bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lynch syndrome-associated upper tract urothelial cancer: Assessment of clinical screening criteria and tissue-based point of care testing.
Authors: Metcalfe Michael J. , Rao Priya , Mork Maureen E , Petros Firas G. , Xiao Lianchun , Broaddus Russell , Matin Surena F. 
Published: March 2017

371 Background: Lynch syndrome (LS) is an inherited syndrome that places patients at risk for upper tract urothelial carcinoma (UTUC). Our goal was to identify the most reliable means of screening for LS in patients with UTUC at the point of care (POC). Methods: Patient information was retrospectively collected in an IRB-approved protocol on UTUC patients. LS screening was universally performed on all patients presenting from 1/2013-7/2016. We evaluated patient and family history (Amsterdam I and II criteria; AMS1 and AMS2, respectively), tumor immunohistochemistry (IHC) for 4 mismatch repair proteins (MMRP), tumor and normal tissue polymerase-chain reaction for microsatellite instability (MSI), and clinical genetic analysis and counseling (GAC), in those with undiagnosed LS. Patients who were AMS 2 positive, MSI positive, or IHC positive were considered as presumed Lynch syndrome (PLS) and were referred for GAC. Results: 101 UTUC patients without a history of LS were universally screened during clinical follow-up. A total of 15/101 (15%) patients were PLS. 7/101 (7%) patients met AMS2 criteria. 4 patients meeting AMS2 criteria had intact expression of MMRP and no MSI instability. 11 (11%) patients had either loss of one or more MMRP. There were two cases of MSI high instability, both in patients with MMRP loss. There were no cases of MSI-high instability and negative IHC. Insufficient tissue was found in 1/101 (1%) of IHC and 8/88 (9%) of MSI tests (p=0.0164). All patients with any positive screen were referred for GAC, 5 followed-up and all 5 patients had a confirmed germline mutation. The remaining did not follow through with GAC because of financial/insurance barriers. Conclusions: We identified 15% of universally screened UTUC as PLS at the POC using IHC and AMS2 criteria. IHC and AMS2 criteria appear to provide the most reliable screening. MSI is limited by requirement for normal tissue, a greater amount of tumor tissue, and can miss cases of MMRP loss. There are significant barriers to GAC. Our findings of a 15% rate of LS-related UTUC is consistent with prior laboratory tissue studies and has significant implications for universal POC testing of UTUC patients.
Prognostic classification of muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) alone or with perioperative chemotherapy: Analysis of the U.S. National Cancer Database (NCDB).
Authors: Sonpavde Guru , Nelson Rebecca A. , Pond Gregory Russell , Nix Jeffrey , Chennamsetty Avinash , Pal Sumanta K. 
Published: March 2017

372 Background: While the role of adjuvant therapy for MIBC is being evaluated in randomized trials of patients (pts) following RC with or without neoadjuvant chemotherapy (NC), pts receiving adjuvant chemotherapy (AC) have been excluded. Understanding the prognosis of a broad spectrum of pts undergoing RC with or without perioperative chemotherapy may aid patient selection, stratification and interpretation of nonrandomized data. We conducted a retrospective analysis of the NCDB to construct a comprehensive prognostic nomogram in this broad population. Methods: Data from NCDB was obtained for all patients diagnosed with clinical (c)-T2-T4aN0M0 urothelial carcinoma of bladder who underwent RC in the US from 2004-2013. Those who underwent RC > 6 months (mo) after initiating NC, received AC > 4 mo after RC were excluded to allow only those receiving optimal therapy. Pts with unknown race and number of lymph nodes (LNs) examined were also excluded. Multivariate analyses were conducted to determine the impact on survival of: clinical stage, pathologic (p)-stage, treatment group (RC alone, NC, AC), age, year of diagnosis, Charlson Comorbidity Index (CCI), race, number of examined LNs examined and sex. Results: A total of 10,256 pts were evaluable for analysis: 6864 in the RC group, 1380 in the AC group and 2012 in the NC group. On multivariate analysis, the following variables were significantly (p < 0.001) associated with survival: treatment group, age ( < 65 vs. ≥ 65 years), CCI, p-stage and number of examined LNs. Calibration was performed and the c-index was 0.79 (95% CI: 0.76-0.81). Limitations of a retrospective analysis apply. Conclusions: A comprehensive prognostic nomogram to predict the survival of pts with MIBC undergoing RC with or without NC or AC was proposed. The estimation of residual risk of mortality after RC alone or with AC or NC aids optimal stratification of pts in more inclusive randomized trials of subsequent adjuvant therapy. The nomogram also highlights the impact of comorbidities and age, and helps interpret non-randomized data evaluating perioperative regimens.
Comprehensive genomic characterization of upper tract urothelial carcinoma (UTUC).
Authors: Moss Tyler J. , Qi Yuan , Xi Liu , Peng Bo , Mosqueda Maribel E , Guo Charles , Ittman Michael , Wheeler David A. , Lerner Seth P. , Matin Surena F. 
Published: March 2017

