bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations of DNA damage response (DDR) genes correlate with favorable response and overall survival (OS) in anti-PD-1/PD-L1-treated advanced urothelial cancer (UC).
Authors: Joshi Monika , Grivas Petros , Mortazavi Amir , Monk Paul , Clinton Steven K. , Woo Michele Sue-Ann , Holder Sheldon L. , Drabick Joseph J. , Yin Ming
Published: March 2019

438

Background: DDR gene alterations may contribute to higher tumor mutational burden (TMB) via genomic instability in addition to APOBEC mutagenesis. We previously showed that ATM mutations correlated with shorter OS in UC, while Teo et al. showed patients (pts) with DDR alterations benefited from PD-1/PD-L1 blockade in advanced UC. Here, we aimed to validate those findings and further explore the prognostic role of ATM mutations in advanced UC treated with anti-PD-1/PD-L1 agents. Methods: The study included 53 pts who had FoundationOne tumor tissue genomic sequencing and anti-PD-1/PD-L1 therapy. Fisher exact test was used to test difference in objective response rate (ORR). OS was measured from time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: The cohort had a median age of 66 (range 21–81) with 34% females and 64.2% platinum-based chemotherapy. DDR alterations (including ATM) were present in 49.1% pts (26/53) and favored a higher ORR (37.5% vs. 23.1%, p = 0.26). Compared with those without DDR alterations, pts with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached likely due to a short follow-up time (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations seemed to favor higher response rate to PD-1/PD-L1 blockade (ORR, 40% vs. 28.9%, p = 0.6), but was associated with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006) in overall pts and in subgroups with/without platinum-based chemotherapy (data not shown). Pts with ≥ 3 DDR alterations (including ATM) had substantial higher TMB (13.9–72.2 perMb, median 22.6) and benefited the most from PD-1/PD-L1 blockade with 80% ORR vs. 24.4% ORR in pts with < 3 DDR alterations. Conclusions: Our study supported that DDR alterations are associated with higher response rate and prolonged OS in advanced UC pts receiving anti-PD-1/PD-L1 agents, likely from impact on TMB. However, ATM alterations correlated with poor prognosis also in those pts. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.
A comparison of pathologic and intermediate term oncologic outcomes following open and robotic radical cystectomy.
Authors: Kukreja Janet Baack , Li Roger , Seif Mohamed , Wang Xuemei , Kamat Ashish M. , Dinney Colin P.N. , Pisters Louis L. , Navai Neema
Published: March 2019

440

Background: Conflicting data regarding the oncologic efficacy of robotic surgery has led to concerns for possible inferiority. Despite recent prospective results from the RAZOR trial demonstrating non-inferior progression free survival, results from another prospective randomized trial from Memorial Sloan Kettering suggests a possible difference in the pattern of recurrences. We examined our experience with both open (ORC) and robotic radical cystectomy (RRC) with the objective of establishing recurrence patterns and pathologic comparisons at a high volume tertiary referral center. Methods: We performed a retrospective cohort study at a high volume academic tertiary referral center for patients who underwent radical cystectomy (RC) for bladder cancer from 2005 to 2017. The surgical choice of RRC or ORC is based on provider preference. A multivariable analysis was carried out to determine factors predictive of recurrence free survival (RFS) and overall survival after RC. Analysis was done with SAS 9.4. Results: 1813 patients were identified, 10% underwent RRC and no difference in recurrence patterns were found compared to ORC. There was no difference in the severity of pathology distribution between the two cohorts. There was no difference in positive surgical margin status, 2.4% in ORC and 1.1% in RRC. Peritoneal carcinomatosis was seen in 1.1% of ORC and 0.5% in RRC. Shorter RFS was associated with younger age (HR 1.04, 95%CI 1.03-1.05, p<0.001), neoadjuvant chemotherapy (HR1.55 95%CI 1.32-1.82, p<0.001), higher pathologic stage (stage T4 HR 4.38, 95%CI 3.17-6.06, p<0.001), positive lymph nodes at RC (HR 1.82 95%CI 1.53-2.17, p<0.001) and positive surgical margins (HR 1.50 95%CI 1.19-1.89, p<0.001). At a median follow up of 60 months neither progression free or overall survival for ORC compared to RRC was significantly different. Conclusions: The data from this study supports continued use of RRC as a safe oncologic procedure with similar outcomes to ORC.
The timing from perioperative chemotherapy and disease recurrence could have clinical impact on survival in bladder cancer patients treated with salvage chemotherapy.
Authors: Kikuchi Eiji , Hayakawa Nozomi , Ogihara Koichirou , Omura Minami , Mizuno Ryuichi , Oya Mototsugu
Published: March 2019

