bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of AKT expression with degree of pathologic response in patients with esophageal cancer undergoing neoadjuvant therapy.
Authors: Saeed Nadia , Doepker Matthew , Shridhar Ravi , Weber Jill , Hoffe Sarah E. , Almhanna Khaldoun , Meredith Kenneth L.
Published: February 2017

89

Background: Neoadjuvant therapy (NCRT) has become standard in the treatment of locally advanced esophageal adenocarcinoma (EAC) with survival correlated to degree of pathologic response. The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorgenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of AKT in chemoresistance in patients with esophageal adenocarcinoma (AC) who received NCRT. Methods: After IRB approval, a prospective trial was initiated in which patients with EAC requiring NCRT were consented for endoscopic biopsies of normal and tumor tissue prior to instituting therapy. After completion of NCRT patients then proceeded to esophagectomy. The tissues obtained preoperatively underwent gene expression profiling using the Affymetrix 133 Plus 2.0 Gene chip. SAM method was used to analyze significant differentially expression of AKT within normal and tumor tissue. Expression was then correlated to degree of pathologic response. Results: One-hundred patients were consented for the study, of which 67 met final eligibility. Nineteen patient’s tumors ultimately underwent gene expression profiling via microarray. The differential expression of all AKT probesets in tumor tissue was markedly overexpressed compared to normal tissue (p=6x10-5). There were 3 patients designated as pNR, 5 as pPR, and 11 as pCR. Investigating the relationship between the degree of expression of AKT and pathologic response demonstrated a linear correlation between over-expression of AKT and degree of pathologic response. Partial and non-responders had higher expressions of AKT compared to pCR with the non-responders consistently illustrated the highest expression of AKT (p=0.02). There was a significant correlation between individual probesets AKT1, AKT2, and AKT3 and degree of pathologic response (p=0.002, 0.04, and 0.04 respectively). Conclusions: AKT is overexpressed in patients with AC of the esophagus. Moreover, pathologic response to NCRT may be correlated with degree of AKT expression. Additional data is needed to clarify this relationship further and add potential targeted therapies.
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.
Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study.
Authors: O'Donnell Peter H. , Plimack Elizabeth R. , Bellmunt Joaquim , Berger Raanan , Montgomery Robert B. , Heath Karl , Dolled-Filhart Marisa , Pathiraja Kumudu , Gause Christine K. , Cheng Jonathan D. , Perini Rodolfo F. , Gupta Shilpa
Published: February 2017

296

Background: Pembro, an anti-PD-1 monoclonal antibody, has shown antitumor activity in several advanced solid tumors. The safety, tolerability, and antitumor activity of pembro in pts with recurrent or metastatic urothelial cancer was assessed in a cohort of KEYNOTE-012 (Clinicaltrials.gov: NCT01848834). Methods: PD-L1 expression was assessed in archival or newly obtained tumor samples from pts with advanced carcinoma of the renal pelvis, ureter, bladder, or urethra using a prototype immunohistochemistry assay. Only pts with PD-L1 expression in stroma or ≥1% of tumor cells were eligible. Pts received pembro 10 mg/kg every 2 wks until complete response, progression, or unacceptable toxicity. Pts deriving benefit could remain on pembro beyond initial progression. Response was assessed every 8 wks per RECIST v1.1 by the investigator and by independent central review (primary efficacy end point). Results: 33 pts enrolled (n=30 with transitional cell histology; median age, 70 y [range 44-85]; ECOG PS 1, 70%; 2 prior therapies for advanced disease, 52%; liver metastases, 21%). 22 pts (67%) received ≥3 pembro doses. Median follow-up duration was 11 mos (range 10-13), and 7 pts (21%) remain on therapy. At least 1 drug-related AE was reported by 61% of pts, most commonly fatigue (n=6), peripheral edema (n=4), and nausea (n=3). Grade 3-4 drug-related AEs were reported for 4 pts (12%), with only rash seen in >1 pt (n=2). 29 pts received ≥1 dose of pembro and had a baseline scan with measurable disease and were evaluable for response. ORR was 24% (95% CI, 10%-44%) by investigator review, with 7 partial responses. ORR by central review was also 24% (95% CI, 10%-44%), with 3 (10%) complete and 4 (14%) partial responses. Response duration is 16-40+ wk (median not reached) by both investigator and central review. ORR in key subgroups, including visceral vs. nodal metastasis, will be presented. In pts evaluable for response, median PFS is 8.8 wks by investigator review and 8.6 wks by central review. In all pts, median OS is 9.3 mos (6-mo OS rate, 58%). Conclusions: Pembro shows acceptable safety and tolerability and provides promising antitumor activity in pts with advanced urothelial cancer. Evaluation of pembro for the treatment of urothelial cancer is ongoing. Clinical trial information: NCT01848834.
Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes.
Authors: Gandhi Nilay M , Baras Alexander S , Munari Enrico , Faraj Sheila , Reis Leonardo O , Liu Jen-Jane , Kates Max , Hoque Mohammad , Berman David , Hahn Noah M. , Eisenberger Mario A. , Netto George J. , Schoenberg Mark , Bivalacqua Trinity
Published: February 2017

