bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of HER2 mutant bladder urothelial carcinomas reveals unique mutational signature.
Authors: Juckett Luke , Madison Russell , Chung Jon , Schrock Alexa Betzig , Alexander Brian , Miller Vincent A. , Ali Siraj Mahamed , Ross Jeffrey S. 
Published: March 2019

460 Background: Early work has described the presence of HER2 alterations in metastatic urothelial carcinomas (UC), particularly the micropapillary urothelial carcinoma (MPUC) subtype. We reviewed the genomic profiles of a large set of UC cases to further characterize HER2 altered UCs and how such alterations would suggest benefit from the expanding array of anit-HER2 therapeutics. Methods: Tissue from 2,150 UCs were assayed using hybrid capture-based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly arranged in cancer. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Results: Within the UC dataset 74.6% of cases were male (1603/2150), with a median TMB of 7 mut/Mb. 383 genomic alterations (GA) of HER2 were identified in 15.5% (334/2150) of cases which exhibited a median TMB of 8.7 mut/Mb (p < 1E-5) vs patients with wildtype HER2, median TMB of 7 mut/Mb. The most frequent HER2 alterations were amplification HER2amp (45.7%, 175/383), S310F (19.8%, 76/383), and S310Y (7/6%, 29/383). Patients harbouring a HER2amp, S310 (n = 105) exhibited a median TMB of 8.7 and 12.2 mut/Mb, respectively. 42 patients presented with multiple ( > 1) HER2 GA and exhibited a median TMB of 11.3 mut/Mb (p < 0.1) vs patients with single HER2 GA, median TMB of 12.3 mut/Mb. Of patients with multiple HER2 alterations, 57% (24/42) harbored a HER2amp. The most common co-occuring HER2 alteration pair was an amplification and extracellular S310X alteration (38.1%, 16/42). Of these 16, the median TMB was 19.5 mut/Mb (average 22.7 mut/Mb). Morphological assessments were performed on the 24 cases harbouring a HER2amp and an additional HER2 GA. 8 cases displayed MPUC features 44.4% (8/18; 6 cases histology unavailable); of these MPUC cases, 75% (6/8), harboured a HER2 amp and S310 extracellular mutation. Conclusions: CGP of bladder urothelial (transitional cell) carcinomas reveals subclasses of HER2 altered cases. Drawing on recent advances in targeting HER2 alterations in breast cancer, dual HER2 blockade (e.g. combinations of mAB/TKI/mAB+ADC) may be needed for HER2amp cases. For cases with both HER2amp and S310 GA, neratinib monotherapy may be the agent of choice and thus may be effective in MPUC.
Small cell bladder carcinoma: Single institution experience.
Authors: Wheelden Megan , Kaag Matthew , Zhu Junjia , Holder Sheldon L. , Drabick Joseph J. , Raman Jay D. , Tuanquin Leonard , Merrill Suzanne , Warrick Joshua , Joshi Monika 
Published: March 2019

468 Background: Small cell bladder carcinoma (SCBC) is an uncommon neuroendocrine tumor with poor prognosis. Treatment has largely been derived from data for small cell lung carcinoma and typically includes a multimodality approach with chemotherapy (chemo) serving as the backbone along with radical cystectomy (RC), and radiation (RT). Prior studies have demonstrated conflicting results regarding survival benefit. Methods: We performed a retrospective chart review of patients with SCBC between 2003 and 2017. We compared baseline patient characteristics and patient outcomes. OS was measured from time of initial diagnosis to death or last follow-up. Subgroup analyses were performed between patients treated with chemoRT vs. chemoRC using Fisher’s exact test for categorical variables, and nonparametric Wilcoxon Rank-Sum test for quantitative variables. Kaplan-Meier analyses were done on OS and RFS. All tests were two-sided and statistical significance level of 0.05 was used. Results: We identified a total of 31 patients with SCBC; 28 were non-metastatic and 3 were metastatic. Of the non-metastatic, 14 received chemoRT and 4 received chemoRC. The median age was 70; M:F ratio was 17:1. The median RFS in chemoRT patients was 3.05 yrs, and in chemoRC, RFS was not reached (p = 0.18). The median OS in chemoRT and chemoRC were 10.1 and 10.7 yrs respectively (p = 0.38). The overall median OS for SCBC was 2.45 yrs. Conclusions: There were no statistically significant differences in regards to median RFS or OS between the chemoRT and chemoRC patients, but this analysis was limited by the small sample size. However, the median OS in non-metastatic SCBC patients who received treatment with curative intent (chemoRT or chemoRC) was noticeably longer than that of all SCBC patients. This median OS is also longer than anticipated with small cell lung cancer and suggests that SCBC has a different natural history. These findings warrant further investigation.
A comprehensive assessment of postoperative complications in female patients undergoing robot versus open radical cystectomy.
Authors: Narayan Vikram M , Seif Mohamed , Lim Amy , Li Roger , Qiao Wei , Hwang Hyunsoo , Dinney Colin P.N. , Navai Neema 
Published: March 2019

