bluuebunny/crossref_metadata_2025_split huggingface dataset:
The initial report of RTOG 0436: A phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery.
Authors: Suntharalingam Mohan , Winter Kathryn , Ilson David H. , Dicker Adam , Kachnic Lisa A. , Konski Andre A. , Chakravarthy Bapsi , Gaffney David K. , Thakrar Harish V. , Horiba Margit Naomi , Deutsch Melvin , Kavadi Vivek , Raben Adam , Roof Kevin S. , Videtic Gregory M. M. , Pollock Jondavid , Safran Howard , Crane Christopher H. 
Published: February 2017

LBA6 Background: RTOG 0436 is a randomized Ph III trial designed to evaluate the benefit of cetuximab added to the concurrent chemoradiation for patients undergoing non-operative management of esophageal carcinoma. Methods: Pts with biopsy-proven squamous cell or adenocarcinoma of the esophagus (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions ± weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2). Patients were stratified by histology, tumor size (< 5 cm vs > 5cm), and the status of celiac lymph nodal involvement. Overall survival (OS) was the primary endpoint, with a planned accrual of 420 pts to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided 0.025 alpha. An interim analysis of cCR was planned for the first 150 of each histology. Results: The study accrued 344 pts from 2008-2013 and 328 were eligible. Based on interim analyses, the study stopped accruing adeno pts in 5/2012 and SCC pts in 1/2013. Pts were well matched for pretreatment characteristics: 80% with T3/4 disease, 66% N1, and 19% with celiac nodal involvement. Incidence of grade 3/4/5 treatment (tx) related AEs was 45%, 22%, 4% in Arm 1 (cetuximab) and 49%, 17%, 1% in Arm 2 (no cetuximab). A cCR rate of 56% was observed in Arm 1 vs 59% in Arm 2 (p=0.72). No differences were seen in cCR between tx arms for either histology. The 12 and 24 mo OS rates for cCR pts were 79% and 58% vs 53% and 30% for those with residual disease (p<0.0001). Median follow-up for all pts is 15.4 mos. The 12 and 24 mo OS (95% CI) for Arm 1 is 64% (56%, 71%) and 44% (36%, 52%) vs 65% (57%, 72%) and 42% (34%, 50%) for Arm 2 (p=0.70). Adeno pts (n=203) had a 12 and 24 mo OS of 65% and 43% for Arm 1 vs 64% and 41% for Arm 2 (p=0.37). The 12 and 24 mo OS for the 125 SCC pts was 62% and 46% for Arm 1 vs 67% and 43% for Arm 2 (p=0.97). Conclusions: The addition of cetuximab to concurrent chemoradiation did not improve OS. There were no differences in cCR rates by tx arm. These Ph III results point to little benefit for current EGFR targeted agents in the tx of esophageal cancer. Supported by RTOG CA21661 and CCOP CA3742 NCI grants and Bristol Myers Squibb. Clinical trial information: NCT00655876.
Independent validation of a genomic classifier in an at-risk population of men conservatively managed after radical prostatectomy.
Authors: Klein Eric A. , Li Jianbo , Stephenson Andrew J. , Yousefi Kasra , Kattan Michael W. , Magi-Galluzzi Cristina 
Published: February 2017