444

Background: Our aim was to clarify whether the duration between perioperative chemotherapy and disease recurrence could affect therapeutic efficacy of salvage chemotherapy in bladder cancer patients treated with radical cystectomy. Methods: We retrospectively identified 201 patients treated with radical cystectomy and perioperative chemotherapy of neoadjuvant chemotherapy (NAC) and/or adjuvant chemotherapy (AC) for bladder cancer at our 7 institutions between 2003 and 2015. Of them 56 patients received salvage chemotherapy for disease recurrence and were included in the present analysis. We classified these patients according to the time from perioperative chemotherapy received to disease recurrence ( < 12 months, 12-24 months, and 24 < months) and compared their clinical characteristics and survival outcomes. Results: Overall, 33, 14, and 9 patients developed disease recurrence in < 12 months, 12-24 months, and < 24 months, respectively after perioperative chemotherapy. Patients in the 12-24 months group had a higher smoking rate compared to those in the other two groups, and were higher rate of female in comparison to the < 24 months group. Twenty-four (42.8%) patients received NAC alone, 23 (41.1%) received AC alone, and 9 (16.1%) received both NAC and AC. Twenty-two (66.7%), 9 (64%), and 4 (44.4%) patients received NAC in the < 12 months group, the 12-24 months group, and the < 24 months group, respectively. Furthermore, 19 (57.6%), 7 (50%), and 6 (66.7%) patients received AC in the < 12 months group, the 12-24 months group, and the < 24 months group, respectively. The 5 year overall survival in the < 12 months group was 26.6%, which was significantly lower than those in the 12-24 months group (51.1%, p < 0.001) and in the 24 months group (46.9%, p = 0.014). Multivariate Cox regression analysis revealed that disease recurrence after perioperative chemotherapy within 12 months was the only independent prognostic indicator for overall death (p = 0.032). Conclusions: Bladder cancer patients with disease recurrence within 12 months from their perioperative chemotherapy have a worse overall survival after salvage chemotherapy.
Relationships between anticancer effects and serum gemcitabine levels, human antigen-R expression, and their combination in advanced urothelial cancer treated with gemcitabine and platinum agents.
Authors: Sagara Yuji , Miyata Yasuyoshi , Yuno Tsutomu , Araki Kyohei , Nakamura Yuichiro , Matsuo Tomohiro , Ohba Kojiro , Sakai Hideki
Published: March 2019