375 Background: Integrated analysis of UTUC was performed to characterize the genomic landscape of UTUC and provide insights into biology. Methods: 31 untreated samples underwent WES, RNAseq, and RPPA. Consensus mutation calls from independent pipelines of 2 centers identified gene expression clusters using unsupervised consensus hierarchical clustering (UCHC). Results: Clinical data are shown in the Table. WES identified mutations in FGFR3 (74.1%; 92% low grade, 60% high grade), KMT2D (44.4%), PIK3CA (25.9%), TP53 (22.2%). APOBEC and CpG signatures were identified. Expressed marker genes from bladder TCGA were not associated with molecular subtypes in this study. UCHC of RNAseq segregated samples into 4 molecular subtypes. Cluster 1: no PIK3CA mutations; enriched for nonsmokers, high grade non-muscle invasive tumors, high recurrence rates and favorable survival. Cluster 2: 100% FGFR3 mutations; enriched for low grade, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations; high tobacco use and bladder recurrence (62.5%); tumors all non-muscle invasive. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations; enriched for high grade, muscle-invasive disease, tobacco use, CIS, reduced survival; novel fusion of SH3KBP1-CNTNAP5 was identified, with high expression levels in the sample. Conclusions: We show mutations in UTUC occurring at differing frequencies and subtypes than bladder cancer. Novel fusion SH3KBP1 regulates RTK signaling and acts to recycle TGFβ receptors. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. [Table: see text]
High responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.
Authors: Szabados Bernadett , Wimalasingham Akhila Ganeshi , Tang Yen Zhi , Sahdev Anju , Gomez De Liano Lista Alfonso , Lim Louise , Hopkins Thomas , Berner Alison , Powles Thomas 
Published: March 2017

377 Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUB. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 20 sequential patients collected from one institution who received chemotherapy after CI. Patients were separated into 2 groups. Group A had not previously received chemotherapy (n=10), group B had previously received at least 1 chemotherapy regimen (n=10). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). The commonest chemotherapy regimen in group A and B were cisplatin-gemcitabine (80%) and carboplatin paclitaxel (70%) respectively. Results are summarised in the table. The median change in target lesions in the front line immunotherapy cohort was -49% (-81 to +8%). Only two patients (20%) in group B responded to chemotherapy and both presented a long interval between first and 2ndline chemotherapy (9-12 months); compared to 56% responding in group A. Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting. [Table: see text]
Relationships between an androgen receptor output signature (ARoS), AR expression, and poor prostate cancer prognosis in RP tissues.
Authors: Alshalalfa Mohammed , Santiago-Jimenez Maria , Erho Nicholas , Fishbane Nicholas , Yousefi Kasra , Ashab Hussam Al-Deen , Davicioni Elai , Ross Ashley , Schaeffer Edward M. 
Published: March 2017