16 Background: Patients with locally advanced prostate cancer after radical prostatectomy (RP) are at risk for clinical progression and by current guidelines are candidates for adjuvant radiation. While clinical trials comparing adjuvant radiation to observation demonstrated benefits for many of these patients about 50% men on the control observation arm did not progress. This study evaluated whether a validated genomic classifier ([GC], Decipher) for predicting metastasis can be used to identify high-risk patients that may be spared unnecessary secondary therapy. The objective was to validate GC predictions in an at risk population conservatively managed after RP. Methods: A case-cohort design was used to sample patients with either preop PSA>20 ng/mL, pT3, positive surgical margin or Gleason score 8 or more disease, treated at Cleveland Clinic with RP from 1987 to 2008. Patients with lymph node metastasis or neo-adjuvant or adjuvant treatment were excluded. Cases were defined as local recurrence and/or regional/distant metastasis confirmed by biopsy or positive CT/bone scan. Random sampling of the cohort, including all cases, yielded 220 patients. Tissue was available for 196 and GC scores were generated for 184 patients. AUC for survival data, weighted Cox regression analysis and cumulative incidence adjusting for competing risk were used to assess GC performance for predicting distant metastasis (DM) in comparison to the 2005 Stephenson nomogram. Results: GC had an AUC of 0.89 (95% CI 0.62-0.97) for predicting DM at 5 years post-RP. A combined GC-Stephenson model yielded an AUC of 0.81 (95% CI 0.62-0.96). GC was the predominant predictor in multivariable Cox analysis with an HR of 1.55 (95% CI 1.25-1.90) for a 10% increase in score. Patients with high (21.7%) and low GC scores (58.7%) had a 3.97 fold higher and 3.88 fold lower incidence of DM at 5 years than the intermediate group (19.6%), respectively. Conclusions: We present results of a second, blinded independent validation study of GC performance in a conservatively managed RP cohort. In an at risk population use of GC may further allow identification of men that may be safely spared adjuvant radiation therapy.
An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC).
Authors: Kabbinavar Fairooz F. , Zomorodian Nazy , Rettig Matthew , Khan Faraz , Greenwald Daniel Reif , DiCarlo Brian , Davidson Sheldon J. , Patel Ravindranath , Pandit Lalita , Chandraratna Rosh , Sanders Martin 
Published: February 2017

169 Background: IRX4204 is a potent, selective, oral small compound agonist of retinoid X receptor (RXR) nuclear receptor pathways. In preclinical studies IRX4204 synergizes with insulin-like growth factor binding protein-3, to induce apoptosis in human prostate cancer cells and was effective in reducing human prostate tumor burden in a murine xenograft model. The only prostate cancer patient in a phase I trial of IRX4204 trial manifested a sustained greater than 90% prostate-specific antigen (PSA) reduction and a PR lasting over seven months. These findings led to the current open label phase II trial of IRX4204 to evaluate safety and activity or futility, for treatment of advanced castration-resistant metastatic prostate cancer (CRPC). Methods: The trial enrolled 23 men with metastatic CRPC, who had failed a taxane or declined chemotherapy, with ECOG 0-2 with evidence of biochemical or radiographic progression on bone scan, CT and/or MRI. Patients continued with androgen blockade and had to have adequate organ function. Patients were deemed to have demonstrated benefit of IRX4204 treatment if they had PFS greater than 56 days, and/or a 50% PSA decrease, and/or PR or CR by RECIST. Futility defined as four or fewer patients demonstrating benefit in the planned enrollment of 37 patients. Patients received IRX4204 (20 mg/orally daily). PSA was checked Q4 weeks and radiographic assessments Q8 weeks. Radiographic, not PSA progression, was used to determine progression. Results: IRX4204 was well tolerated for up to 11 months. No drug related serious adverse events (SAE) have occurred. Manageable decreases in the thyroid-stimulating hormone (TSH) and increases in triglycerides, both known adverse effects of RXR agonists, have been observed. Protocol defined patient benefit was observed in 13 out of 23 (57%) patients. Progression-free survival (PFS) more than 56 days observed in 13 out of 23 (57%). PFS more than 112 days observed in 9 out of 23 (39%), range 113 to 330 days. PSA 50% response occurred in 3 out of 23 (13%), including one additional PSA 90% response. No objective responses have occurred. Conclusions: This study demonstrates that IRX4204 treatment of taxane-resistant CRPC is well tolerated, and provides an activity signal warranting further evaluation of IRX4204 as a treatment for chemo-refractory CRPC. Funding: Supported by Io Therapeutics, Inc. 1805 East Garry Ave., Suite 110, Santa Ana, 92705. Clinical trial information: NCT01540071.
Does Gleason score (GS) predict efficacy of abiraterone acetate (AA) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)? An analysis of AA phase 3 trials.
Authors: Fizazi Karim , Flaig Thomas W. , Ohlmann Carsten-Henning , Scher Howard I. , De Bono Johann Sebastian , Rathkopf Dana E. , Ryan Charles J. , Kheoh Thian San , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Molina Arturo , Stöckle Michael 
Published: February 2017