445

Background: Combination therapy of gemcitabine (GEM) and platinum agents and immune-checkpoint inhibitors are standard regimens for advanced urothelial carcinoma (UC), and optimum selection is important to improve the prognosis. Human antigen R (HuR) increases the protein expression of the enzyme deoxycytidine kinase, which is involved in metabolizing the prodrug GEM into its active metabolites. HuR expression is a predictor for the response to gemcitabine-based chemotherapy in a variety of cancers. This study evaluated the relationship between combination pattern of serum GEM level and HuR expression in cancer cells and anti-cancer effects of GEM-based regimens in patients advanced UC. Methods: Twenty-seven advanced UC patients (bladder = 8 and upper urinary tract = 19) were treated with a combination of GEM and platinum agents (cisplatin = 15 and carboplatin = 12) as first-line chemotherapy in Nagasaki University Hospital. Serum samples were collected 30 min after GEM injection. HuR expression was examined by immunohistochemical methods. Results: Positive expression of HuR was detected in 17 (63.0%) patients, and the mean/SD of serum GEM level was 14.9/5.1 μg/mL. C-HuR expression was not associated with anti-cancer effect (P = 0.066). Serum GEM level in the progressive disease (PD) group (10.4/4.7 μg/mL) was lower than that in groups with CR + PR (16.2/3.7) or SD (16.3/6.1); however, these differences were not significant. For the anti-cancer effect of the combination of serum GEM level and HuR expression, all 3 patients with low GEM levels (under median) and negative HuR expression showed PD. In contrast, among 7 patients with high GEM levels and positive C-HuR expression, no patients showed PD, and relationship between their combination pattern and anti-cancer effect was significant (P = 0.010). Conclusions: Serum GEM level or HuR expression was not associated with anti-cancer effects; however, their combination pattern was significantly associated. Although we examined a small number of patients, our results are useful for determining treatment strategies in patients with advanced UC.
Genomic profiling of variant urinary tract tumor histologies.
Authors: Nassar Amin , Mouw Kent William , Curran Catherine , Agarwal Archana , Acosta Andres , Preston Mark A. , Mossanen Matthew , Ravi Arvind , Hirsch Michelle S. , Choueiri Toni K. , Kwiatkowski David J. , Sonpavde Guru
Published: March 2019

450

Background: Little is known about the genomic features of rare histologic variants of urinary tract (UT) tumors. The purpose of this study is to compare the pattern of genetic alterations in UT tumors with adenocarcinoma (AD), small cell (SC), or squamous cell (SQ) histology to UT tumors with urothelial carcinoma (UC) histology. Methods: We identified patients with pure variant (AD, SC, or SQ) or UC histology evaluated at Dana Farber Cancer Institute (DFCI). Tumors with mixed histology were excluded. We employed Oncopanel, which assesses 275-447 cancer genes for somatic mutations and copy number variations (CNVs). Alterations observed at an allele frequency > 0.1% in the ExAC database were assumed to be germline variants and were excluded. Mutation frequencies, CNVs, and tumor mutation burden (TMB) were determined for AD, SC, SQ, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis Test. Nominal p values were obtained, and fdr correction was employed (q < 0.1). Results: Genetic data was available for 11 AD, 6 SC, 9 SQ, and 120 UC tumors. All patients had muscle-invasive disease. The mean age was 67.8 years and 74% of patients were male. Overall, UC had significantly higher TMB than AD (median = 9.5 vs median = 6 respectively, p = 0.03). There were no significant differences in the CNV count among the four subtypes. Statistically significant differences in genetic alterations by subtype are shown in the Table. ARID1A and KDM6A mutations were less common in the variant histologies; while DICER1, FBXW7, MAP2K4, and MYB alterations were higher in ≥1 variant histology. RB1 and TP53 mutations were enriched in SC tumors while SMAD4 alterations were enriched in AD tumors. Conclusions: Genetic features of variant histology UT tumors differ from those seen in UC, suggesting biological differences and possibly different therapies. Validation in larger datasets is warranted. [Table: see text]
Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC).
Authors: Gupta Shilpa , Sonpavde Guru , Grivas Petros , Apolo Andrea B. , Plimack Elizabeth R. , Flaig Thomas W. , Hahn Noah M. , Balar Arjun Vasant , Bajorin Dean F. , Galsky Matt D. , Rosenberg Jonathan E. ,   Platinum-Ineligibility in Bladder Cancer Working Group
Published: March 2019