38 Background: The Androgen-receptor (AR) signaling plays a pivotal role in prostate cancer initiation and progression. AR amplification and overexpression have been associated with lethal PCa and CRPC; however, much of the impact of these events on cancer progression is poorly understood with an unclear prognostic significance of down-stream targets of AR. Methods: A total of 2,555 RP expression profiles were extracted from the Decipher GRID database; 262 of which were from retrospective natural history cohort with known metastasic outcomes and the remaining from anonymized prospective cases with basic demographic and pathological data available. We built a 9 gene AR-output signature (ARoS) score based on canonical androgen regulated genes to represent AR-output activity in RP tissues. The 9 genes were weighted based on their distribution skewness in the prospective data (n = 2,293) and then scores were calculating by summing the weighted expression of the 9 genes. Results: AR expression and ARoS score were not strongly correlated with approximately 50% of samples with low ARoS have relatively high AR expression. In a prospective cohort of 2,293 patients, low ARoS was associated with higher Decipher metastasis risk scores (OR: 3.1, p < 0.001), higher Gleason grade (OR: 2.4, p < 0.001), ERG-fusion negative (OR: 1.8, p < 0.001) and SVI (OR: 2.1, p < 0.001). Additionally, low ARoS was associated with higher expression of neuroendocrine biomarkers (NCAM1, ENO2). In a large retrospective cohort with long term clinical follow-up, patients with low ARoS score had a higher probability of 10-year metastasis rate (p = 0.002). In 55 patients from this cohort who received ADT post metastasis, the ARoS signature derived from primary tissue was lower in patients who developed CRPC (p < 0.001). Furthermore, ARoS was significantly lower in mCRPC samples (p < 0.001) compared to primary PCa tissues. Conclusions: ARoS derived from primary prostate cancer tissue is correlated with metastatic outcomes and progression to CRPC. With further validation, such a signature may better predict those patients which require early intensification of systemic therapy.
Characterization of POLE-mutated (POLE+) urothelial carcinoma of the bladder and urinary tract (UC).
Authors: Teo MinYuen , Al-Ahmadie Hikmat , Cha Eugene K. , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Berger Michael F. , Taylor Barry S. , Bajorin Dean F. , Iyer Gopa , Rosenberg Jonathan E. 
Published: March 2017

387 Background: The POLE gene encodes for the catalytic and proofreading unit of DNA polymerase epsilon. Mutations in POLE gene, recently observed in endometrial and colorectal cancers, are associated with unique clinical features and an ultramutated phenotype. We sought to quantify and characterize POLE+ in UC. Methods: POLE+ cases were identified from a database of 532 UC tumors sequenced with the MSK-IMPACT assay (Cheng et al J Mol Diagn 2015). Tumors were classified based on total mutation: hypermutated (20 - 149 mutations) and ultramutated ( ≥ 150 mutations) as previously described in colon cancer (Stadler et al J Clin Oncol 2016). An institutional cohort of patients with metastatic UC was used as historical POLE- control (n = 94). Results: Thirty two POLE+ patients (6%) and 42 mutations were identified. Median age of diagnosis was 65 years (range: 31 - 94) and 81% were male. Seven patients were found to have Lynch’s syndrome, 8 with ERCC2 mutations which were hotspots or within the helicase domains and 1 with germline NBN mutation. These were excluded from further analysis. Of the remaining 16 patients (3%) and 22 mutations, four were found within the proofreading domain (positions 268 – 471), one was a previously reported hotspot (P286R) and one was a truncating mutation (R114*). Four cases were considered hypermutated and two ultramutated based on mutation counts. Clinically, four had non-invasive disease and 4 had metastatic disease at diagnosis. Eight patients had muscle-invasive disease, five of whom received neoadjuvant chemotherapy. All 8 patients developed metastatic disease with a median time interval of 10.3 months (range: 3.3 – 29.6). Nine of the 12 metastatic patients had nodal metastases while only one had visceral metastasis. With median follow-up of 25.4 months, median overall survival from metastatic diagnosis was not reached and 83% remained alive at 2 years, which was superior to survival for POLE- metastatic patients (HR 0.36, p = 0.04) and POLE- nonvisceral, node only metastatic patients (HR 0.33, p = 0.03). Conclusions: POLE+ prevalence is low in UC but might exhibit superior overall survival. It remains to be investigated if this is strictly the effect of POLE+ or other as yet unidentified genomic events.
The impact of peri-operative chemotherapy for patients with lymph node-positive urothelial cancer.
Authors: Kaiser Jeenan , Li Haocheng , Lee-Ying Richard M. , Heng Daniel Yick Chin , Alimohamed Nimira S. 
Published: March 2017