490 Background: Radical cystectomy (RC) is the standard of care for non-metastatic, muscle invasive bladder cancer. Studies comparing robotic to open RC have found that the robotic approach confers non-inferior oncologic outcomes while potentially decreasing morbidity, but to date there have been no comparisons performed exclusively within female patients, who have unique anatomic considerations. Women undergoing RC may be at higher risk for urethral margin positivity, wound complications, and bleeding. Methods: Female patients who underwent either open or robot-assisted RC at the MD Anderson Cancer Center from 1/2014-6/2018 were identified. We assessed co-morbidities, pathologic data, and outcomes including complications. Descriptive statistics, along with uni- and multivariable logistic regression, were performed. Results: 122 female patients underwent either open (n=76) or robotic (n=46) RC. There were no statistically significant differences in age, BMI, smoking history, exposure to neoadjuvant chemotherapy, Charlson comorbidity index, or cTNM stages between the groups. In both uni- and multivariable models, open RC in females was associated with greater blood loss (median EBL 775 mL, IQR 600 mL) compared with robotic RC (median EBL 300 mL, IQR 350 mL), p<0.001. Female open RC was also associated with greater risk of transfusion compared to robotic RC (OR 6.2, 95% CI 2.7-14.3, p<0.001). Robotic RC conferred a higher median lymph node yield (27 nodes (range 7,57) vs 20 nodes (0,57), p, <0.001). Operative times were longer in the robotic cohort (median 507 min vs 388 min, p<0.001). There were no differences between robotic vs open groups in margin positivity (5.3% vs 4.4%, p≥0.99), length of stay (6.3 vs 6.9 days, p=0.32), or readmission rates at 30 (26.1% vs 22.7%, p=0.67) and 90 days (32.6% vs 28%, p=0.68). Conclusions: In this cohort of women undergoing RC, the robotic approach was associated with a lower risk of transfusion and EBL, and a higher median lymph node yield and operative time. Unique anatomic considerations in female patients and the improved visualization conferred by the robotic approach may be responsible for these findings, particularly with respect to blood loss.
Clinical features and outcomes of secondary somatic malignancy (SSM) arising from teratoma in late relapse germ cell tumor (GCT).
Authors: Wong Nathan Colin , Dason Shawn , Dean Lucas W. , Isharwal Sumit , Donoghue Mark , Jia Liwei , Joseph Gabriella , Tap William D. , Funt Samuel Aaron , McHugh Deaglan Joseph , Al-Ahmadie Hikmat , Reuter Victor E. , Bajorin Dean F. , Motzer Robert J. , Bosl George J. , Sheinfeld Joel , Solit David B. , Feldman Darren R. 
Published: March 2019