451

Background: Patients (pts) with mUC who are ineligible to receive cisplatin have limited treatment options. Pembrolizumab and atezolizumab were approved as 1st-line therapy in these pts, but their use is now restricted in pts with tumors with high PD-L1 expression, or platinum-ineligible. “Platinum-ineligible” mUC (cisplatin and carboplatin ineligible), remains undefined, and a clear definition is needed for determining treatment and clinical trial eligibility. Methods: We surveyed 56 genitourinary medical oncologists in the US using an online tool consisting of several clinical parameters (Round 1) and based on the responses, we refined the survey (Round 2) and then compiled the responses to generate a consensus definition. Results: Responses were received from 43/56 (77%) of those surveyed in Round 1 and 44/56 (78.5%) in Round 2. Based on the results shown in the Table, we recommend 1 of the following 5 parameters be used to define "platinum-ineligible” mUC: ECOG PS > 3; Cr Cl < 30 ml/min; Peripheral neuropathy > 3; NYHA Heart Failure Class > 3; ECOG PS 2 and Cr Cl < 30 ml/min. Conclusions: “Platinum-ineligible” mUC is a new and undefined category with a substantial definition variability among investigators. Results from consensus definition are proposed for standardization of this mUC category. [Table: see text]
Circulating cell-free methylated DNA (cfmeDNA) to predict postoperative recurrence in patients with muscle-invasive bladder cancer (MIBC).
Authors: Nuzzo Pier Vitale , Spisak Sandor , Solymosi Norbert , Chakravarthy Ankur , Shen Shu Yi , Pomerantz Mark , Boccardo Francesco , Nassar Amin , Lee Gwo-Shu Mary , Sonpavde Guru , Choueiri Toni K. , De Carvalho Daniel , Freedman Matthew L
Published: March 2019

454

Background: CfmeDNA is a promising non-invasive biomarker to assess solid tumor burden: i) CpG island methylation changes in cfDNA are stable ii) methylation is tissue- and tumor- specific iii) methylation target size is larger and more sensitively detected than genomic alterations. CfmeDNA Immunoprecipitation and high throughput sequencing (cfMeDIP-seq) is an innovative assay for genome-wide bisulfite-free plasma DNA methylation profiling, that permits CpG enrichment. We tested the feasibility of cfmeDNA to predict recurrence of MIBC post- radical cystectomy (RC). Methods: We selected 12 pts who underwent RC for MIBC: 6 pts who had recurrent disease within 2-3yrs after RC (A) and 6 pts who did not (B). 119 healthy pts without BC were controls. cfDNA isolated from 1ml of plasma samples collected after RC and before recurrence (A) or during follow-up in those who did not recur (B) was analyzed by the cfMeDIP-seq using 10ng cfDNA. The data were analyzed using the MEDIPS program and differentially methylated regions (DMR) between the cohorts were studied. ENCODE ChIP-seq analytical pipeline was used for fastq file processing and peak calling. Results: The average cfDNA isolated from 1ml of plasma was 13.1 ng (6.4-19.7) in A and 17.1 ng (13.6-21.2) in B. The median time from RC to plasma collection were respectively 9.3 mos (3.4-91.3) vs 12.3 mos (2.9-150). Median time from plasma collection to recurrence was 21.9 mos (0.25-141.3). We identified ~137,000 peaks in ≥1 sample. The supervised classification identified 61 DMR (FDR<0.050), predominantly located in intergenic region, which distinguished A from B. Randomized sample tests proved the discriminatory power of the identified set. Supervised analysis comparing the status of the identified DMRs relative to healthy controls showed 28 regions were differentially methylated (logFC > +/- 1, FDR < 0.05). The study is limited by retrospective design and sample size. Conclusions: This is the first study to demonstrate that cfmeDNA can be readily harvested from MIBC pts to detect cancer-specific methylation patterns and predict recurrence post-RC. Prospective validation will enable the selection of suitable pts for adjuvant therapy.
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

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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

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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.
A multibiomarker approach to predict prostate cancer pathology outcomes.
Authors: Paris Pamela , Cooperberg Matthew R. , Cowan Janet , Lindquist Karla , Kobayashi Yasuko , Simko Jeff , Bengtsson Henrik , Singh Khushboo L , Newcomb Lisa F. , Lin Daniel W. , Carroll Peter
Published: March 2019