388 Background: Patients with locally advanced urothelial cancer with regional lymph node involvement (LN+) have a poor prognosis. Surgical management of these patients is controversial and practice patterns vary. We evaluated the outcomes of patients with LN+ disease treated with pre-operative chemotherapy and cystectomy, cystectomy and post-operative chemotherapy, and chemotherapy alone. Methods: Patients with urothelial cancer with TxN1-3M0 disease treated with chemotherapy in Alberta from 2005 to 2015 were evaluated. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis. Cox regression analysis was performed to evaluate the impact of age, gender, T stage, and N stage on survival. Results: 184 patients with LN+ disease treated with chemotherapy were evaluable for outcomes; 42 underwent pre-operative chemotherapy (Group A), 92 underwent post-operative chemotherapy (Group B), and 50 received chemotherapy alone (Group C). The median age at diagnosis was 65 years (range 31-89) and most patients (83%) were male. The median follow-up time was 23.2 months. A higher T stage was seen in patients in Group A, while patients in Group C had a higher N stage. The median number of chemotherapy cycles delivered was equal in all arms at 4. Patients in Group A or B had significantly better PFS and OS compared with patients in Group C (Table). When adjusting for age, gender, T stage, and N stage, patients in Group C had significantly lower OS compared with those patients in Group A (HR 1.87, 95% CI 1.09 – 3.18, p=0.02). Conclusions: In this real-world analysis of patients with LN+ urothelial cancer, patient outcomes were improved with surgical resection of disease in combination with pre-operative chemotherapy. After chemotherapy in fit patients with LN+ disease, surgical management is a reasonable consideration. [Table: see text]
Difference in risk factors associated with biochemical recurrence after salvage RT compared to post-prostatectomy patients with negative margins.
Authors: Hopper Austin B , Sandhu Ajay Pal , Einck John Paul 
Published: March 2017

39 Background: Previous research has also shown that higher pathologic stage, higher Gleason score (GS) and positive margins are associated with increased rates of disease recurrence after prostatectomy and may be indicators for early intervention with adjuvant or salvage radiotherapy (SRT). Conversely, a negative surgical margin is a negative prognostic factor for the success of SRT. We sought to investigate the relative significance of prognostic factors in patients grouped by margin status and differences in their response to treatment. Methods: 227 patients were treated with SRT at our institution between Jan 2005 and Dec 2013. Patients with positive lymph nodes at surgery, those treated with adjuvant radiation and patients with metastases prior to SRT were excluded, leaving 196 for analysis. Biochemical recurrence (BCR) was defined as post-SRT PSA nadir + 0.2 ng/mL. Median follow-up was 48 mo. Covariates evaluated were factors found to be significant in previous studies on SRT (pre-SRT PSA, pathologic stage, GS) as well as treatment to the pelvis vs fossa. Patients were grouped by margins and evaluated using Kaplan-Meier and multivariate Cox regression. Results: In univariate analysis of patients with positive margins significant factors for increased rates of recurrence were pre-SRT PSA (p = 0.016), GS (p < 0.001), and pathologic stage (p < 0.001). Treatment to the pelvis was not significant. Conversely, in patients with negative margins, pre-SRT PSA and GS no longer significantly affected BCR and pathologic stage only approached significance (p = 0.061). In these patients treatment to the pelvis was significantly associated with decreased BCR (p = 0.005). On multivariate analysis these trends in significance were maintained. Conclusions: In post-prostatectomy patients with negative margins treatment to the pelvis is associated with improved bPFS, while traditional factors associated with recurrence such as pathologic stage, GS and pre-treatment PSA were not significant. Patients with negative margins and PSA recurrence after prostatectomy should be considered for treatment to the pelvic nodes, even in the absence of nodal involvement on imaging.
Dacomitinib (Daco) induction therapy for locally advanced (LA) or metastatic penile squamous cell carcinoma (PSCC): An open label, single-arm, phase II study.
Authors: Necchi Andrea , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Calareso Giuseppina , Togliardi Elena , Colecchia Maurizio , Busico Adele , Perrone Federica , Gloghini Annunziata , Sonpavde Guru , Mariani Luigi , Salvioni Roberto 
Published: March 2017