336

Background: To evaluate gemcitabine-cisplatin (GC) neoadjuvant chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and identify clinical parameters associated with pR. Methods: We studied 150 consecutive cases of MIBC that received GC NAC followed by open RC (2000-2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index (JHH-DI) to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance. Results: No significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non-muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (p=0.99). NAC pR (≤pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, p<0.01) and decreased nodal positivity rates (0% vs. 41.3%, p<0.01) compared to non-responders (≥pT2). Clinicopathologic outcomes were inferior in NAC pathologic non-responders (pNR) compared to the entire RC-only treated cohort. A lower pNR rate was seen in patients tolerating sufficient dosing of NAC as stratified by the JHH-DI (p=0.049), congruent with NCCN guidelines. A multivariate decision tree model demonstrated age ≤60 years and clinical stage cT2 as significant of NAC response (p<0.05). Conclusions: Pathologic non-responders fare worse than patients proceeding directly to RC alone. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients most likely to benefit from GC NAC.
Characterization of molecular features of pediatric urothelial bladder carcinomas.
Authors: Collazo Lorduy Ana , Castillo-Martin Mireia , Hyun Grace , Gladoun Nataliya , Cordon-Cardo Carlos
Published: February 2017

345

Background: Bladder cancer is a rare entity in the pediatric population making it difficult to define surveillance protocols and long term outcomes. Notably, most pediatric tumors are low grade and non-muscle invasive and do not recur. In order to determine the source of the different natural history between pediatric population and adults, we hypothesized that pediatric bladder cancer may potentially stem from different molecular pathways than its adult form. Our main objective was to study the molecular pathogenesis in this rare disease using immunohistochemical (IHC) and mutational analysis of the main known genes involved in bladder cancer. Methods: Paraffin-embedded tissue slides of bladder tumors from three pediatric patients were retrospectively identified from our institution's pathology archives (1990-present) and re-evaluated. Clinical data was reviewed. FGFR3, H-RAS, and PI3K mutational analysis of the most well-known mutated spots was conducted by PCR amplification and Sanger sequencing. IHC analysis was conducted using antibodies against p53, Pten, Rb, EGFR, Her2Neu and ki-67. Results: Two patients had low-grade Ta disease, whereas the other tumor was classified as a Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP). None of the lesions recurred. Two patients were female and one was male. The ages at diagnosis were 13, 11, and 17, with a mean follow-up of 5.2 years (Range: 1.5-8.0 years). All specimens showed H-RAS G12V mutation, whereas they were characterized by wild-type FGFR3 and PI3K. Nuclear p53 was not detected, whereas PTEN and Rb expression were maintained. EGFR was homogenously expressed in the three cases, and Her2Neu was negative. The proliferation rate analyzed by Ki-67 expression was very low in all cases (<5%). Conclusions: Pediatric tumors may arise from a pathway that is not initiated by FGFR3 or p53 mutations, but by H-RAS mutations. This distinction may explain the relatively few recurrences seen in the pediatric population. Molecular investigation of larger series of pediatric tumors is warranted, and will aid in determining the surveillance and the clinical follow up, if any, needed in this rare entity.
Effectiveness of chemotherapy administration and time to cystectomy following neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) in the academic and community settings.
Authors: Rose Tracy Lynn , Deal Allison Mary , Basch Ethan M. , Godley Paul Alphonso , Rathmell Kimryn , Kim William Y. , Whang Young E. , Dunn Mary , Nielsen Matthew Edward , Pruthi Raj , Wallen Eric , Woods Michael , Smith Angela , Milowsky Matthew I.
Published: February 2017

