bluuebunny/crossref_metadata_2025_split huggingface dataset:
The usefullness of low-molecular-weight protein tyrosine phosphatase as a prognostic factor in metastatic hormone-sensitive prostate cancer.
Authors: Ohtaka Mari , Kawahara Takashi , Yasui Masato , Uemura Kouichi , Yoneyama Shuko , Mochizuki Taku , Hattori Yusuke , Teranishi Jun-ichi , Yumura Yasushi , Yokomizo Yumiko , Uemura Hiroji , Miyamoto Hiroshi , Yao Masahiro , Miyoshi Yasuhide 
Published: March 2017

277 Background: Protein tyrosine phosphorylation is an important event that is associated with the processes of cellular metabolism. The control of protein tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTP). Thus, these proteins can control diverse processes like cell proliferation, adhesion, and migration. Recent studies revealed the importance of PTP in the oncogenic process, especially, the significance of low-molecular-weight protein tyrosine phosphatase (LMW-PTP) as a prognostic factor in early prostate cancer. In this study, we evaluated the significance of expression of LMW-PTP in metastatic hormone-sensitive prostate cancer (mHSPC) as a prognostic biomarker. Methods: We identified consecutive 48 men with mHSPC. The prostate cancer tissues obtained by needle biopsies were immunohistochemically stained for LMW-PTP. A pathologist blindly evaluated the expression of LMW-PTP and intensity of staining was classified into two groups, high (diffusely strongly positive) and low (at least focally weak-negative). The correlations between clinicopathological characteristics including age, initial PSA levels, Gleason scores, T stage, N stage, extend of disease on bone scan (EOD), and expression of LMW-PTP and overall survival (OS) were analyzed by multivariate analysis using cox proportional hazards regression model. Results: Median age was 70.0 years and median initial PSA level was 85.4 ng/mL. Gleason scores were 6-7 in 16 patients (33.4%) and 8-10 in 32 patients (66.6%). Clinical T stages were T2-3 disease in 34 patients (70.8%) and T4 in 14 patients (29.2%). Clinical N stages were N0 disease in 21 patients (43.7%) and N1 in 27 patients (56.3%). EOD grades were 0 in 13 patients (27.0%), 1 in 12 patients (25.0%), 2 in 14 patients (29.2%), 3 in 8 patients (16.7%), and 4 in 1 patient (2.1%). Multivariate analysis revealed that Gleason score (≥ 8 vs ≤ 7; HR: 5.795, 95%CI: 1.266-26.520, p = 0.024) and LMW-PTP expression (high vs low; HR: 2.736, 95%CI: 1.035-7.232, p = 0.042) were independent prognostic factors for OS. Conclusions: LMW-PTP might be a potential biomarker to predict overall survival for men with mHSPC.
Muscle-invasive bladder cancer: Molecular subtypes and response to neoadjuvant chemotherapy.
Authors: Seiler Roland , Winters Brian , Douglas James , van Rhijn Bas W.G. , Sjödahl Gottfrid , Lerner Seth P. , Hoadley Katherine A. , North Scott A. , McConkey David James , Choi Woonyoung , Kim William Y. , van Kessel Kim E.M , Thalmann George N. , Davicioni Elai , Crabb Simon J. , Boormans Joost L , Dall'Era Marc , Wright Jonathan Lawrence , Van Der Heijden Michiel Simon , Black Peter C. 