399 Background: The prognosis of patients (pts) with PSCC is primarily depending on the involvement of regional lymph nodes (LN). Owing to the limited efficacy of chemotherapy (ChT), new drugs are warranted. Daco is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: In a phase 2 study (NCT01728233), pts received Daco 45 mg/d orally continuously. Inclusion criteria were SCC histology, and clinical stage N2-3 or M1; no prior ChT was allowed. Computed tomography (CT) and PET/CT scans were repeated q8 wks. Responding pts with LA-PSCC were offered radical surgery. The primary endpoint was the objective response-rate (ORR = CR+PR according to RECIST v1.1). The study was conducted according to a Bayesian design, based on predictive probability; the target was to demonstrate that the ORR exceeded 20%. Translational analyses on pre-Daco tumor samples included: EGFR and HER2 amplification (ampl), in-situ hybridization for HPV, and next generation sequencing. Results: From 06/13 to 09/16, 26 pts were treated. 7 (26.9%) had visceral metastases. 50% had pelvic and 57.7% clinically-involved bilateral LN. 1 CR + 7 PR were obtained (ORR = 30.4%, 95% credibility interval 14.9-48.6%). Median follow up = 16.6 months; 12-m PFS = 24.1% (95%CI: 11.1-52.3); 12-m OS = 50.7% (95%CI: 31.7-80.9). The current Bayesian posterior probability of exceeding the 20% ORR target is 89%. Tissue samples from 23 pts were analyzed. Only 2 pts were HPV+ (1SD, 1PD). EGFR ampl was found in 4 pts (1 CR, 1 PR, 2 SD) and it was confirmed in all post-Daco samples. TERT mutations (60%) were found in responders (R) only. Mutations in genes potentially associated with resistance to EGFR inhibitors ( HRAS, BRAF, PIK3CA, PTEN, STK11) were found in 47% non responders (NR) vs 25% R. HRAS and BRAF mutations segregated with NR (20%). Additional unfrequent mutations of druggable targets were found: RAC1, TSC1 and mTOR in R, FGFR2, RAD50, PDGFRB and FLT4 in NR, IGF2R in both. Conclusions: Dacomitinib was active in HPV-negative, advanced PSCC. Among multiple altered pathways, we were able to delineate the possible molecular profile of responders. An expansion cohort to confirm the translational findings is planned. Clinical trial information: NCT01728233.
Prostate cancer outcomes for African American and caucasian patients undergoing radical prostatectomy.
Authors: Cullen Jennifer , Kuo Huai-Ching , Chen Yongmei , Hurwitz Lauren , Rosner Inger L. , Porter Christopher , Brand Timothy C. , Sterbis Joseph , Stroup Sean , Rebbeck Timothy , D'Amico Anthony Victor , Lu-Yao Grace L. 
Published: March 2017

40 Background: A disproportionate burden of prostate cancer (CaP) incidence and mortality is observed for African American (AA) versus Caucasian (CA) patients in the US. Potential underlying reasons for racial disparity include biology, comorbidity profiles, access to health care, adherence to follow-up care and/or treatment aggressiveness. This study examined CaP progression and overall survival (OS) among AA and CA patients undergoing radical prostatectomy (RP). Methods: This retrospective cohort study examined men enrolled in the Center for Prostate Disease Research (CPDR) Multi-Center National Database between January 1, 1990 and December 31, 2014. Patients with biopsy-detected CaP without metastasis and treated with RP within 12 months of CaP diagnosis were eligible. Biochemical recurrence (BCR) was defined as a PSA value of > = 0.4 ng/mL followed by a subsequent increase. PSADT was categorized as < 3, 3-8.99, 9-14.99, and > = 15 months. Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis were used to examine BCR and OS. Results: A total of 6,785 patients were eligible; 21.5% self-reported as AA and 78.5% self-reported as CA. Median follow-up time was 6.1 years. Comparable distributions of pathologic features at RP and adjuvant treatment over time were observed across race but several comorbid conditions were more common in AA patients including cardiovascular disease, hypertension, diabetes, and other cancer types. In race-specific unadjusted Kaplan Meier analyses, PSADT was an important predictor of BCR and OS for both AA and CA patients (Log rank p < 0.0001 for all KM models). In multivariable analysis, a greater odds of BCR over time was observed for AA versus CA patients (HR = 1.28, CI = 1.11, 1.48, p = 0.0009) after adjustment for D’Amico risk stratum, comorbidity, pathological features, and PSADT. PSADT was a critical predictor of BCR, with worst outcomes at extreme comparison of PSADT categories: HR < 3 vs. > = 15 months= 41.5, CI = 33.6, 51.3, p < 0.0001). Conclusions: In a large racially diverse, longitudinal cohort with equal health care access, there was a striking relationship between PSADT and time to BCR for each racial group and poorer outcomes for AA versus CA patients.