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Background: Distinguishing indolent from aggressive prostate cancer remains a key challenge for prostate cancer management decision-making. A growing number of biomarkers are now on the market to help address this need, but have rarely been examined together in the same patients to determine their relative value. Methods: We identified men with low-risk cancers defined by biopsy Gleason score ≤3+3, PSA ≤10ng/ml, and clinical stage ≤T2 who underwent immediate prostatectomy. We collected archived prostate tissue and pre-surgical plasma samples from N = 381 cases from UCSF and N = 279 cases from UW. Plasma was analyzed for TGFb1 and IL6SR, previously validated markers for prostate cancer prognosis, using ELISA. From prostate tissue, DNA and RNA were extracted and analyzed for the GEMCaP copy number variation score and the cell cycle progression (CCP) score, respectively, both well-validated and previously reported scores. Pathologic outcomes were minor (pGS 3+4 or pT3a) or major (pGS ≥4+3 or ≥pT3b) upgrading/upstaging (UGUS), and multinomial regression was performed to determine putative markers’ ability to predict these outcomes, controlling for PSA, percent of biopsy cores positive, age, and clinical site. Results: Overall, 357 men had no UGUS event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFb1 nor IL6SR statistically significantly predicted any UGUS or major UGUS. On the other hand, both CCP and GEMCaP were directly associated with minor UGUS on univariate analysis. On multivariable multinomial analysis including both scores, the CCP score predicted minor UGUS (OR 1.70, 95% CI 1.07-2.72, p = .03) and GEMCaP also predicted minor UGUS (OR 1.04, 95% CI 1.01-1.07, p < .01). Neither CCP nor GEMCaP predicted major UG/US, but the number of events was small. Noteworthy, both GEMCaP and the CCP score were statistically significant predictors of outcomes in the same model, suggesting they can complement each other by offering additional information. The other clinical parameters were not significant in this model. Conclusions: Biomarker signatures based on analysis of DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy.
Hypofractionated dose painting IMRT using 20 fractions for intermediate to high-risk localized prostate cancer: Two-year outcome data (BIOPROP20, NCT02125175).
Authors: Syndikus Isabel , Chan Joachim Kwok-Chiu , Rowntree Thelma , Howard Laura , Staffurth John
Published: March 2019

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Background: Prostate dose painting (boosting intra-prostatic tumour volumes) may improve biochemical relapse-free survival similar to whole organ dose-escalation without the associated increased toxicity. We present a pre-defined secondary endpoint of 2 year outcome for patients at one of two UK centres in a phase II trial (BIOPROP20) on dose-painting radiotherapy for intermediate to high risk patients treated with 60Gy/20# and concurrent 68Gy boost. Methods: Pinnacle software was used for VMAT planning and boost volumes were outlined by18F choline PET/CT and mpMRI. Patients with positive lymph nodes also had concurrent pelvic radiotherapy of 45Gy with boost to 50Gy. Patients were followed up until year 2 with PSA and toxicity scores. Results: Overall 56 patients were treated, 5 with pelvic radiotherapy. Median age and PSA was 67.5 years (range 50 - 77) and 10.0ng/ml (3.9 - 39.4). All patients had tumour volumes > 10mm diameter on pre-biopsy mpMRI. 13 and 43 patients had intermediate and high risk disease. Median % LN risk was 18% (15 - 40). ADT duration was 6 months, 2 years, and 3 years for 42, 5, and 9 patients. At the 2 year follow up review, no grade 3 late toxicity was observed. For prostate only dose painting, grade 2 GU and GI toxicity was noted in 6% and 2% respectively. For prostate and nodal dose painting, no grade 2 toxicity was noted. Median IPSS score was 5 and 9, and median PSA was 0.3 and 0.1, in the two groups respectively. 1 patient had biochemical and metastatic relapse at 18 months (prostate, pelvic nodes and bone metastasis) and 1 patient had died of unrelated disease. Conclusions: Prostate radiotherapy with hypofractionated dose painting schedule of 60Gy/20# with 68Gy boost to intra-prostatic lesions was well tolerated at 2 years follow up. Clinical trial information: NCT02125175. [Table: see text]
Synchronous and metachronous cases of renal cell carcinoma and hematologic malignancies in a state cancer registry.
Authors: Henegan John Clark , Mitchell Katelyn , Maher Joseph
Published: March 2019

