bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of phosphoglycerate mutase 2 in UM-UC3 bladder cancer cell metabolism.
Authors: Didde Ryan , Liu Weiya , Pirani Karim , Kaushik Gaurav , Woolbright Benjamin L. , Abbott Erika , Taylor John Arthur , Anant Shrikant , Holzbeierlein Jeffrey M. , Lee Eugene K. 
Published: March 2019

410 Background: Bladder cancer remains the fourth most common cancer in American males with a higher risk of recurrence and progression for patients with diabetes mellitus. Urothelial bladder cancer is characterized by aerobic glycolysis with upregulation of glycolytic enzymes (known as the Warburg effect) such as phosphoglycerate mutase. Phosphoglycerate mutase 2 (PGAM2), a reversible glycolytic enzyme expressed highly in muscle, represents a target for modulation because of its differential expression from another isoform, phosphoglycerate mutase 1. PGAM2 knockdown may impact bladder cancer growth significantly via its effect on glucose metabolism at different glucose concentrations seen in patients with diabetes mellitus. Methods: UM-UC3 bladder cancer cells were assessed for PGAM2 expression at different glucose concentrations via Western blot and quantitative PCR. One native UM-UC3 line, three PGAM2 knockdown lines, and one vector control cell line were included in the western blot study. Cellular proliferation was analyzed using an enzyme based hexoseaminidase assay and was further supported with an automated cell counter. The effects of cisplatin were also investigated. Results: Increased PGAM2 expression at increased glucose concentrations in UM-UC3 was confirmed by Western blot and quantitative PCR. PGAM2 knockdown cells responded differently to changes in glucose concentration compared to the control cell lines, with a large increase in growth at a low glucose level of 25mg/dL after day 4. Cell proliferation demonstrated similar growth between the knockdown and controls at higher glucose concentrations of 100 and 200mg/dL. Proliferation data using automated cell counter demonstrate the same growth trend. Conclusions: Increased cell growth of PGAM2 knockdowns, most notably at 25mg/dL, suggests that PGAM2 may play a different role in glycolysis than expected, possibly serving as a modulator in cell growth instead of a simple reversible enzyme. We are currently investigating its differential expression compared to PGAM1, an enzyme recently characterized to have an opposite effect to PGAM2.
Serum cytokeratin 19 fragments: A novel preoperative prognostic marker in patients with upper urinary tract urothelial carcinoma.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Obayashi Kotaro , Takeda Hayato , Hayashi Tatsuro , Kondo Yukihiro 
Published: March 2019

412 Background: Current guidelines do not yet provide any recommendations for any serum tumor markers in patients with upper tract urothelial carcinoma (UTUC). Even today radiological images cannot diagnose muscle invasion correctly. Previous studies have shown that serum cytokeratin levels were correlated with depth of tumor invasion and metastases in patients with bladder cancer. In this study we evaluated whether preoperative serum cytokeratin 19 fragment levels (sCK19) could be a prognostic marker for survival in patients who received nephroureterectomy (NU). Methods: 160 cases with UTUC underwent NU from December 2003 to 2014 at our institution. The median age was 73 years. Preoperative sCK19 was measured in 138 cases. The patients were divided into two groups, high sCK19 group (HG) and low group (LG) based on sCK19 (a cut-off value: 3.5 ng/mL). Cancer-specific survival (CSS) and progression-free survival (PFS) were measured by Kaplan–Meier curves and statistical analysis was performed by the log–rank test. Multivariate analysis was carried out using the Cox proportional hazards model. Results: Of 138 cases ≤pT1 was 54 (39%), pT2 in 31 (22%), pT3 in 45 (32%) and pT4 in 8 (5%). 37 cases (23%) were the HG and 101 (78%) were the LG. sCK19 were significantly correlated with pT (rs 0.213, p=0.013, Spearman rank correlation). The median follow-up time was 34.0 months. In all cases the 5-year CSS was 78% and PFS was 60%. The 5-year CSS of the HG (57%) was significantly lower than the LG (86%) (p=0.001). The 5-year PFS of the HG (36%) was significantly lower than that of the LG (67%) (p<0.001). On univariate analysis, pT stage, lymphovascular invasion, positive margin (PM) and sCK19 were the significant factors for CSS. On multivariate analysis, sCK19 (HR4.2, p=0.001) and PM (HR2.9, p=0.001) were the independent poor prognostic factors. Conclusions: Preoperative sCK19 was the prognostic factor for the patients with UTUC. Systemic chemotherapy should be considered before NU in patients with high preoperative sCK19 levels independent of radiological findings.
Development of myeloid-derived suppressor cells (MDSC) targeted therapy for the treatment of cisplatin-resistant bladder cancer.
Authors: Takeyama Yuji , Kato Minoru , Shimizu Yasuomi , Hamada Kosuke , Iguchi Taro , Tamada Satoshi , Nakatani Tatsuya 
Published: March 2019

415 Background: The emergence of immune checkpoint inhibitors (ICI) has brought hope for cure and survival for those suffering from various cancers, including bladder cancer. However, the response rate of ICI monotherapy is modest, and recent reports indicate that myeloid-derived suppressor cells (MDSC) might play a role in the resistant mechanism of ICI. In this study, we assess the effect of chemokine signal on the proliferation of bladder cancer and investigate whether MDSC could be a new target for the treatment of cisplatin-resistant bladder cancer. Methods: We established a cisplatin resistant strain (MB49R) of mice bladder cancer cell line MB49, and examined the alteration of the expression levels of inflammatory chemokines by chemokine array. Next, we isolated MDSCs from spleen and tumor in tumor-bearing mice to examine gene expression levels of chemokine receptors (CXCR2 and CCR2) and immunosuppression genes (Arg-1 and iNOS). Furthermore, we assessed the efficacy of CDDP, α-PD-L1 and chemokine antagonists against the proliferation of tumors in MB49 and MB49R xenograft models. Results: Expression levels of CCL2 and CXCL1/2, which are involved in the migration of MDSC, were significantly increased in the culture supernatant of MB49R compared to those in MB49 cell lines. This result was confirmed by real-time RT-qPCR of tumor extract, and this increase was also observed in human bladder cancer cell lines (T24 and T24R). CXCR2 and CCR2 were highly expressed in PMN-MDSC and M-MDSC, respectively, which were isolated from spleen or tumors in tumor-bearing mice, and gene expression levels of Arg-1 and iNOS were dramatically increased in M-MDSCs from the tumor tissues compared to those from spleen. Also, analysis by flow cytometry revealed that PMN-MDSC dramatically decreased in MB49R compared to parental MB49 tumors, while the proportion of M-MDSC was not changed in MB49R, which indicates that M-MDSC could be a target for the treatment of CDDP resistant bladder cancer. Conclusions: The results in the present study might indicate that the combination treatment with ICI and MDSC-targeting therapy could be an option for the treatment of cisplatin-resistant bladder cancer.
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.