20 Background: GS is strongly prognostic in localized PC but is less so in mCRPC (Halabi S, J Clin Oncol 2003; Armstrong AJ, Eur J Cancer 2010). Pts with high-risk localized PC and high GS who undergo radiation therapy benefit from long-term androgen deprivation therapy (Horwitz EM, J Clin Oncol 2008). In mCRPC, the impact of GS at initial diagnosis on response to AA therapy is unknown. We retrospectively evaluated efficacy outcomes in pts with mCRPC treated with AA plus prednisone (P) vs P alone in pivotal studies COU-AA-301 (post-docetaxel) and COU-AA-302 (chemo-naive) by GS (≥ 8 or < 8). Methods: 1,048 pts in COU-AA-301 and 996 in COU-AA-302 with mCRPC treated with AA 1 g + P 5 mg po BID or placebo + P had GS data at diagnosis. Efficacy end points evaluated: overall survival (OS), radiographic progression free survival (rPFS), and time to prostate-specific antigen progression (TTPP) (de Bono JS, NEJM 2011; Fizazi K, Lancet Oncol 2012; Ryan CR, NEJM 2013). Distributions and medians were estimated by the Kaplan-Meier method, and hazard ratio (HR) and 95% confidence interval were estimated by the Cox model. Results: Proportion of pts with GS ≥ 8 and GS < 8 was similar across treatment groups and studies. Outcomes by GS are summarized in the Table. Conclusions: GS (≥ 8 or < 8) at initial diagnosis was not predictive of treatment benefit of AA + P vs P alone in post-docetaxel and chemo-naïve pts with mCRPC, with both groups benefiting. In this era of novel androgen signaling targeted agents, GS may not be relevant in predicting efficacy with AA for pts with mCRPC. Clinical trial information: NCT00638690, NCT00887198. [Table: see text]
Circulating tumor cell (CTC) enumeration in patients with metastatic neuroendocrine prostate cancer (NEPC) and castration-resistant prostate cancer (CRPC).
Authors: Kaur Gurveen , Singh Beerinder , Beltran Himisha , Akhtar Naveed Hassan , Nanus David M. , Tagawa Scott T. 
Published: February 2017

204 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer. Circulating tumor cell (CTC) counts as measured by CellSearch are prognostic for large groups with metastatic prostate cancer (PC), but are not well described in NEPC. Methods: With institutional review board approval, we retrospectively identified patients with metastatic PC and available CTC enumeration (CellSearch methodology) and compared counts/7.5 mL blood and overall survival (OS), measured from the first recorded CTC count until death or last follow up. Entry criteria for clinical trials were used to define NEPC, including histology (small cell/neuroendocrine carcinoma or adenocarcinoma with more than 50% NE staining), serum chromogranin greater than 5x ULN and/or neuron specific enolase greater than 2x ULN, and/or predominant liver/brain metastases with lack of prostate-specific antigen [Beltran ASCO 2013, clinicaltrials.gov NCT01799278 ]. Frequency of detectable and unfavorable counts was tabulated and OS was compared across groups. Results: Sixty one patients were identified: 21 NEPC with median age 73.7 and 40 patients with castration-resistant prostate cancer (CRPC) with median age 73.9 over contemporary time periods 2009 to 2012. Median OS for the entire group was 22.6 months (mo), with a trend for shorter OS in NEPC (20.7 mo) than CRPC (22.7 mo), p=0.11. 47.6% of NEPC and 55% of CRPC had detectable CTC counts (p=0.58); 38.1% of NEPC and 40.0% of CRPC had greater than or equal to five CTCs (p=0.89). CTC counts of 0 to 4 versus greater than or equal to five were prognostic for both groups: NEPC with 0 to 4 CTCs had median OS of 22.6 versus 6.6 mo for CTCs greater than or equal to 5 (p<0.001) and CRPC with 0 to 4 CTCs median OS not reached (mean 40.6 mo) versus 11.2 mo for those with greater than or equal to five CTCs (p<0.001). Conclusions: Patients with NEPC have similar frequency of detectable and elevated CTC counts by CellSearch methodology as compared to an overall CRPC population. CTC counts are prognostic for both groups.
Prediction of prostate cancer Gleason score using a MRI-based nomogram.
Authors: Siddiqui Mohummad Minhaj , Rais-Bahrami Soroush , Truong Hong , Stamatakis Lambros , Walton-Diaz Annerleim , George Arvin , Rothwax Jason , Su Daniel , Shakir Nabeel , Wood Bradford J. , Merino Maria , Turkbey Baris , Choyke Peter L. , Simon Richard , Pinto Peter A. 
Published: February 2017