518 Background: Late relapse (>2 years) GCT is associated with an increased rate of SSM. We report our experience with SSM in the setting of late relapse and determine predictors of overall survival (OS). Methods: From 1985 to 2018, 46 patients with GCT and SSM at late relapse were identified. Clinical and pathologic parameters were reviewed. The Kaplan-Meier method was used to estimate OS from time of relapse and a Cox proportional hazards model to assess predictors of OS. Results: Of 46 men (44 testicular primary, 2 mediastinal primary), median time to late relapse with SSM was 10.4 years (range, 2.3 - 38.1). Most (n=27, 59%) were symptomatic at presentation but 11 were detected by elevated tumor markers (AFP 8, HCG 2, both 1) and 8 by surveillance imaging. SSMs were adenocarcinoma (25), sarcoma (14), poorly differentiated neoplasm (3), Wilms (2), PNET (1) and glioma (1). Median time to relapse was longer for adenocarcinoma vs other histotypes of SSM (14.6 vs 4.1 years, p < 0.001). The initial site of relapse was the retroperitoneum (RP, 26), pelvis (7), lung (6), retrocrural space (3), mediastinum (2), neck (1) and duodenum (1). Only 10 of 26 men with late relapse in the RP had undergone prior RPLND (all at outside institutions; variable templates) with histology in 7/10 showing teratoma. The other 16 men had received chemotherapy only (8), orchiectomy only for stage I (3), RPLND aborted due to cardiac arrest (1), and unknown (4). All 46 late relapses were managed with surgical resection; 26 also received chemotherapy (16 SSM-directed, 10 GCT-directed). Overall, 12 patients died and the median OS was 14.2 years. On univariable analysis, symptomatic presentation (HR = 3.1), SSM at multiple sites (HR = 3.9), extra-RP disease (HR: 3.9), and incomplete/no resection of SSM (HR = 3.6) predicted mortality. On multivariable analysis, only extra-RP disease was independently associated with inferior OS (5-year OS, 82 vs 52%, p = 0.017). Conclusions: SSM is an important potential complication of late relapse GCT and seems to be associated with the lack of resection of retroperitoneal metastases. Early identification and complete surgical resection prior to SSM arising in extra-RP sites is critical to optimizing outcomes.
Early predicting factor for biochemical failure for patients with intermediate and high-risk prostate cancer treated by definitive radiotherapy.
Authors: Kang Hye Jin , Kay Chul Seung , Yu MI NA 
Published: March 2019

52 Background: The prostate-specific antigen nadir (nPSA), a strong prognostic factor for prostate cancer, does not occur until several years after definitive radiotherapy. Our aim was to assess an early predictive factor for biochemical failure (BCF) in patients with intermediate- and high-risk prostate cancer treated with definitive radiotherapy. Methods: Between 2007 and 2017, 97 patients with localized prostate cancer underwent radiotherapy at two institutions. We used a pelvic lymph node involvement risk of 15% as the cutoff value, calculated using the Roach formula, to decide whether to deliver prostate and seminal vesicle only radiotherapy (PORT) or whole-pelvis radiotherapy (WPRT). Twenty-seven patients (27.8%) underwent PORT with the prostate receiving 45 Gy (4.5 Gy per fraction) and the other 70 patients (72.2%) underwent WPRT with the prostate receiving 72 Gy (2.4 Gy per fraction). The median equivalent dose in 2 Gy fractions to the prostate was 80.3 Gy based on the assumption that the α/β ratio is 1.5 Gy. Sixty-two patients (63.9%) were treated with androgen deprivation therapy (ADT). Results: The median follow-up time was 40 (range, 10 to 133) months. The 4-year BCF-free survival (BCFS) rate was 87.0%. In the univariate analysis, the nPSA, the nPSA within 12 months (nPSA12), and ADT use were significant predictive factors for BCF. nPSA ( p = 0.003) and ADT use ( p = 0.041), but not nPSA12 ( p = 0.485), were independent predictive factors for BCF in the multivariate analysis. However, there was a strong correlation between nPSA and nPSA12 in this study ( r = 0.854, p < 0.001). The receiver operating characteristic curve identified 0.47 ng/ml as the optimal cutoff value of nPSA12 for predicting BCF. The 4-year BCFS rate in patients with nPSA12 < 0.47 ng/ml was 100% in contrast to 71.3% in patients with nPSA12 ≥ 0.47 ng/ml. Conclusions: The nPSA12 has a strong correlation with nPSA and is a considerable predictor of BCF. Therefore, the treatment outcome can be predicted early using nPSA12. Furthermore, ADT can significantly reduce BCF in patients with intermediate- and high-risk prostate cancer.
Excellent outcomes in bilateral testicular germ cell tumors over four decades.
Authors: Lu Ning-Ning , Hansen Aaron Richard , Bedard Philippe L. , Warde Padraig Richard , Sweet Joan , Hamilton Robert James , O'Malley Martin , Chung Peter W. M. 
Published: March 2019

