bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodality imaging and radiological-pathological analysis of ethiodized oil: Imaging biomarker of tumor necrosis after TACE?
Authors: Kyere Sampson K , Duran Rafael , Schernthaner Rüdiger E. , Greene Samuel , De Lin Ming , Sohn Jae Ho , Sahu Sonia , Wood Laura D. , Anders Robert A , Geschwind Jean-Francois 
Published: February 2017

TPS503 Background: In transarterial chemoembolization (TACE) for primary and metastatic liver malignancies ethiodized oil (Lipiodol) serves 3 roles: vehicle to deliver high concentration of the chemotherapeutic agent to the tumor, embolic agent to the tumor feeding artery and a contrast agent. The latter allows for intraprocedural visualization during drug delivery. Because of increased retention in liver tumors, Lipiodol can be visualized post-TACE for several weeks to months. Controversial preclinical and clinical data have been published about the role of Lipiodol as an imaging biomarker for treatment success after TACE. Here we investigate whether increased tumor Lipiodol deposition correlates with tumor response and survival using multimodality imaging and radiological/pathological correlation. Methods: This is a prospective phase 2, single center, IRB-approved study. Inclusion criteria include adult patients (Child-Pugh class of A or B and ECOG performance status of 0-2) with unresectable HCC with liver predominant disease or hepatic metastases from any solid tumor. Dynamic contrast-enhanced (DCE) MRI and CT of the liver and PET-CT were obtained before TACE. 24 hours after TACE, a noncontrast CT of the liver was obtained to quantify Lipiodol retention in the targeted tumor. Follow-up imaging consisting of DCE-MRI, CT and PET–CT were also performed approximately 1, 3 and 6 months after the last TACE. Follow up imaging will continue every 2-3 months for up to 4 years. Percent deposition of Lipiodol in the targeted tumor was assessed using 3D quantitative analysis on the 24hr post-TACE CT. Tumor response using RECIST, EASL, modified RECIST, tumor volume (volumetric RECIST), and volumetric tumor enhancement (quantitative EASL) were performed on the DCE-MRI, CT, and PET-CT, and correlated with Lipiodol deposition. Spearman rank correlation coefficient and Pearson’s product-moment correlation were used. The Kaplan-Meier method with the log-rank test was used to assess whether Lipiodol is a biomarker of survival. 12/30 patients with HCC and 12/30 patients with hepatic metastases have been enrolled (#NCT01877187). Clinical trial information: NCT01877187.
IMPALA, a randomized phase III study in patients with metastatic colorectal carcinoma: Immunomodulatory maintenance therapy with TLR-9 agonist MGN1703.
Authors: Cunningham David , Zurlo Alfredo , Salazar Ramon , Ducreux Michel , Waddell Tom Samuel , Stein Alexander , Tournigand Christophe , Scheithauer Werner , Sobrero Alberto F. , Van Cutsem Eric , Arnold Dirk 
Published: February 2017

TPS791 Background: The potent TLR-9 agonist MGN1703, a synthetic DNA-based immunomodulator, was compared to placebo in metastatic colorectal cancer (mCRC) patients with disease control after standard induction chemotherapy +/- bevacizumab in the phase II IMPACT trial and showed a superior effect with a hazard ratio for the primary endpoint PFS on maintenance of 0.55 (p=0.041) by local investigator assessment and 0.56 (p=0.070) by independent radiological review. In the MGN1703 arm 3 objective responses were observed, two of them appearing as late as 9 months after the start of treatment. At time of study closure 4 MGN1703 patients were still without progressive disease and continued treatment by self-administration in a compassionate use setting. Exploratory Cox regression and ROC analyses suggested a potential predictive role at baseline for normal CEA, objective response to prior chemotherapy and presence of activated NKT-cells. Methods: The pivotal IMPALA study has been designed to confirm these data and started to enroll patients with smaller tumor burden after a good response to chemotherapy, as best candidates to receive a maintenance treatment with immunotherapy. IMPALA is a randomized, international, multicenter, open-label phase III trial that will include 540 patients from 120 centers with the collaboration of the AIO, TTD, and GERCOR cooperative groups and is currently recruiting patients. In this study mCRC patients with an objective tumor response following any first line induction therapy will be randomized to MGN1703 monotherapy maintenance or local standard of care. At time of relapse, patients will reintroduce the induction treatment whenever feasible, with those in the experimental arm continuing to receive MGN1703 in the weeks without chemotherapy. Patients will also be stratified by CEA level and activated NKT at baseline. The primary endpoint of the study will be overall survival. Secondary endpoints include PFS, response rates, safety, and QoL in selected centers. All patients will be evaluated for cytokines and chemokines in serum and the activation status of various immune cell populations. Clinical trial information: NCT02077868.
Influence of prostate cancer disease state and therapeutic selection on peripheral whole-blood RNA signature.
Authors: Liaw Bobby Chi-Hung , Chippada-Venkata Uma , Gong Yixuan , Wang Li , Zhu Jun , Heck Matthias Michael , Tsao Che-Kai , Galsky Matt D. , Oh William K. 
Published: February 2017

