Anti vascular endothelial growth factor (VEGF) drugs represent the standard of care for the treatment of clear cell renal cell carcinoma (RCC). However, despite the initial clinical benefit, patients develop progressive disease. An activated coagulation cascade has been implicated in tumor angiogenesis and metastases. RCC has been reported to have high level expression of tissue factor. Thus, there is a rationale for combining an effective anticoagulant with anti VEGF therapies. Methods: Primary objective of the study was to evaluate the safety and tolerability of dalteparin, a low molecular weight heparin, in combination with sunitinib. A lead –in phase with sunitinib and dalteparin monotherapy was followed by combination therapy. Dose limiting toxicity (DLT) was defined as grade 3 or 4 toxicity related to dalteparin (first 4 weeks of combination). Main eligibility criteria were clear cell histology and no prior treatments. Platelet rich plasma and serum were collected to analyze VEGF, cytokines and microRNAs, respectively. Results: This phase I study consisted of 3 dose levels of dalteparin (70, 140 or 200 IU/kg/day sc) and a fixed standard dose of sunitinib (50 mg PO) according to a 3+3 design. We enrolled nineteen patients. Six patients have been treated at dose level 3 (+4 patients in the expansion cohort). Grade 3 hematological (anemia, thrombocytopenia, neutropenia, leucopenia) and non-hematological toxicities (back pain, dehydration, dyspnea, vomiting) were 7.6% and 3.7%, respectively. One DLT (anemia) was observed at the 3rd dose level. Ten treatment-related severe adverse events were observed including dyspnea, anemia, thrombocytopenia, acute renal failure, chest pain, dehydration and atrial fibrillation. To date, the median progression-free survival is 14 months (2.4-NR). The correlative studies are ongoing and will be presented at the meeting. Conclusions: Our results suggest that combination of sunitinib (50 mg) with therapeutic dose of dalteparin (200 IU/kg/day sc) is safe and well tolerated. The clinical benefit of effective anticoagulation in combination of anti-VEGF therapies in RCC patients should be evaluated prospectively. Clinical trial information: 01061411.
Bendamustine and rituximab and lenalidomide (BRR) in the treatment of relapsed and refractory low grade non-Hodgkin lymphoma (NHL): Final results of phase 1 study NCCTG N1088/ALLIANCE.
Authors: Grzegorz S. Nowakowski, Betsy LaPlant, William R Macon, Morie A. Gertz, Thomas Matthew Habermann, David James Inwards, Ivana N. M. Micallef, Donald B. Wender, John Leonard, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2015)

8540 Background: The combination of bendamustine and rituximab is effective in the treatment of low grade NHL. Lenalidomide shows significant synergy when combined with rituximab and rituximab-containing chemotherapy. The primary aim of this phase 1 study was to establish a maximum tolerated dose (MTD) of bendamustine, rituximab and lenalidomide. Secondary endpoints included toxicity, overall response and progression-free survival. Methods: Eligible patients (pts) had relapsed or refractory low grade NHL, treated with at least 1 prior regimen. A 3+3 phase was used. Dose levels are shown in the Table. Bendamustine was given on day 1 and 2, rituximab on day 1 and lenalidomide orally, daily, days 1-10 of 28-day cycle for up to 6 cycles. Pegfilgrastin was given on day 3 of the cycle. Results: 15 patients were enrolled. The median age was 58 years (47-71), 5/15 patients were female, 12/15 patients had stage 4 disease. The histological subtypes were: follicular lymphoma grade 1 and 2 (6/15 pts), marginal zone lymphoma (5/15 pts) and lymphoplasmacytic lymphoma (4/15 pts). No dose-limiting toxicity was seen. Dose escalation beyond 25 mg daily of lenalidomide was not performed, since 25 mg is considered a biologically effective dose. The most common toxicity was hematological, with 2/15 pts experiencing grade 3 neutropenia. The overall response was 100% (Table). Only 1/15 pts experienced grade 3 or more non-hematological toxicity (grade 3 urticaria). All patients remain alive with median follow up of 17 months (6-28) and only 1 pt disease progression at 12 months. Conclusions: Lenalidomide at 25 mg/day, days 1-10 of a 28-day cycle can be safely combined with the standard dose bendamustine rituximab regimen and is well tolerated. The encouraging response rates in a relapsed setting warrant further evaluation of this combination in larger trials. Support: U10CA180821, U10CA180882, CA025224 Clinical trial information: NCT01429025.Dose escalation and response summary. Dose level Lenalidomide Days 1-10 Bendamustine Day 1-2 Rituximab Day 1 DLTs Response 1 15 mg 70 mg/m2 375 mg/m2 0/3 3 PR 2 20 mg 70 mg/m2 375 mg/m2 0/3 1 CR, 2 PR 3 20 mg 90 mg/m2 375 mg/m2 0/3 2 CR, 1 PR 4 25 mg 90 mg/m2 375 mg/m2 0/6 3 CR, 3 PR
Effect of oxaliplatin-based adjuvant therapy on post-relapse survival (PRS) in patients with stage III colon cancer: A pooled analysis of individual patient data from four randomized controlled trials.
Authors: Christopher Twelves, Hans-Joachim Schmoll, Michael O'Connell, Thomas H. Cartwright, Edward McKenna, Weijing Sun, Wasif M. Saif, Luen F. Lee, Greg Yothers, Daniel G. Haller
Journal: Journal of Clinical Oncology (2012)