359

Background: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy is the standard of care for MIBC. Many patients are referred to an academic medical center (AMC) for cystectomy but receive NAC in the community setting. It is unknown if administration of NAC in the community is associated with differences in type of NAC received, pathologic response rate (pT0), and time to cystectomy as compared to NAC administered at an AMC. Methods: This is a retrospective study of 135 patients referred to a single AMC with MIBC (cT2a-T4-Nx-M0) between 1/2012 and 1/2014. We analyzed patient demographics, clinical stage, treatment, pT0 and time to cystectomy in patients who received NAC at our AMC compared to those referred to the community setting. Comparisons were made using Wilcoxon rank-sum, Fisher’s exact test, and multivariable linear regression. Results: Median age was 70, 73% were male, and 83% Caucasian. Most patients (73.3%) had clinical stage II disease. 94 (69.6%) underwent cystectomy and of those, 47 (50%) received NAC. 34% received NAC at our AMC and 66% in the community. Age, sex, clinical stage, and renal function did not differ significantly between those who received NAC in the community and those at our AMC. Those who received NAC in the community had a similar total dose of cisplatin (median 280 mg/m2 for both groups, p=0.89) and pT0 rate (25% vs. 30%, p=0.72) compared to those who received NAC at our AMC. However, community administration of NAC was associated with a significantly prolonged time from initial visit to cystectomy (median number of days 128 vs. 162, p<0.01). This remained significant after adjusting for age and renal function (p=0.04). Conclusions: Patients with MIBC treated with NAC in the community as compared to an AMC received similar chemotherapy and achieved comparable pT0 rates suggesting the effective implementation of NAC in the community setting. However, those who received NAC in the community had a significantly longer time from initial visit to cystectomy, suggesting a delay in the transfer of care between settings and an area for improvement.
Effect of early detection of asymptomatic visceral recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.
Authors: Hatakeyama Shingo , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Kusaka Ayumu , Ohyama Chikara
Published: February 2017

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Background: It is unknown whether routine follow-up with computed tomography (CT) to detect asymptomatic visceral recurrence after radical cystectomy improves patient survival. We accessed the impact of symptoms at recurrence on patient survival after radical cystectomy and survival after recurrence. Methods: A total 348 radical cystectomy for muscle invasive bladder cancer (MIBC) were performed at our institution between January 1996 and December 2013. All patients had regular followup examinations with urine cytology every 3 months, blood biochemical test, and CT of the chest and abdomen every 6 months. Additional examinations were required for symptomatic recurrence. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of diagnosis (asymptomatic vs. symptomatic) was estimated using the Kaplan-Meier methods and compared with the log rank test. Cox proportional hazard regression models were used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: A total 91 patients (20%) experienced recurrence after surgery. Seven patients (8%) were excluded due to missing data. Finally, 84 patients were enrolled in this retrospective study. Of those, 46 (55%) were asymptomatic and 38 (45%) were symptomatic. Recurrence sites included lymph nodes in 46 patients (55%), local recurrence in 23 (27%), bone in 14 (17%) and visceral organs in 21 (25%). The most common symptoms at recurrence were pain in 20 patients (53%). Overall survival after radical cystectomy and recurrence were significantly shorter in patients with asymptomatic recurrence. The median survival after surgery and after tumor recurrence in patients with asymptomatic vs. symptomatic recurrence were 33 and 14 vs. 13 and 5 months, respectively (P=0.0142 and P=0.0001). Multivariate analysis showed that a symptomatic recurrence was one of the independent factors for overall survival after surgery and recurrence. Conclusions: Routine CT followup after radical cystectomy for early detection of asymptomatic recurrence may contribute better prognosis in patients with MIBC.
Is measuring serum levels of microRNA miR-371a-3p superior to the classical biomarkers of testicular germ cell tumors?
Authors: Dieckmann Klaus-Peter , Spiekermann Meike , Ruf Christian G , Oechsle Karin , Belge Gazanfer
Published: February 2017

376

Background: There is need for more serum biomarkers of testicular germ cell tumors (GCTs) because the management of GCT is largely based on marker monitoring but only 60% of patients express the classical markers AFP and beta HCG. We measured serum levels of microRNA miR-371a-3p (miR-371) in GCT patients with the aim of establishing a new biomarker. Methods: Serum samples of 130 consecutive patients with GCT (75 seminoma, 55 nonseminoma; 90 clinical stage 1, 40 higher stages) were examined for miR-371a-3p before and after treatment. 105 young males with nonmalignant testicular diseases and 10 patients with non-GCT testis tumors served as controls. Serum levels of miR-371a-3p were measured by quantitative polymerase chain reaction with quantification in relation to miR-20a as internal standard. Measurements were correlated with clinical data, analysis involved descriptive statistical methods. Results: Over 90% of all patients had higher serum levels of miR-371a-3p than controls. After treatment, all elevated levels decreased to the normal range. All metastasized patients had significantly higher mean levels than stage 1 patients, serum levels appear to correlate with tumor bulk. Upon chemotherapy levels decreased with each cycle of therapy. After orchiectomy in stage 1 cases, serum levels dropped by 95% within 24 hours. Nonseminomas had higher mean levels than seminoma. Teratoma does not express miR-371a-3p. The levels remained low during follow-up. Conclusions: Serum levels of microRNA miR-371a-3p appear to comprise of all attributes of a valuable serum biomarker of germ cell tumors. This marker is also expressed in seminoma and it apparently outperforms the classical markers. Evaluation in a large scale multicentric study is warranted.
Receipt of inguinal lymph node dissection in patients with T2 penile cancer: Results from the National Cancer Database.
Authors: Haseebuddin Mohammed , Handorf Elizabeth , Waingankar Nikhil , Wong Yu-Ning , Viterbo Rosalia , Greenberg Richard Evan , Uzzo Robert G. , Kutikov Alexander , Smaldone Marc C. , Chen David Y. T.
Published: February 2017