Published: March 2017

281 Background: Molecular subtypes of muscle-invasive bladder cancers (MIBC) have recently been discovered based on gene expression. We investigated the impact of different subtyping methods on response to neoadjuvant cisplatin-based chemotherapy (NAC) and developed a single sample model for subtyping. Methods: Transcriptome-wide microarray analysis was conducted on pre-NAC transurethral resection (TUR) specimens of 223 patients with MIBC who received NAC followed by cystectomy at 5 centers. The specimens were classified according to four published methods for molecular subtype (UNC, MDA, TCGA, Lund). Overall survival (OS) for each subtype was compared between NAC patients in this study and non-NAC patients from the provisional TCGA. A genomic classifier (GSC) was trained to predict subtype in a single sample model and validated in independent NAC (2 centers) and non-NAC datasets. Results: The models generated subtype calls similar to previously published ratios. Concordance of a given subtype between the different methods was high. Luminal tumors had the best OS independent of NAC. Patients with tumors classified as UNC basal, MDA basal and TCGA cluster III experienced the greatest improvement in OS after NAC compared to surgery alone. Tumors assigned as UNC claudin-low had the worst OS irrespective of treatment regimen (p=0.005). GSC accurately predicted four classes (luminal, luminal-infiltrated, basal, claudin-low) and the differential impact of a basal subtype on patient OS in NAC (3-yr survival of 75.2%; p=0.001) and non-NAC (3-yr survival of 42.4%; p=0.014) cohorts could be validated. Conclusions: The benefit of NAC varies between molecular subtypes. The good prognosis of luminal/cluster I tumors could not be improved with NAC, which suggests these patients may be managed best with surgery alone. The prognosis of patients with basal tumors improved the most when treated with NAC compared to surgery alone. Poor OS of claudin-low tumors even after NAC implies that these tumors are resistant to cisplatin-based chemotherapy, and these patients should be included in protocols investigating alternative treatment options like immunotherapy. Further validation prior to clinical implementation is needed.
Borealis-2: A randomized phase II study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial cancer (mUC) (Hoosier Cancer Research Network GU12-160).
Authors: Choueiri Toni K. , Hahn Noah M. , Werner Lillian , Regan Meredith M. , Rosenberg Jonathan E. ,   BOREALIS-02 investigators
Published: March 2017

289 Background: OGX-427 (apatorsen; A) is an antisense oligonucleotide that binds Heat shock protein 27 (Hsp27) mRNA with synergistic effect with chemotherapy. Borealis-2 is a randomized multicenter phase 2 study of A in combination with docetaxel (D) vs. D alone in advanced UC patients (pts) after at least 1 prior platinum-based therapy. Methods: The primary objective was to determine whether D+A prolonged overall survival (OS) vs D. Patients were stratified (time from prior systemic chemotherapy; Bellmunt criteria) and randomized in a 1:1 ratio. D was administered for up to 10 cycles in both arms. OGX-427 maintenance continued in pts with no disease progression. Secondary objectives included safety, objective response, and serum levels of Hsp27. The trial design provided 90% power to detect a 33% decrease in OS hazard (hazard ratio [HR] = 0.667), with one-sided α = 0.10 after 162 deaths, and one interim futility analysis; a p-value < 0.1 would result in a positive study for the primary endpoint. Results: 200 pts were randomized between 8/2013 and 9/2015. 72.5% had 1-3 Bellmunt risk factors and 43.5% were < 3mos from prior chemotherapy. 163 pts had died (77 A+D; 86 D) at final analysis. The A+D group had a statistically-significant reduction in hazard for death vs. D (HR = 0.80; 80% CI, 0.65 to 0.98; one-sided P = 0.08). For A+D, median OS was 6.4 mos (95%CI 4.6-9.2) and 12-mo OS was 34.4% (95% CI 25.1-43.9). For D, median OS was 5.9 mos (95%CI 4.8-7.3) and 12-mo OS was 25.0% (95%CI 17.0-33.8). All causality grade 3 or higher toxicities were similar between A+D group (82%; 95%CI 73%-89%) and the D group (75%; 95%CI 65%-83%). The treatment effect of pts with baseline serum Hsp27 < 5.7ng/mL (median) vs. Hsp27 ≥ 5.7ng/mL was not different (2-sided p = 0.87 for interaction). Conclusions: In this platinum-pretreated population of advanced UC, adding OGX-427 to D provided a statistically significant improvement in OS and is worthy of further investigation in previously treated metastatic UC pts. Clinical trial information: NCT01780545.
