bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of IGF1R to predict outcome in invasive urothelial carcinoma of urinary bladder.
Authors: Kim Jenny J. , Gonzalez-Roibon Nilda , Chaux Alcides , Munari Enrico , Faraj Shiela F. , Ellis Carla , Sharma Rajni , Bivalacqua Trinity , Schoenberg Mark , Carducci Michael Anthony , Netto George J. 
Published: February 2017

280 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed (OE) in several tumors including bladder cancer and is currently under investigation as a target of Rx. Here we explore IGF1R expression in urothelial carcinoma (UC), its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered OE in cases with score 1. Endpoints of the study included overall survival and cancer-specific survival. Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R was OE in 62% of UC. No differences were noted between normal urothelium and malignant counterparts (74% vs. 60%; P=0.14). IGFR1 was more frequently OE in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). pT4 tumors OE IGF1R more frequently than pT1-pT3 tumors (71% vs. 29%, P=0.005). No association was found with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis). Overall survival (OS) and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients whose tumors OE IGF1R had a lower OS and DSS compared to those whose tumors did not OE IGF1R (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R overexpression remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: Overexpression of IGF1R was found in 62% of UC. High stage tumors OE IGF1R more frequently than low stage tumors. More importantly, IGF1R overexpression was a significant independent predictor of OS and DSS.
Presence of carcinoma in situ (CIS) in bladder cancer biopsies and its relationship to pathologic complete response (pCR) rates to neoadjuvant chemotherapy (neo-CTx).
Authors: Thomas Derek E. , Rice Kevin , Pedrosa Jose Alexandre , Johnston Paul , Moore Marietta L. , Reed Angela D. , Cregar Dylan M. , Franklin Cindy , Koch Michael O. , Bihrle Richard , Foster Richard , Masterson Timothy A. , Gardner Thomas A. , Sundaram Chandru , Powell Charles R. , Beck Stephen , Grignon David A. , Cheng Liang , Hahn Noah M. 
Published: February 2017

286 Background: Despite an improved overall survival with neo-CTx for muscle-invasive urothelial carcinoma (miUC) patients (pts) prior to cystectomy, the adoption of neo-CTx in suitable pts has been suboptimal. While associated with a more aggressive phenotype in early stage UC, the prognostic role of CIS in miUC is less clear. In particular, the effect of concurrent CIS in pts undergoing neo-CTx prior to cystectomy is unknown. Methods: A retrospective review of the Indiana University Simon Cancer Center urology and medical oncology clinical databases was performed spanning the years 1991 – 2012. Subjects with miUC, pathology reports available for both transurethral resection of bladder tumor (TURBT) and cystectomy procedures, and confirmed receipt of neo-CTx were included in this analysis. Pts with clinically positive lymph nodes (LN+) were included provided they underwent cystectomy with curative intent. Associations between pCR and pt baseline age, gender, race, clinical stage (T2N0 vs. T3/T4/N+), chemotherapy regimen received (cisplatin combination therapy (CisCTx) vs. non-cisplatin based), and presence of CIS on TURBT sample were tested by multinomial logistic regression analysis with statistical significance set at p<0.05. Results: 72 miUC pts satisfying the inclusion criteria were identified. Cohort demographics included: median age – 59 yrs, 76% male, 93% Caucasian, 63% T2N0, 32% LN+, 81% CisCTx neo-CTx regimen, 32% CIS on TURBT, pCR for entire cohort 18%. The presence of CIS on TURBT was significantly associated with decreased rates of pCR (1/23 vs. 12/49) p=0.002. TURBT CIS was not associated with decreased rates of less than pT2N0 (12/23 vs. 18/49) p=0.562. Seven pts (30%) with CIS on TURBT sample achieved pTisN0 at cystectomy. Conclusions: The presence of CIS in TURBT specimens is associated with decreased rates of pCR at cystectomy in miUC pts treated with neo-CTx. The finding of pTisN0 at cystectomy is common after neo-CTx in pts with CIS in preop TURBT specimens. Validation of the prognostic significance of TURBT CIS on pCR rates and characterization of pTisN0 clinical course in TURBT CIS pts after neo-CTx is warranted.
Effect of germ-line BRCA mutations in biochemical relapse and survival after treatment for localized prostate cancer.
Authors: Castro Elena , Olmos David , Goh Chee Leng , Saunders Ed , Leongamornlert Daniel , Tymrakiewicz Malgorzata , Bancroft Elizabeth , Page Elizabeth , Dadaev Tokhir , Govindasami Koveela , Guy Michelle , Ellis Steve , Frost Debra , Peock Susan , Antoniou Antonis C. , Easton Douglas , Kote-Jarai Zsofia , Eeles Ros A. ,   EMBRACE and UKGPCS Collaborators
Published: February 2017