523 Background: Bilateral testicular germ cell tumours (BTC) form a small minority of testicular cancer and detailed management data are sparse. Methods: Bilateral testicular cancer (BTC) patients managed at a single cancer centre were retrospectively analyzed. Synchronous BTC was defined as uni+contralateral presentation within 3 months. Patient characteristics, treatment and outcomes were collected. Kaplan-Meier method was used to calculate the overall survival (OS) and relapse-free survival (RFS). Results: Between Jan 1971 to Jun 2018, 118 pts were included. Nine patients (7.6%) had cryptorchidism. Twenty-two patients (18.6%) had synchronous BTC at median age of 30(21-54) years, 11 presented with concordant histology (10-seminoma). Median follow-up time was 96(1-220) months. Two of 14 patients (14%) with stage I disease on surveillance had retroperitoneal nodal recurrence, other 3 (21%) had testicular recurrence after partial orchiectomy alone. No recurrence occurred for 8 stage II/III patients (36%) who received stage-appropriate treatment. All patients were alive without disease at last follow-up. For metachronous BTC, the median age was 27(16-68) and 37(19-78) years for first and second diagnosis, respectively. The median time interval was 88 (8-352) months, with shorter interval when second primary was non-seminoma, median 69 vs. 92 months. Concordant histology was present in 58 (38-seminoma) patients and discordant in 38 patients. There were 66, 23, 7 and 84, 9, 3 patients with stage I, II, III disease for first and second testicular cancer (TC), respectively. For all stage I disease, 69% of non-seminoma (n = 33) and 79% of seminoma (n = 81) were on surveillance, of whom the crude relapse rate was 15%. The median follow-up time after second diagnosis was 87 months. In all, 35 patients (30%) with recurrence except 1 were successfully salvaged. The 10-year OS and RFS for whole cohort was 99% and 69.8%, respectively. Conclusions: In our series, seminoma was the more common pathology, and management based on pathology and stage yielded excellent outcomes regardless of prior therapy. Metachronous BTC may occur at extremely long time intervals such that longer follow-up is needed to capture the majority of contralateral primary TC.
Seminomatous germ cell tumors are heterogenic and metastasis can be predicted based on a gene signature of the tumor invasive front.
Authors: Nestler Tim , Haidl Friederike , Wittersheim Maike , Dalvi Priya , Paffenholz Pia , Wagener-Ryczek Svenja , Pfister David J. K. P. , Hellmich Martin , Büttner Reinhard , Odenthal Margarete , Heidenreich Axel 
Published: March 2019

528 Background: Up to 40% of pure seminomatous germ cell tumors (GCTs) are clinically metastasized at initial diagnosis. Additionally, up to 20% of patients have occult metastasis but are not diagnosed due to missing markers. We hypothesize that pure seminomatous GCTs differ from metastasized to non-metastasized patients, possibly owing to differences in tumor heterogeneity. Since in few other tumor types genes linked to metastasis are shown to be more often upregulated at the tumor front, we investigated different regions of seminomas in non-metastasized and metastasized patients. Methods: Seminoma patient samples without metastasis, with no adjuvant therapy, and with recurrence-free follow-up of at least two years (n = 21), and patients showing metastasis (n = 14) were selected for the study. Based on formalin-fixed paraffin embedded tissues, the tumor front (TF) and tumor center (TC) regions of each patient were determined and separately collected using laser capture microdissection. RNA was extracted and a multiplex gene expression analysis was performed on all TF and TC samples using nCounter technology of Nanostring. A panel of 770 transcripts was analyzed using the PanCancer Progression panel. Different bioinformatics tools were employed for analyzing the expression data. Results: Hierarchical cluster analysis showed no differential gene clustering between metastasized and non-metastasized patients. Comparing TF and TC in the metastasized group more genes (29 genes) were significantly differentially expressed (log2 fold change > 1.5, FDR < 0.05) compared to cSI patients (12 genes). Pairwise comparison of TF and TC for each individual patient showed differential expression of genes in these two regions. Lasso regression analysis of TC could not reveal any signature to predict metastasis. However, with respect to the TF a signature of only six genes was sufficient to predict metastasis with a specificity of 100%, and a sensitivity of 92.9%. Conclusions: This study describes tumor heterogeneity in seminomas and identifies a gene signature that could predict metastasis and has to be validated on occult metastasized seminomatous patients.
Genomic analysis and clinical outcomes of Primary Gleason Pattern 5 (PG5) prostate cancer (PCa) treated with radical prostatectomy (RP).
Authors: Isaacsson Velho Pedro , Lotan Tamara L. , Markowski Mark Christopher , Antonarakis Emmanuel S. , Carducci Michael Anthony , Denmeade Samuel R. , Wang Hao , Lim David , Pritchard Colin , Eisenberger Mario A. 
Published: March 2019