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Background: Per the NCCN guidelines, inguinal lymph node dissection (ILND) is recommended for patients with intermediate (T1b) or high (Any T2 or Grade 3) risk disease even in the absence of palpable inguinal nodes. Our objective was to assess temporal trends in utilization of ILND and to determine factors associated with the receipt of ILND using National Cancer Database (NCDB). Methods: The NCDB was queried for all patients diagnosed with T2 penile cancer from 1998-2011. Temporal trends for receipt of ILND were assessed. Adjusting for patient, demographic, and clinicopathologic characteristics, multivariable logistic regression models were used to examine the association between available covariates and receipt of ILND. Results: Of 2019 patients identified over the study period, 693 (34.3%) underwent ILND. Rates of ILND did not significantly improve from 1998 to 2011 (34.2 to 40.0%; p = 0.09). Significant differences were observed in patients undergoing ILND with respect to age (p<0.001), Hispanic ethnicity (p=0.04), insurance status (p<0.001), and facility type (p<0.001), while no changes were seen with respect to race, income, education, urban/rural location, tumor grade, or Charlson co-morbidity score. Following adjustment, patients with high grade disease (OR 1.35 [CI 1.1-1.7]) and those treated at academic centers (OR 3.2 [CI 2.2-4.7]) were more likely to receive ILND, while patients >70 years of age (OR 0.41 [CI 0.28-0.60]) were less likely to receive ILND. Conclusions: In the NCDB, less then 35% of patients with T2 penile cancer receive ILND and the rates have not significantly changed over the last decade. Referral of patients with this uncommon, highly morbid lethal disease to experienced centers may increase adherence to guideline recommended care.
The proportion and characterization of patients with metastatic renal cell carcinoma who are never treated or have delayed treatment with targeted therapy: Results from a large prospective cohort.
Authors: Bains Param , Heng Daniel Yick Chin , Knox Jennifer J. , Bjarnason Georg A. , Kollmannsberger Christian K. , Hotte Sebastien J. , Kapoor Anil , Vanhuyse Marie , Reaume M. Neil Neil , Czaykowski Piotr , Soulieres Denis , Basappa Naveen S. , Saarela Olli , Wood Lori
Published: February 2017

424

Background: The proportion and characterization of patients (pts) with metastatic renal cell carcinoma (mRCC) who never start or delay starting targeted therapy (TT) is unknown. It is important to understand and characterize these pts. Methods: Data from the Canadian Kidney Cancer information system (CKCis) database were utilized. CKCis data were collected prospectively from 14 REB-approved academic centers in Canada. The study population included pts with mRCC managed from 2006 (when VEGFR TT became available) to 2014. Results: 920 pts met the inclusion criteria, but 67 pts had <6 months (mo) follow up and were excluded. Thus, 853 pts make up the study cohort with a median follow up of 21 mo. The cohort was divided into 3 groups: early (started TT within 6 mo), delayed (started TT after 6 mo), and never (never started TT). The groups consisted of 406 pts (47.6%), 182 pts (21.3%), and 265 pts (31.1%), respectively. In those that started TT, median time to initiation was 3.2 mo; 69% by 6 mo, 82% by 12 mo, 92% by 24 mo, and 99.7% by 5 yrs. Multiple baseline characteristics were determined, compared, and will be presented. On univariable analysis, pts never treated were older, had a longer interval from original diagnosis to metastases (mets), fewer metastatic sites, fewer liver mets, more lung-only mets, more metastectomies, and less radiation (RT). On Cox regression analysis, pts were less likely to initiate TT if they were older, had earlier year of diagnosis of mets, had metastectomy, never had RT, fewer sites of mets, and brain mets. Median survival from time of metastatic diagnosis was 1.53 yrs, 3.54 yrs, and 1.41 yrs in the early, delayed, and never treated groups, respectively. Conclusions: 31% of pts with mRCC never received TT in this cohort of pts treated in academic centers, which may underrepresent the reality in the community. Baseline characteristics in the delayed treatment group were better and likely represent a more indolent biology. More data on the untreated group will be presented as it comprises a heterogenous group of pts: potentially those lost to follow up, those treated with metastectomy, pts too ill with limited survival, and pts felt to have excellent outcomes without treatment.
A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma.
Authors: Choueiri Toni K. , Michaelson M Dror , Posadas Edwin M. , Sonpavde Guru , McDermott David F. , Walsh Meghara K. , Wall Kevin C. , Seon Ben K. , Jivani Manoj A. , Adams Bonne J. , Theuer Charles P.
Published: February 2017