29 Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter cause-specific survival (CSS). Germline BRCA mutations are associated with worse PrCa outcomes. In this study, we analyzed biochemical-progression free survival (bPFS) after conventional treatments for localized PCa in a cohort of BRCA patients from the UK. Currently, BRCA1/2 carriers are treated with the same protocols used for non-carriers. Methods: In this retrospective case-control study, each BRCA carrier (10 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by: age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment (RT or RP), androgen-deprivation therapy (ADT) and year of treatment (±5yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 176 patients (pts) were included. Median follow-up was 97 months (ms). Median age at diagnosis was 58.5 yrs (43-75). 80 pts received RT (16 BRCA2, 4 BRCA1, 60 NC) and 85% also received ADT≥6 ms. 96pts underwent RP (18 BRCA2, 6 BRCA1 and 72 NC). Following RT treatment, 5yrs-CSS was 96% in NC and 47% in BRCA carriers (p=2x10-5), whilst no difference was seen after RP (5yrs-CSS was 98.5% in NC vs 93.3% in BRCA). Five-years bFPFS after RT was 74% in NC and 24% in BRCA (p=0.002). No difference was observed in 5yrs-bPFS between BRCA carriers and NC treated with RP (52% vs 66% , p=0.346). The adjusted MVA (including tumour stage, local treatment, ADT and BRCA status) confirmed the independent prognostic value of BRCA status for bPFS and CSS. Among BRCA carriers, the independent risk was greater when the analysis was limited to BRCA2 pts . Conclusions: Our results suggest that BRCA carriers have worse local disease control than NC when conventionally treated with RT. No differences in bPFS were observed in pts treated with RP after >8 yrs median follow-up. These results may have implications for tailoring clinical management in these patients.
Prediction of pathologic complete response to neoadjuvant chemotherapy in urothelial cancer by genetic determinants of platinum sensitivity.
Authors: O'Donnell Peter H. , Alanee Shaheen , Cao Hongyuan , Ostrovnaya Irina , Garcia-Grossman Ilana Rebecca , Ganshert Cory , Smith Norm D. , Steinberg Gary D. , Offit Kenneth , Stadler Walter Michael , Bajorin Dean F. 
Published: February 2017