166 Background: Prostate cancer is a heterogeneous disease with differences in tumor stromal interactions contributing to variability in treatment response and outcome. Gene expression of peripheral blood cells is altered by interactions with neoplastic tissue. We previously developed a peripheral whole blood six-gene signature prognostic for survival in mCRPC. Here we evaluate how different clinical disease states and treatment with different therapeutic agents impact this signature. Methods: Whole blood was collected in PAXgene Blood RNA tubes in two cohorts of prostate cancer patients, one at Mount Sinai (n=135), the other in Munich (n=59), in the context of prospective clinical studies. Whole blood RNA was extracted and the six target genes were amplified using qPCR. Scores were derived using normalized cycle threshold (ΔCT) values of the six genes, according to the model: 2 x ABL2 + SEMA4D + ITGAL – C1QA – TIMP1 – CDKN1A. Patients were categorized by disease state in the Mount Sinai cohort, and by treatment received in the Munich cohort, for data analysis. Results: CRPC is the only disease state with a mean six-gene score (18.06) above the high-risk cutoff (17.9), and is significantly higher than localized or hormone sensitive advanced disease (16.07, 16.52, respectively; p=0.0002). Among patients with localized disease, there was no significant difference in the mean six-gene scores for patients with low-, intermediate-, and high-risk disease (16.07, 15.33, 16.66, respectively; p=0.27). In CRPC patients treated with docetaxel, there are significant changes to the six-gene score over the course of treatment (p=0.002), with a notable percentage decrease (-6.2%) at the 2-8 week timepoint that is not observed in patients treated with abiraterone or enzalutamide. Conclusions: Gene expression profiling of whole blood is influenced by the clinical state of prostate cancer as seen by differences to the six-gene score from localized to castrate resistant disease. Cytotoxic chemotherapy appears to modulate the six-gene score, something not seen with AR-directed therapies. Further investigation will be needed to understand the significance of these changes.
Initial results from a phase II study of increased-dose abiraterone acetate in patients with castration resistant prostate cancer (CRPC).
Authors: Friedlander Terence W. , Graff Julie Nicole , Zhang Li , Paz Rosa , Premasekharan Gayatri , Dilip Archana , Hsieh Andrew Caleb , Aggarwal Rahul Raj , Kim Won , Lin Amy M. , Fong Lawrence , Small Eric Jay , Paris Pamela , Ryan Charles J. 
Published: February 2017