54 Background: PG5 (5+5 and 5+4) PCa is historically associated with poor clinical outcomes such as progression to metastatic disease, poor response to androgen deprivation therapy (ADT) and short survival. To characterize the clinical features and biology of this aggressive type of PCa, we studied patients with PG5 who underwent a RP. Methods: Patients with surgical PG5 who underwent RP for localized PCa at Johns Hopkins Hospital were retrospectively studied. Pathological staging, tumor genomic data by Next Generation Sequencing (NGS), and PTEN and TP53 by IHC were correlated with clinical outcomes, such as biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Fisher’s test and Kaplan-Meier were used for statistical analysis. Results: 60 pts, 90% pT3-4, 26% pN1, 46% R+, 90% seminal vesicle invasion (SVI) had a median follow up of 9 years. Overall median survival estimates: BCR: 17.4 months (m), MFS:86.4m and OS:111m. 26 patients developed metastasis (bone 77%, visceral 31%) with a median time to metastasis of 21.8m and TCR of 12m. On multivariate analysis, ductal/intraductal histology (HR 4.5, p<0.01) and SVI (HR 4.4, p<0.01) were associated with poor prognosis. Of 49 pts with NGS, 22% had Homologous recombination (HR) and 12% mismatch repair (MMR) alterations. In addition, 32% had TP53 mutation and 51% PTEN loss. Genomic event frequencies and outcomes are in Table. Conclusions: Patients with PG5 have adverse pathological features, short BCR, MFS and resistance to ADT, but outcomes are variable, suggesting heterogeneity. TP53 mutations and PTEN loss are associated with poor outcomes in univariate analysis, while ductal/intraductal and SVI are associated with poor outcomes in multivariate analysis. Although genomic data were not independently associated with outcomes, the high incidence of HR and MMR alterations provides the rationale for the design of adjuvant clinical trials. [Table: see text]
Inflammatory bowel disease and risk of prostate cancer: A matched-cohort analysis.
Authors: Weiner Adam , Burns Jacob A , Catalona William J , Li Eric , Schaeffer Edward M. , Hanauer Stephen , Strong Scott , Burns James , Hussain Maha H. A. , Kundu Shilajit 
Published: March 2019

55 Background: There are few data on the risk of prostate cancer (PCa) in men with inflammatory bowel disease (IBD) and there are no data comparing serum prostate-specific antigen (PSA) values between men with IBD and matched men without IBD. Methods: This study retrospectively matched men with IBD based on race and age 1 to 9 to men without IBD (controls) who underwent PCa screening with at least one PSA at a single academic medical center from 1996 to 2017. Kaplan-Meier and multivariable Cox analyses were used to compare the risk of any and clinically significant PCa (Gleason grade group > 1) between the two groups adjusting for number of PSA tests, abnormal rectal exam, age, and race. A mix-effects regression was used to assess the association between PSA and IBD status. Results: After a median follow-up of 6.5 years for 1,033 men with IBD and 4.7 years for 9,306 controls, the median number of PSA tests was 2, 74% were white, and median age at first PSA (starting point of follow-up) was 53 years. At 10 years of follow-up, the incidence of any PCa was 0.65% for controls and 4.4% for men with IBD (HR 4.37, 95% CI 3.08-6.19, p < 0.001) and of clinically significant PCa was 0.42% for controls and 2.4% for men with IBD (HR 3.78, 95% CI 2.40-5.96, p < 0.001). When only men with IBD were assessed, use of biologic medications, duration of IBD diagnosis, history of bowel resection, Crohn’s disease versus ulcerative colitis were not associated with PCa diagnoses (all p > 0.1). Any steroid treatment for IBD was associated with decreased incidence of any PCa (HR 0.22, 95% CI 0.06-0.78, p = 0.019), but not with clinically significant PCa (p = 0.5). PSA values were higher among men with IBD starting at age 60 (1.12 ng/mL vs 1.04 ng/mL, p = 0.031) and this gap widened with increasing age (age 70: 1.54 ng/mL vs 1.32 ng/mL, p = 0.007). Conclusions: Men with IBD being screened for PCa had an increased incidence of all and clinically significant PCa compared to age- and race-matched controls and had increased PSA values at older age. These findings should be further validated to consider IBD as a risk factor for PCa and optimize screening for this population.