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Background: A Swedish national family-cancer database reported an association between renal cell carcinoma (RCC) and hematologic malignancies within families. Our hypothesis was that a search of a state cancer registry would detect an increased incidence of observed (versus expected) synchronous and metachronous cases of RCC and select hematologic malignancies. Methods: A query of the Mississippi Cancer Registry was performed for synchronous ( < 6 months between diagnoses) and metachronous ( > 6 months) cases of RCC and select hematologic malignancies (non-Hodgkin lymphoma (NHL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, and Hodgkin lymphoma) in the state from 2003 to 2013. The expected number of cases was calculated based on crude case numbers available from https://www.cancer-rates.info/ms/. The percentage of the population < 18 years of age was removed from the eligible population. 2x2 tables were constructed to calculate a chi-square score of expected versus observed cases. Using one degree of freedom, a p-value was calculated from this statistic. Due to privacy issues, the registry was unable to provide an exact number of observed combined cases if there were < 5 in the time period. Results: Conclusions: There is a statistically significantly increased incidence of observed (versus expected) synchronous and metachronous cases of RCC with the B-cell malignancies NHL, MM, and CLL in Mississippi between 2003 and 2013. Future research will focus on clinical characteristics of patients with synchronous or metachronous cases of RCC and these hematologic malignancies.[Table: see text]
Clinical predictors of sarcomatoid kidney cancer: The results of a UCLA and french UroCCR network collaboration.
Authors: Lebacle Cedric Michel , Pooli Aydin , Bernhard Jean-Christophe , Paparel Philippe , Bensalah Karim , Beauval Jean Baptiste , Mejean Arnaud , Dariane Charles , Bigot Pierre , Lang Herve , Bessede Thomas , De La Taille Alexandre , Roupret Morgan , Irani Jacques , Patard Jean-Jacques , Belldegrun Arie S. , Shuch Brian , Chamie Karim , Drakaki Alexandra , Pantuck Allan J. ,   French Research Network on Kidney Cancer UroCCR, Bordeaux, France
Published: March 2019

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Background: Predisposing factors for sarcomatoid dedifferentiation of renal cell carcinoma (sRCC) remain unknown. We highlighted the association of potential contributing medical conditions with the presence of sRCC. Methods: Patients with a renal cell carcinoma (RCC) from UCLA and the French UroCCR-45 study (only sRCC) were included in the study. Characteristics of patients with sRCC were compared with patients with RCC without sarcomatoid features (nsRCC) in univariable and multivariable logistic regression analyses. We quantified the association of age, gender, smoking status, hypertension, kidney function, and endocrine disorders: diabetes and hypothyroidism with sRCC. Results: A total of 2764 were included in the study (586 sRCC vs. 2178 nsRCC). On univariable analysis, age (OR=1.02, 95%CI [1.01-1.03], p<.0001), male gender (OR=1.35, 95%CI [1.10-1.65], p=.004), active smoking (OR=1.87, 95%CI [1.48-2.36], p<.0001), and diabetes (OR=1.32, 95%CI [1.03-1.70], p=.026) were associated with the presence of sRCC (Table 1). On multivariable analysis, age (+2.1% per year, OR=1.02, 95%CI [1.01-1.03], p<0.0001), male gender (OR=1.33, 95%CI [1.08-1.64], p=.008), and active smoking (OR=1.95, 95%CI [1.54-2.47], p<0.0001) were independently associated with the presence of sRCC. The AUC of the model was 0.61. Conclusions: In this study we found that sarcomatoid dedifferentiation was associated with age, male gender, and active smoking. Further studies are needed to confirm these findings and establish the underlying biology. Univariable logistic regression analysis of the association between potential pathogenic factors and sRCC. N=2764 [Table: see text]