188 Background: Resistance to abiraterone is hypothesized to result from increased systemic or tumor androgen production, mutations in the androgen receptor (AR) signaling pathway leading to ligand-independent, autonomous AR activity, and/or AR-independent pathways. This study investigated the clinical benefit of maximization of androgen suppression by increasing the abiraterone acetate dose at the time of initial resistance to standard-dose therapy. Methods: Eligible patients had progressive metastatic CRPC per consensus criteria. No prior abiraterone, enzalutamide, or chemotherapy was allowed. All patients started therapy with abiraterone acetate 1,000 mg daily and prednisone 5mg BID. Patients achieving any PSA decline after 3 cycles continued abiraterone until PSA or radiographic progression. At progression the abiraterone acetate dose was increased to 1,000 mg BID, prednisone was maintained at 5mg BID, and patients were monitored for response for a minimum of 12 weeks or until a second PSA or radiographic progression. Results: 41 patients were accrued from 3/2013 through 3/2014, and 13 patients currently remain on therapy. Median age was 68 (range 55-79), median ECOG PS was 0 (range 0-2), and median baseline PSA was 27.4 (range 3.9-1763). Thirteen men (31%) underwent a pre-treatment metastatic biopsy. To date 13 men who experienced progressive disease on standard-dose therapy were treated with 1,000 mg BID therapy, and are evaluable for response. No PSA declines ≥30% nor radiographic responses have been observed at the elevated-dose. Grade 3 transaminitis was observed in 1 patient on the elevated dose and resolved with dose decrease. Conclusions: Pharmacokinetic failure alone is unlikely to explain resistance to standard-dose abiraterone acetate and increasing the dose at the time of resistance may be of limited clinical utility. Analysis of serial androgen levels, abiraterone pK, and molecular and genomic analysis of circulating tumor cells and metastatic biopsies is underway, with a specific focus on the contributions of AR amplification, AR splice variation, and mesenchymal and neuroendocrine differentiation to the development of abiraterone resistance. Clinical trial information: NCT01637402.
Fractionated dose radiolabeled antiprostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) with or without docetaxel for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Batra Jaspreet S , Karir Beerinder S , Vallabhajosula Shankar , Christos Paul J. , Hodes Gillian , Date Pravin R. , Nikolopoulou Anastasia , Jhanwar Yuliya , Beltran Himisha , Nanus David M. , Goldsmith Stanley J. , Bander Neil Harrison , Tagawa Scott T. 
Published: February 2017

194 Background: A phase II trial single-dose 177Lu-J591 was published. Dose fractionation offers theoretic advantages and 2 phase I dose-escalation studies of 177Lu-J591 have been performed to test the hypothesis that higher cumulative radiation doses can be administered with an acceptable toxicity profile. Methods: Pts with mCRPC and normal neutrophil and platelet counts were enrolled in 2 sequential phase I dose-escalation studies: (1) 177Lu-J591 administered as a single-agent 2 doses 2-weeks apart to determine the maximum tolerated dose (MTD) with expansion cohorts at the recommend phase II doses (RP2D) and (2) fractionated dose 177Lu-J591 in combination with docetaxel 75 mg/m2q3 weeks to determine the MTD. Results: 44 men with median age 75.4 (range 55.1-95.2) were enrolled in the single-agent fractionated dose escalation 177Lu-J591 trial and 15 men with median age 69.1 (49.3-80.8) were enrolled in 177Lu-J591 + docetaxel trial. The RP2D’s of fractionated 177Lu-J591 were 40 mCi/m2 x2 or 45 mCi/m2 x2 with the option for GCSF; at these doses (n=28), 8 (28.6%) with >50%, 11 (39.3%) >30%, and 16 (57%) of 28 pts with any PSA decline; pts at RP2D lived longer (p<0.0001). Predictable, reversible myelosuppression was seen. 18 (40.9%) received chemo prior to RIT and 24 (54.5%) received chemo post 177Lu-J591 [median of 7 cycles (range 1-20)]. In combination with docetaxel, the MTD/RP2D of 177Lu-J591 is 40 mCi/m2x2 doses (delivered with cycle 3), with 73.3% >50%, 80.0% >30%, and 86.7% with any PSA decline. Conclusions: Fractionated 177Lu-J591 is tolerated with subsequent PSA declines and reversible myelosuppression. The apparent dose-response of single-dose 177Lu-J591 appears confirmed with fractionated dosing (improved PSA declines and OS at higher doses). Despite predictable myelosuppression, chemotherapy is able to be delivered prior to 177Lu-J591, concurrently, or following radioimmuotherapy. Clinical trial information: NCT00538668 , NCT00916123 .[Table: see text]
Prostate cancer burden at the Uganda Cancer Institute (UCI).
Authors: Okuku Fred Machyo , Orem Jackson , Holoya George , De Boer Christopher J , Cooney Matthew M. 
Published: February 2017