Atezolizumab (atezo) in patients with metastatic urothelial carcinoma (mUC): A 2-year clinical update from a phase Ia study.
Authors: Petrylak Daniel Peter , Powles Thomas , Bellmunt Joaquim , Braiteh Fadi S. , Loriot Yohann , Morales Rafael , Burris Howard A. , Kim Joseph W. , Ding Beiying , Chang Dannis , Fasso Marcella , O'Hear Carol , Vogelzang Nicholas J. 
Published: March 2017

290 Background: Atezo (anti–PD-L1) has demonstrated safety and efficacy in a broad range of cancers and is approved in the United States for mUC previously treated with platinum-based chemotherapy. Here we report long-term results in mUC from Phase Ia study NCT01375842 (PCD4989g). Methods: Previously treated mUC patients received atezo 15 mg/kg or 1200 mg IV q3w. Enrollment in this Phase Ia expansion cohort initially required PD-L1–selected status and later opened to patients regardless of PD-L1 expression on tumor-infiltrating immune cells. The primary endpoint was safety/tolerability. Secondary endpoints included investigator-assessed RECIST v1.1 ORR (confirmed), DOR and OS. Results: 95 patients were safety evaluable (Table). Median age was 66 years, 76% were male and 80% had primary bladder tumors. 61% had ECOG PS 1. 52% received ≥ 3 prior systemic therapies for mUC (70% platinum). Median treatment duration was 3 months (range: 0-32 months); 24% were treated for ≥ 1 year. Treatment-related AEs occurred in 66% (all Grade) and 8% (Grade 3-4) of patients. No treatment-related deaths were reported. In 94 objective response–evaluable patients (follow-up ≥ 12 weeks), the ORR was 27% (95% CI: 18, 37%), and the CR rate was 10%; the SD rate was 19%. mDOR was 22.1 months (95% CI: 12.1, NE months) in all patients; 56% of responses (7/9 CRs and 7/16 PRs) were ongoing at the December 15, 2015 data cutoff. With a 24-month median follow-up duration (range: 1+ to 32 months), the 1-year OS rate was 47% (95% CI: 36, 58%), and the 2-year rate was 29% (19, 40%); mOS is in the Table. Updated clinical data with further follow-up and analyses by PD-L1 status will be presented. Conclusions: Long-term treatment with atezo was well tolerated, without new safety signals in heavily pre-treated mUC patients. The durability of responses, including CRs, along with extended OS, confirm atezo as a new standard for previously treated mUC patients. Clinical trial information: NCT01375842. [Table: see text]
Targeted DNA and RNA sequencing of paired urothelial and squamous bladder cancers to reveal discordant genomic and transcriptomic events and unique therapeutic opportunities.
Authors: Hovelson Daniel H. , Lazo De La Vega Lorena , McDaniel Andrew , Udager Aaron , Mehra Rohit , Palapattu Ganesh S. , Weizer Alon Z. , Morgan Todd Matthew , Montgomery Jeffrey Scott , Tomlins Scott A. 