426

Background: Resistance to VEGF-targeted therapy is a major challenge in contemporary treatment of metastatic renal cell carcinoma (mRCC), and endoglin (CD105) activation may be an important mechanism leading to resistance. Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and mRCC cancer stem cells that is upregulated following VEGF inhibition. TRC105 is an anti-endoglin monoclonal antibody that potentiates bevacizumab (Bev) and VEGF receptor tyrosine kinase inhibitors (VEGFR TKI) in preclinical models. Methods: Heavily-pretreated mRCC pts with ECOG PS 0-1, and acceptable organ function were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg PO BID and then escalated per patient tolerance to a maximum of 10 mg PO BID). Results: Eighteen mRCC pts (median age=61.5; M:F 16:2; median number of prior therapies=3, including >1 VEGFR TKI, clear cell=13, prior axitinib allowed) were treated. TRC105 dose escalation proceeded from 8 mg/kg (n=3) to 10 mg/kg (n=15) without dose limiting toxicity. Low grade AEs characteristic of each drug were not increased in frequency or severity at the recommended phase 2 doses of the two drugs. Three pts (18%) were PR by RECIST and 8 of 17 pts (47%) exhibited >10% tumor reduction. Median PFS is not mature and is at least 5.8 months in the overall population and at least 5.9 months in ccRCC pts. The single patient who progressed on axitinib immediately prior to study entry remains progression free at month 5 with minor tumor regression. Conclusions: TRC105 at 8 and 10 mg/kg was well tolerated with axitinib in mRCC pts with signs of activity. A multicenter randomized phase II trial of axitinib +/- TRC105 is accruing at this time. Clinical trial information: NCT01806064.
Specificity of radiographic lymphadenopathy for lymph node metastasis in renal cell carcnioma.
Authors: Mossanen Matthew , Dighe Manjiri , Wilson Bryan , Lin Daniel W. , Wright Jonathan L. , Harper Jonathan D. , Gore John L.
Published: February 2017

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Background: Approximately 30% of patients with renal cell carcinoma (RCC) will have metastatic disease at the time of diagnosis. Patients without preoperative lymphadenopathy (LAD) radiographically rarely have positive nodes at the time of nephrectomy. We sought to evaluate the specificity of radiographic LAD for lymph node metastases in patients with and without clinical metastatic RCC. Methods: We retrospectively reviewed all nephrectomies performed at our institution from 2003-2013. We identified patients with clinical stage classification T2-T3 (cT2-T3) RCC and stratified patients by clinical N and M classification. Lymphadenectomy was performed at surgeon discretion. Performance statistics for preoperative imaging for pathologic lymph node metastases and multivariable logistic regressions models to identify patient characteristics associated with lymph node metastases were generated. Results: A total of 223 patients were identified. Of these, 85 (38%) had clinical evidence of metastatic disease while 138 (62%) did not. In patients with clinical metastatic disease, LND was performed in 68%; of those without clinical metastatic disease, LND was performed in 48%. Radiographic LAD for those with clinical metastatic disease (26/85 patients, 31%) had sensitivity of 94%, specificity of 49%, positive predictive value (PPV) of 43%, and negative predictive value (NPV) of 95% for pathologically confirmed lymph node involvement. Radiographic LAD for patients without clinical metastatic disease (37/138 patients, 27%) had sensitivity of 90%, specificity of 52%, PPV of 25%, and NPV of 96% for pathologically confirmed lymph node involvement. On multivariate logistic regression analysis (adjusted for age, gender, smoking status, obesity, non-clear cell histology, and grade) having clinical metastatic disease was significantly associated with pathologic node positivity (RR = 3.37, 95% CI 1.19 – 20.6). Conclusions: Radiographic lymphadenopathy is a nonspecific finding in patients with RCC and LND is not routinely performed at our institution. However, in the setting of clinical metastatic disease, radiographic LAD is more likely to represent pathological lymph node metastases.