255 Background: Gleason score grading is a cornerstone of risk stratification and management of patients with prostate cancer (PCa). The only reliable method to determine Gleason score remains by direct pathologic determination from a tissue specimen. In this work, we examine the feasibility of MRI and clinical patient characteristics to predict biopsy Gleason scores (bGS). Methods: We reviewed 143 men who underwent multiparametric prostate-MRI (MP-MRI) prior to any prostate biopsy from 8/2007 to 12/2012. Patient demographics, PSA, PSA density (PSAD), and imaging findings were assessed for association with PCa Gleason score on biopsy. Screen positive lesions (SPLs) were defined as lesions positive on T2W and DWI B-MRI images. Logistic regression modeling was used to assess association of the different parameters with bGS (no cancer, Gleason 6, 7, and ≥8). An optimized model for the prediction of bGS was determined and a nomogram was generated. Results: The mean age of the cohort was 60.7 ± 7.7 years and mean PSA of 6.8 ± 6.5 ng/ml. Factors associated with Gleason score include age, PSA, PSAD, prostate volume, MRI suspicion score, total lesions seen on MRI, number of SPLs. Various models were examined utilizing factors positively associated with Gleason score and the combination of PSA density with SPLs outperformed most other combinations. A nomogram was generated to derive the probability of No cancer, Gleason 6, 7, and ≥8 PCa using the inputs of PSAD and number of SPLs. The correlating c-indexes to Gleason 6, 7, and ≥8 PCa detection were 0.87, 0.87, and 0.92 respectively. When tested on the original cohort, the most probable nomogram generated Gleason score correlates with actual pathologic bGS findings in 53% of the men. The top two most probable nomogram Gleason scores contained the actual bGS findings in 81% of the men. Conclusions: PSAD combined with prostate MRI imaging characteristics shows potential for prebiopsy determination of prostate cancer Gleason score and presence. Further improvement in predictive performance of this test may ultimately yield a clinical tool that is of benefit for prebiopsy risk stratification of patients for PCa of clinical significance.
Frequent truncating mutations of the cohesin complex gene STAG2 in urothelial carcinoma of the bladder.
Authors: Solomon David A. , Kim Jung-Sik , Bondaruk Jolanta , Shariat Shahrokh F. , Wang Zeng-Feng , Elkahloun Abdel , Gerard Julia , Zhuang DaZhong , Zhang Shizhen , Robinson Brian D. , Rubin Mark A. , Volkmer Bjoern , Hautmann Richard , Kuefer Rainer , Netto George J. , Theodorescu Dan , Czerniak Bogdan , Miettinen Markku , Waldman Todd 
Published: February 2017

290 Background: We have recently identified the cohesin complex subunit STAG2 as a gene that is somatically mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy (Solomon et al, Science, 2011 Aug 19). However, the complete tumor spectrum harboring STAG2 mutations and the clinical significance of STAG2 inactivation in cancer remain undefined. Methods: Immunohistochemistry was used to screen 2,214 tumors from each of the major tumor types for somatic loss of STAG2 expression. Sequencing of the STAG2 gene was performed on 111 urothelial carcinomas, and Affymetrix CytoscanHD Arrays were performed on STAG2 mutant tumors. Clinical data from 34 patients with non-muscle invasive urothelial carcinoma treated with transurethral resection and 349 patients with invasive urothelial carcinoma treated with radical cystectomy was correlated with tumor STAG2 status. Results: Complete loss of STAG2 expression was discovered in 52/295 urothelial carcinomas (18%), ranging from low grade papillary to high grade muscle invasive tumors. DNA sequencing revealed somatic truncating mutations of STAG2 in 23/111 urothelial carcinomas of the bladder, including 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (16%). STAG2 mutation was found to be an early event in bladder tumorigenesis, frequently associated with alterations in p53 signaling, and often correlated with numerous chromosomal copy number aberrations per tumor. STAG2 loss in non-muscle invasive urothelial carcinomas treated with transurethral resection was found to be associated with increased disease-free survival (p=0.05), while STAG2 loss in invasive urothelial carcinomas treated with radical cystectomy was found to be associated with increased lymph node metastasis (p=0.03), earlier disease recurrence (p=0.04), and reduced cancer-specific survival (p=0.04). Conclusions: These results identify STAG2 as one of the most commonly mutated genes in bladder cancer, and demonstrate that STAG2 loss defines molecular subgroups of urothelial carcinomas with distinct clinical outcomes.
Phase I dose-escalated image-guided adaptive bladder radiotherapy study: Results of first dose cohort (68Gy).
Authors: Huddart Robert , McDonald Fiona , Hafeez Shaista , Warren-Oseni Karole , Taylor Helen , Thompson Alan , Khoo Vincent , Harris Victoria , McNair Helen , Mohammed Kabir , Thomas Karen , Jones Kelly , Dearnaley David Paul , Horwich Alan 
Published: February 2017