246 Background: In Uganda prostate cancer is the most common cancer and the incidence is increasing 5.2% annually. This burden is seen without screening programs in a country with limited access to cancer care. Data describing patient presentation and outcomes are lacking. Methods: Retrospective chart review for men with histologically-confirmed prostate cancer at the UCI from January 1 to December 17, 2012. Patient characteristics, treatments, and survival data were obtained. Results: There were 181 men with confirmed prostate cancer [C1] . Mean age was 69.5 (SD 9.0) with a median age of 70 (IQR: 64-75). Men presented with symptoms of lower urinary tract symptoms 73% (n=131), bone pain in 18% (n=32), elevated PSA 3% (n=5) and other causes 6% (n=11). Median baseline PSA was 91.3 ng/ml (IQR: 19.5-311.3 ng/ml) and upon presentation 51.1% (n=92) had a PSA value over 100 ng/ml. Gleason Score was 9 or 10 in 66.7% (n=120), Gleason Score 7 to 8 in 23.4% (n=44), and Gleason six or lower in 10% (n=18). Ninety percent (n=136) of patients had stage IV disease, 6.5% (n=11) were stage III, 11.9% were (n= 20) stage II, and 1 individual (0.6%) had stage I. Common sites of metastases included bone 73% (n=102), visceral metastases 21% (n=29), and lymph node involvement 4% (n=5). Spinal cord compression occurred in 30.9% (n=55) and 5.6% (n=10) experienced a fracture. A total of 14.9% (n=27) patients underwent radical prostatectomy and 17.7% (n=32) received radiotherapy. GNRH agonist was given to 45.3% (n=82) of patients, 29.2% (n=53) of men received diethylstilbestrol, and 26% (n=47) underwent bilateral orchiectomy. Chemotherapy was administered to 21.6% (n=39) and 52.5% (n=95) received bisphosphonates. During the 12 months of study 23.8% (n=43) of men experienced death and 54.4% (n=98) were lost to follow up. Conclusions: UCI patients present with significant symptoms, high PSA, and aggressive Gleason Scores. 90% present with stage IV disease and almost 33% develop spinal cord compression. Prostatectomy and radiotherapy are infrequently given and the primary treatments are hormonal manipulation and chemotherapy. Almost 25% of patients succumb within a year of presentation and there is a high rate of patients lost to follow up.
Characterizing the risk of drug-drug interactions in patients receiving enzalutamide for castration-resistant prostate cancer.
Authors: Lee Esther K. , Jamani Rehana , Berry Scott R. , DeAngelis Carlo , Giotis Angie , Emmenegger Urban 
Published: February 2017

261 Background: Enzalutamide (E) is an androgen receptor antagonist used to treat castration-resistant prostate cancer (CRPC). It inhibits various cytochromes (e.g. CYP2C8), or induces others (e.g. CYP3A4). Since these CYPs are involved in the metabolism of other widely-used medications, E may expose a significant number of patients to drug-drug interactions (DDI). These DDI may diminish the efficacy of E or concurrent medications, or they may increase the risk of DDI-related adverse events (AE); but the scale of E-related DDI is not yet established. Methods: We retrospectively reviewed pharmacy records and electronic patient charts to retrieve individual drug histories, comorbidities, and on-treatment AE of CRPC patients starting E between Oct 2012 and Apr 2014. Baseline medications of individual patients were analyzed for potential DDI using two commercial databases, Lexicomp and Micromedex. Results: 69 informative patients were identified. Using Lexicomp, the most common DDI flagged as being of potential clinical significance (i.e. “avoid combination”, or “consider therapy modification”) were with amlodipine, atorvastatin, tamsulosin, ondansetron, and oxycodone administered to 12 (17%), 12 (17%), 10 (14%), 5 (7%), and 5 (7%) patients, respectively. Micromedex identified a moderate risk for amlodipine and oxycodone. At baseline, 38/69 patients (55%; Lexicomp) and 24/69 patients (35%; Micromedex) used ≥ 1 drug at risk for clinically significant DDI with E. The most common AE were fatigue in 36 patients (52%), decreased appetite in 15 (22%), peripheral oedema and weight loss each in 13 (19%), and back pain in 10 (14%). There was no conclusive evidence to link these AE to DDI. One patient had recurring episodes of hypertension, a possible result of a DDI between E and nifedipine (Lexicomp/Micromedex class “avoid”/”major”). Conclusions: The risk of clinically relevant E-related DDI in CRPC patients seems substantial, yet the selection of flagged drugs is database-dependent. Further investigations with larger populations are warranted to understand the clinical relevance of these DDI more clearly.
TAS3681: New class of androgen receptor antagonist with androgen receptor downregulating activity.
Authors: Minamiguchi Kazuhisa , Seki Masanao , Aoyagi Hiroki , Kajiwara Daisuke , Mori Tomoko , Masuko Norio , Fujita Ryouto , Okajima Shigeo , Hayashi Yukio , Sasaki Eiji , Utsugi Teruhiro 
Published: February 2017