290 Background: Despite level 1 evidence demonstrating survival benefit for cisplatin-based neoadjuvant chemotherapy in urothelial cancer, its utilization remains low, likely due to the modest benefit and potentially significant toxicities. To improve selection of patients (pts) most likely to benefit, we evaluated the association of pharmacogenomic markers of cisplatin sensitivity with neoadjuvant therapy outcome. Methods: Pts receiving standard neoadjuvant cisplatin-based chemotherapy for muscle-invasive disease were recruited to provide a germline DNA sample. Nine single nucleotide polymorphisms (SNPs) selected for their associations with platinum sensitivity in various clinical and pre-clinical studies were tested for association with complete pathologic response (pT0) rate at cystectomy. Results: Sixty-three Caucasian pts were analyzed (median age=64; 67% male; all bladder primary and cN0). The overall pT0 rate was 27%; 52% were <pT2. Using a multivariate, recessive genetic model, rs244898 in RARS (odds ratio [OR] 6.8 [95% CI 1.6-32.6], P=0.01) and rs7937567 in GALNTL4 (OR 5.2 [95% CI 1.1-26.2], P=0.03) were associated with likelihood of achieving pT0. For each SNP, pts carrying the favorable genotype achieved pT0 in >58% of cases. Demonstrating the apparent independent nature of the two SNPs, pts carrying either favorable genotype had pT0 OR=8.5 (95% CI 2.5-31.8, P=0.0008). The combined effect of detecting both SNPs was most informative, as 2/3 pts with both favorable genotypes achieved pT0 (67%), compared to 9/15 pts with one favorable genotype (60%), and only 6/43 lacking both favorable genotypes (14%). The negative predictive value considering both SNPs was 86%. Conclusions: Two germline SNPs having prior evidence of governing platinum sensitivity in pre-clinical and clinical models were demonstrated to confer strong associations with complete response to cisplatin-based neoadjuvant chemotherapy. Validation testing in an independent, multi-institutional cohort of urothelial cancer pts is underway. If reproducible, these SNPs deserve consideration as predictive clinical biomarkers to inform the use of neoadjuvant chemotherapy in this disease.
The preclinical anti-angiogenic and pro-apoptotic activity of lenalidomide in urothelial carcinoma (UC).
Authors: Jian Weiguo , Levitt Jonathan M. , Chan Keith S. , Lerner Seth P. , Sonpavde Guru 
Published: February 2017

294 Background: Lenalidomide (Len) is an immunomodulatory drug (IMiD) approved for hematologic conditions and demonstrates immune modulation, anti-angiogenic activity and direct anti-tumor cytotoxicity. A rationale can be made to evaluate the preclinical activity of Len in UC. Methods: The in vitro anti-tumor activity of Len was evaluated in 4 human (5637, TCC-SUP, RT4, RT112) and 1 murine (MB49) cell line. Anti-proliferative activity activity (MTT assay), apoptosis (Annexin-FITC immunohistochemistry [IHC], flow cytometry) and cell viability by colony forming assay were measured. In vivo activity of daily oral Len 10 mg/kg or placebo orally for 5 days a week for up to 4 weeks was examined in syngeneic immunocompetent C57BL/6 mice bearing subcutaneous (SC) MB49-Luc25 tumors and RT4 subcutaneous xenografts. Tumors underwent immunohistochemistry (IHC) for microvessel density (CD31), apoptosis (cleaved caspase [cc]-3) and CD3+/CD20+ lymphocyte infiltration. Cereblon, a molecular target of Len was analyzed by IHC. Results: In vitro cultures for 3 days with daily repletion of Len showed significant pro-apoptotic activity (flow cytometry) at low micromolar concentrations attainable in human subjects (2.2 µM) against RT4 cells, a superficially invasive human UC cell line. Long-term cultures of RT4 cells for 2 weeks with daily repletion of Len significantly reduced cell viability and colony forming ability. Cereblon expression was numerically lower in sensitive RT4 cells compared to resistant 5637 cells (p=NS). In the immunocompetent model in vivo, Len did not decrease tumor size, or increase cc-3 and CD3+/CD20+ lymphocytes, but post-Len tumors exhibited decreased CD31 (p<0.05). In RT4 xenografts, Len significantly decreased the size of tumors and CD31, and increased cc-3 (all p<0.05). Cereblon expression increased in Len treated RT4 xenografts (p=0.024). Conclusions: Lenalidomide demonstrated selective preclinical activity against superficially invasive low grade human UC cells attributable to direct tumor cell apoptosis and anti-angiogenic activity. Clinical evaluation in patients with low grade or non-invasive UC and further study of cereblon as a predictive biomarker may be warranted.
Current management and proposal for guidance of radiation cystitis (RC): Results of a British Uro-oncology Group (BUG) survey.
Authors: Bahl Amit K. , Huddart Robert Anthony , Payne Heather 
Published: February 2017