291 Background: Prospective study assessing the safety of dose escalation in the treatment of localised muscle-invasive bladder cancer using image-guided adaptive radiotherapy (RT) with a reduced high-dose tumour volume. Methods: Radical RT was planned and delivered in 3 phases. Phase I was delivered to the empty whole bladder (10Gy 5#). Bladder variation assessed on phase I daily imaging was used to determine the adaptive approach for phase III (composite volume or plan of the day). Phase II was delivered to a tumour boost volume on a partially filled bladder (18Gy 9# if normal tissue dose-constraints were met, or to 14Gy 7# if they were not). The adaptive phase III (40Gy 20#) was delivered to the empty whole bladder. The primary endpoint was late RTOG toxicity. Results: Of the twenty-six patients recruited to 68Gy, 20 patients met the normal tissue constraints for dose escalation. For the phase III adaptive technique, 14 patients were treated with a composite volume approach and 12 with a plan of the day. At median follow-up of 24 months, 13 (65%) dose escalated patients remain alive and disease free. Within this dose cohort there has been 1 muscle invasive local recurrence, 1 superficial recurrence and 1 patient has developed metastases. 5 patients in the dose-escalated group have died; 3 from cardiac events, 1 from hospital acquired pneumonia and 1 from metastatic bladder cancer. 1 patient in the dose-escalated group has experienced grade 3 late toxicity (cystitis) occurring 24.6 months after the end of radiotherapy. Conclusions: Image-guided adaptive RT techniques with reduced high-dose volume allow tumour dose-escalation. Toxicity data to date suggest tolerability of 68Gy. Local disease control rates are promising. Trial recruitment continues at 70Gy using intensity modulated radiotherapy technique to deliver a simultaneous integrated boost. Clinical trial information: 7653.
Using microRNA (miRNA) profiling to differentiate noninvasive and muscle-invasive from metastases of transitional cell carcinoma of the urinary bladder (TCC-UB).
Authors: Ogbata Obiageli Uchenna , Yang Chuan , Pfeffer Lawrence , Ojukwu Somtochukwu , Gaines Grant , Pillappa Raghavendran , O'Brien Thomas , Weir Alva Bowen , Mahadevan Daruka 
Published: February 2017

338 Background: Altered miRNA expression contributes to the pathogenesis of urologic malignancies, including bladder cancer (BC). Individual miRNAs are known to regulate multiple signaling pathways in BC. We hypothesized that identifying miRNA gene expression profiles (GEP) in TCC-UB in the localized (non-invasive Vs invasive) and metastatic setting will help identify predictive and prognostic biomarkers within oncogenic signaling pathways, and novel therapeutic targets. Methods: We conducted a retrospective review of pathology reports of patients with TCC-UB from 2005 - 2013. The samples were categorized into non-invasive, muscle-invasive and metastatic sites. Normal urothelium was used as controls. Bone metastasis and tumors with squamous differentiation were excluded. RNA was extracted from Formalin Fixed Paraffin Embedded (FFPE) tissue blocks and assessed with Nanostring - nCounter miRNA expression assays. The Student t test was used to analyze the data. P value of < 0.05 was considered statistically significant. Results: 36 FFPE tumor samples were identified and analyzed – 18 muscle-invasive (MI), 9 non-invasive (NI), 7 metastatic (M) and 2 normal urothelium (C). Of the over 600 miRNA assessed by the Nanostring microarray, miR21 and 494 were consistently up-regulated, while miR451a, 144-3p, 363-3p, 15b-5p, 200a-3p, 137, 429 were downregulated. Conclusions: MicroRNA profiling differentiates non-muscle invasive versus muscle-invasive BC from metastatic sites. The data provides insights into molecular alterations that will help distinguish signaling pathways of bladder carcinogenesis such as FGFR, PI-3K, STAT-3 and p53. Identified molecular targets will provide an effective and promising strategy to be evaluated in BC cell lines. [Table: see text]