3523 Background: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer; however, its impact on PRS in these patients is unclear. We therefore compared PRS in trials of patients with stage III colon cancer treated with oxaliplatin plus capecitabine (XELOX) or 5-flourouracil (5-FU; FOLFOX) vs. leucovorin/5-FU (LV/5-FU). Methods: Individual patientdata (N = 4,819) from NSABP C-08, XELOXA, X-ACT, and AVANT were pooled and analyzed by XELOX/FOLFOX vs. LV/5-FU; patients treated with bevacizumab were excluded. Hazard ratios (HR) were estimated by Cox regression analyses and multivariate Cox regression analyses controlled for age, gender, T, and N stage. Post-relapse treatment data were collected when available. Results: Patient demographics and disease characteristics (except lymph nodes examined) were well balanced across analytic groups. Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50 months) than in XELOXA and X-ACT (83 and 74 months). PRS was very similar for XELOX/FOLFOX and LV/5-FU (HR 0.94, 95% CI, 0.82–1.07; P = .33). Multivariate analyses supported these findings, but showed that PRS was associated with younger age and lower N stage at diagnosis after controlling for gender and T stage. PRS was also comparable for capecitabine or XELOX vs. LV/5-FU or FOLFOX (N = 5,819, HR 1.07, 95% CI, 0.95–1.20; P = .26). Post-relapse therapies were comparable across the two cohorts. Conclusions: Adjuvant chemotherapy regimen did not impact on PRS in patients with stage III colon cancer; however, both N stage and age demonstrated independent effects on PRS. Studies have demonstrated significantly improved disease-free and overall survival for oxaliplatin-based therapy, and our data show that survival is not compromised by worsened PRS at subsequent relapse. [Table: see text]
Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: P. H. Patel, G. V. Kondagunta, B. G. Redman, G. R. Hudes, S. T. Kim, I. Chen, R. J. Motzer
Journal: Journal of Clinical Oncology (2007)

5097 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up. No significant financial relationships to disclose.
Pharmacogenetic investigation of dabrafenib efficacy in a meta-analysis of three melanoma studies.
Authors: Diptee A Kulkarni, Judong Shen, Linda P Briley, Karen S King, Suzanne Swann, Gursel Aktan, Kiran Patel, Colin F. Spraggs
Journal: Journal of Clinical Oncology (2014)

e20018 Background: Dabrafenib (D) is approved for the treatment of BRAF V600E–mutated metastatic melanoma (MM). Multiple resistance mechanisms to D have been reported, but no validated biomarkers exist for treatment response. This exploratory pharmacogenetic study aimed to identify germline single nucleotide polymorphisms (SNPs) associated with progression-free survival (PFS) in D-treated MM patients (pts). Methods: Sixty-five functional SNPs or their proxies were tested for association with PFS in a meta-analysis of a subset of V600E MM pts from 3 studies: BRF113710, a single-agent study (n=63); BRF113929, a single-agent study in pts with brain metastases (n=100); and BRF113683, a randomized study comparing D (n=145) with dacarbazine (DTIC; n=48). Analysis was performed using Cox proportional hazards models after covariate adjustment. SNPs were considered significantly associated if they met a predefined multiple testing threshold of P<.0008. Results: No SNPs were significantly associated with PFS in this meta-analysis. A SNP in KRAS (rs61764370, T>G; HR, 1.48 [1.04-2.11]; P=.03) and a haplotype of 2 correlated SNPs (R2=0.78) in IL8 (rs2227543 G>A and rs1951242 A>G; HR, 1.24 [1.02-1.52]; P=.04) showed suggestive associations with reduced PFS. KRAS rs61764370 was also associated with reduced PFS in DTIC-treated pts (HR, 2.1 [1.1-4.2]; P=.036). This SNP is reported to weaken Let-7 microRNA binding to KRAS 3’UTR, increasing KRAS expression, and is associated with no response to cetuximab in metastatic colorectal cancer. The 2 IL8 SNPs are proxies for 2 functional IL8 SNPs (rs1126647, 2767A>T and rs4073, -251T>A, respectively) shown to be associated with reduced response to pazopanib in metastatic renal cell carcinoma. Conclusions: A SNP in KRAS and 2 in IL8 showed suggestive associations with PFS in a meta-analysis of D-treated V600E MM pts. Association of KRAS rs61764370 in DTIC-treated pts suggests the SNP may be prognostic of underlying disease rather than predictive of treatment response. Association of IL8 SNPs suggests activation of alternate angiogenesis pathways as a possible resistance mechanism to BRAF inhibition. These associations are exploratory and require confirmation in independent datasets.