297 Background: Although RC is a potentially significant acute and/or chronic complication of radiotherapy to the pelvic area (15-20% incidence), there is limited information about how it is managed in practice. Methods: The BUG membership (comprising of consultant Uro-oncologists) was surveyed as to their perception on and management of RC. Results: 87% (45/52) of respondents supervise radiotherapy to the bladder/pelvis. Of these 45, most consider acute RC during or immediately after treatment a significant problem in ‘some' (56%) or the ‘majority' (11%) of cases (‘minority': 33%). Late RC was mostly considered a significant problem in the ‘minority' of cases (73%), with the rest feeling it was a significant problem in ‘some' cases (27%). During radiotherapy or at follow-up the majority ‘always' (22%) or ‘sometimes' (60%) record the grade of cystitis (‘never': 18%). 93% do not have local guidelines for managing RC. The treatments most frequently used to treat acute RC are: fluids (71%); cranberry juice (36%); analgesia (36%); non-steroidal anti-inflammatory drugs (NSAIDs; 29%); and anti-spasmodics (18%). Mild late RC is treated similarly (fluids: 29%; analgesia: 22%; cranberry juice: 18%; NSAIDs: 16%), although 20% might consider no treatment. For moderate/severe late RC, most refer to an urologist (64%), with grade ≥2 cases, those with haemorrhagic cystitis (20%), and symptoms >90 days post-radiotherapy (18%) being the most common reasons for referral. For those treating moderate/severe late RC, hyperbaric oxygen (38%), fluids (19%), and analgesia (19%) are most commonly used. Over half were not aware of alternative treatment options including mesna (69% not aware), sodium hyaluronate (62%), intravesical prostaglandin E1/E2 (62%), sodium pentosanpolysulphate (60%), or intravesical formalin (51%). All supported the development of national guidelines in collaboration with the British Association of Urological Surgeons and British Association of Urology Nurses. Conclusions: RC is acknowledged as a potentially significant issue, and, with the majority of cases managed by oncology, there is a recognised need for further guidance on optimal treatment and BUG has started this work.
Exome sequencing of extreme phenotypes to identify variants predictive of response to chemotherapy in bladder cancer.
Authors: Alanee Shaheen , Shah Sohela , Stratton Kelly Lynn , Garcia-Grossman Ilana Rebecca , Zabor Emily , Ostrovnaya Irina , Joseph Vijai , Pendse Deepa , Bajorin Dean F. , Offit Kenneth 
Published: February 2017

300 Background: Little is known about germline variants predictive of response to chemotherapy in bladder cancer (BC). We investigated germline variants in patients (pts) treated with neoadjuvant gemcitabine/cisplatin (GC) under the hypothesis that responders and non-responders may differ in rare alleles predictive of treatment outcome. Methods: The Hiseq platform (≥ 20x coverage) was used to sequence the exomes of muscle-invasive (≥cT2) BC pts representing “extreme phenotypes” defined by response to neoadjuvant GC (complete responders vs. non responders). Responders were pT0N0 at cystectomy and remained disease free >1 year. Non-responders had residual disease in the bladder at cystectomy and metastatic disease either at cystectomy or within 1 year. Rare, potentially deleterious single nucleotide variants (SNVs) unique to these phenotypes were confirmed with Sequenom and validated in an independent group of BC pts treated with GC in the neoadjuvant or first line setting. One-sided Fisher’s exact test and multivariate logistic regression were used to estimate association between SNVs and response. Results: The discovery cohort had 6 responders (4 male) with a mean age of 62 and 9 non-responders (6 male) with a mean age of 63. Filtered exome sequences identified 93 rare/potentially deleterious SNVs unique to non-responders and 45 unique to responders of which 84 and 35 were confirmed by Sequenom, respectively. The independent validation cohort consisted of 173 pts, mean age 60, 72% male, and 53% responders (complete or partial). Among 119 SNVs genotyped in this cohort, only 3 responder and 9 non-responder SNVs were identified in ≥ 3 pts. None of the responder SNVs were associated with response. One non-responder SNV (rs150721903) was significantly associated with resistance to GC (OR: 9.7, 90% CI: 1.7-56.8, p=0.011), and remained significant after adjusting for risk score (p= 0.017). rs150721903 is a missense variant in an uncharacterized protein on chromosome 8. Conclusions: Exome sequencing of extreme phenotypes identified a variant that predicts resistance to GC, demonstrating the feasibility of this pharmacogenomics approach. Further evaluation of this SNV is warranted.
Discovery of molecular biomarker signatures for the detection of bladder cancer.
Authors: Gomes Evan , Urquidi Virginia , Cai Yunpeng , Sun Yijun , Rosser Charles Joel , Goodison Steve 
Published: February 2017