266 Background: The persistent activation of the androgen receptor (AR) signaling axis plays a major role in castration-resistant prostate cancer (CRPC). This knowledge has driven the clinical development of new inhibitors of androgen production (e.g., abiraterone) and AR signaling (e.g., enzalutamide). However, in many patients, the efficacy is short-lived and eventually resistance appears. Reactivation of AR signaling occurs by several mechanisms in CRPC. In this study, we report the biological properties of TAS3681, a new AR antagonist with AR downregulating activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For assay of AR transactivation, COS-7 cells were transiently transfected with androgen-responsive reporter gene construct and expression vectors encoding wt or mu ARs. The transfected cells were treated with TAS3681 and androgen in steroid depleted media for 24 h, and luciferase activity was measured. For an in vivo pharmacodynamic assay to confirm AR downregulation in tumor, TAS3681 was orally dosed in CRPC tumor xenograft model. Tumor was isolated and AR level in tumor was determined by Western blot. Results: TAS3681 suppressed the growth of AR positive prostate cancer (PCa) cells but did not affect that of AR-negative DU145 PCa cells, indicating a dependency on AR for efficacy. TAS3681 did not stimulate AR nuclear translocation and suppressed wt and mu ARs (including F876L) transactivation in cells, indicative of its pure AR antagonist profile. In contrast to enzalutamide, TAS3681 effectively suppressed androgen-independent AR transactivation by growth factors and cytokines via AR downregulating activity. Interestingly, in PCa cells which express full-length and splice variant AR, TAS3681 reduced the expression of both ARs. Moreover, TAS3681 treatment effectively decreased AR level in CRPC tumors in vivo. Conclusions: TAS3681 exerts an anti-androgenic effect via two mechanisms of action: pure AR antagonism and AR decreasing activity. It is expected that TAS3681 has a potential to overcome the resistance to current and 2nd-generation therapies targeting AR signaling.
Use of radium-223 in heavily pretreated metastatic castrate resistant prostate cancer (mCRPC) patients.
Authors: Modi Dipenkumar , Kim SeongHo , Mamdani Hirva Mansurali , Hwang Clara , Gayar Hersham , Vaishampayan Ulka N. , Joyrich Richard , Heath Elisabeth I. 
Published: February 2017

275 Background: Ra 223 has been shown to improve overall survival in mCRPC patients with symptomatic bone metastases. Little is known about the utility of following PSA during Ra 223 therapy in heavily pretreated patients. Here we report our experience with Ra 223 in such a setting. Methods: We reviewed 26 heavily pretreated mCRPC patients who received Ra 223 at 3 institutions and evaluated the trend of PSA during treatment, the association of various demographic, clinical and biochemical variables with PSA trend, and the correlation of PSA trend with clinical outcomes. Patients received IV Ra 223 every 4 weeks with a planned total of 6 cycles. Results: Twenty six patients were treated between August 2013 and August 2014. Median age was 70 years (range 49-80); 77% (N=20) were European American (EA), 19% (N=5) were African Americans (AA), unknown for 1 patient. Prior therapy included docetaxel in 77% (N=20) of patients, cabazitaxel in 19% (N=5), enzalutamide in 65% (N=17), and abiraterone in 54% (N=14). 62% (N=16) received at least 3 prior therapies.35% (N=9) received all 6 cycles of Ra 223, while 18% (N=4) received only 1 cycle. Median alkaline phosphatase level increased from 126.0 U/L (54.0, 514.0) to 332.0 U/L (136.0, 566.0) at the end of Ra 223 therapy. Median pre-therapy PSA was 100.3 and median post-therapy PSA was 429.5. 54% (N=14) patients had >50% rise in PSA. Higher pre-therapy PSA was strongly associated with higher post-therapy PSA (Pearson’s correlation coefficient = 0.84, p <0.0001). Faster rate of rise in PSA was observed in patients with higher number of bone metastasis and those who have had prior therapy with docetaxel. The patients with >50% PSA rise had reported overall higher pain scores by visual assessment scale. Ra 223 was discontinued in 15% (N=4) patients due to myelosuppression and in 8% (N=2) due to side effects. Conclusions: All heavily pretreated patients receiving Ra 223 therapy for mCRPC showed PSA progression and reasonable tolerability. Only 35% of patients were able to receive all 6 cycles of Ra 223.