302 Background: Bladder cancer (BCa) is among the five most common malignancies world-wide, and due to high rates of recurrence, one of the most prevalent. Improvements in non-invasive urine-based assays to detect BCa would benefit both patients and healthcare systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with BCa. Methods: Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of BCa and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR). Results: Data analysis identified 52 genes associated with BCa (p≤0.001), and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of BCa with a specificity of 100% at 90% sensitivity. Conclusions: Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected BCa. The refinement and validation of the multi-gene urothelial cell signatures identified in this preliminary study may lead to accurate, non-invasive assays for the detection of BCa. The development of an accurate, non-invasive BCa detection assay would benefit both the patient and healthcare systems through better detection, monitoring and control of disease.
Pre-cystectomy serum levels of CA19-9, CA125, and CEA: Correlation with pathologic stage and oncologic outcome in urothelial carcinoma of bladder.
Authors: Ahmadi Hamed , Djaladat Hooman , Miranda Gus , Cai Jie , Daneshmand Siamak 
Published: February 2017

303 Background: To evaluate the association between pre-cystectomy carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and carcinoembryonic antigen (CEA) levels and pathologic stage and oncological outcome of urothelial carcinoma of bladder (UCB). Methods: Preoperative stored serum samples of 186 patients with UCB who underwent radical cystectomy at USC between 2004 and 2009 were randomly selected to measure CA19-9, CA125, and CEA levels. Laboratory cut-off point values were used to define abnormal marker levels (CA 19-9>35.5, CA125>35.5, CEA>3.8). Pathologic stage was categorized as organ confined (OC) (pT1,T2), extravesical (EV) (>pT2), and lymph node positive (LN+) UCB. Cox regression model was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: The mean age of patients were 70 years (ranges, 36-91) and the median follow-up was 4 years (ranges, 0.1–7). 94 (50.5%) patients had OC, 45 (24%) had EV, and 47 (25.5%) had LN+UCB. The mean CA 19-9, CA125, and CEA levels were14 (0.6–278) U/mL, 11.8 (3–79) U/mL, and 2.3 (0.3–30) ng/mL. 30/186 (16%) patients had at least one abnormal marker. Percentage of abnormal CA19-9 was significantly higher in locally advanced UCB (EV and/or LN+) compared to OC UCB (85.7% vs. 48%; P=0.03). The percentage of abnormal CA125 and CEA levels were comparable between locally advanced and OC UCB.4-year RFS and OS were 66% and 65%, respectively. After controlling for pathologic stage, age, and adjuvant chemotherapy; Abnormal CA19-9 and CEA were independent predictors of worse 4-year OS (HR:2.7; P=0.04 and HR:2; P=0.03). Abnormal CA 19-9 was also an independent predictor of worse 4-year RFS (HR: 2.8; P=0.05). Pre-cystectomy CA 125 level had no correlation with oncological outcome. Conclusions: In patients with UCB, abnormal precystectomyserumCA19-9 is correlated with advanced pathological stage and is an independent predictor of worse oncological outcome. Precystectomy CEA and CA 125 showed no significant correlation with pathological stage and oncological outcome. Prospective studies are encouraged to elucidate the clinical value of these serum markers.