Published: March 2017

296 Background: Expression-based molecular subtypes thought to be intrinsic in bladder cancer have been widely reported, carrying important potential clinical treatment implications. Histologically, bladder cancers are also heterogeneous diseases, with a large portion of urothelial carcinomas exhibiting divergent differentiation. Previous subtyping efforts have been carried out using predominantly fresh frozen tissue samples, potentially obscuring this known differentiation heterogeneity. Methods: Here we performed targeted multiplexed, amplicon-based DNA and RNA sequencing on 100 formalin-fixed paraffin-embedded (FFPE) bladder cancer samples (including 12 paired urothelial / squamous lesions). High-confidence somatic point mutations, short insertions/deletions (indels), and copy number alterations were detected using the DNA component of the Oncomine Comprehensive Assay (OCP). Targeted RNA sequencing was carried out using a custom Ampliseq panel comprised of 8 housekeeping genes and 103 target genes assessing major transcriptional programs as identified from publically available data. Results: By DNA analysis, we observe frequent TP53 (35%) and activating hotspot PIK3CA (23%) somatic mutations across the cohort, as well as targetable high-level (log-2 copy number ratio > = 1.5) focal amplifications of ERBB2 (3%) or EGFR (3%) in a subset of samples. We report a novel approach for detecting sub-gene copy-number alterations, and confirm several detectable multi-exon losses using whole transcriptome RNA sequencing. Pairing targeted RNA expression analysis with DNA-based alterations, we show high level expression of EGFR and ERBB2 in focally-amplified samples. Most importantly, we show that despite identical prioritized somatic genomic alterations, we observe divergent expression-based profiles in 3 of 12 (25%) paired urothelial and squamous samples. Conclusions: Taken together, these results highlight the importance of molecular heterogeneity in bladder cancer and suggest important considerations for using existing expression-based clustering approaches to guide clinical treatment decisions.
Clinical destiny of indeterminate pulmonary nodules in patients undergoing radical cystectomy for urothelial carcinoma of the bladder.
Authors: Cahn David B. , McGreen Brian , Lee Albert , Plimack Elizabeth R. , Geynisman Daniel M. , Zibelman Matthew R. , Ristau Benjamin T. , Smaldone Marc C. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Uzzo Robert G. , Kutikov Alexander 
Published: March 2017

297 Background: Perioperative risks and significant quality of life concerns following radical cystectomy (RC) render accurate pre-operative staging paramount, since metastatic patients are unlikely to benefit from extirpation. Yet, incidental indeterminate pulmonary nodules (IPNs) are a common pre-operative finding in clinical practice, thus representing a significant management challenge. As such, we sought to evaluate the natural history of IPNs in a large institutional cohort that underwent RC. Methods: We reviewed our institutional database for patients who underwent RC from 2000 through 2014 for urothelial carcinoma (UCC) of the bladder and had at least 1 identifiable pulmonary lesion on preoperative staging imaging measuring <2cm in any axis. Patients who were M1 at surgery, had gynecologic, colorectal, or missing pathology, or non-urothelial histology were excluded. We sought to determine the natural history of these pulmonary lesions and evaluated predictors of metastatic etiology. Results: During the study period, 681 RC were performed at our institution. We identified 73 patients with an identifiable preoperative IPN who met inclusion criteria and underwent RC. In this subset, 23.3% were female, 21.9% were active smokers, and 54.8% former smokers. The median age at surgery was 70±8.6 years. Nearly half (49.3%) received neoadjuvant chemotherapy. 61.6% of RC were performed using the traditional open approach, while 38.4% were performed robotically. Final pathologic staging included 16.4% pT0N0Mx, 19.2% pTa/Tis/T1N0Mx, 42.5% pT2-4N0Mx, and 21.9% pTanyN+Mx. Median IPN size was 0.7±0.3cm. At median follow up of 23.5±21.9 months, 93% (68/73) of IPNs in our cohort were clinically benign, with metastatic urothelial cancer confirmed in only 4 patients, and a primary lung malignancy diagnosed in 1 patient. Conclusions: The majority of IPNs in patients who proceeded to RC for UCC of the bladder were stable upon follow-up and rarely represented malignancy. As such, in appropriately screened UCC patients, IPNs should not be a barrier to proceeding with extirpative surgical therapy.
Changes in multiparametric prostate MRI and immune subsets in patients (Pts) receiving neoadjuvant immunotherapy and androgen deprivation therapy (ADT) prior to radiation.
Authors: Madan Ravi Amrit , Turkbey Baris , Lepone Lauren Marissa , Donahue Renee Nicole , Grenga Italia , Borofsky Samuel , Pinto Peter A. , Citrin Deborah E. , Kaushal Aradhana , Krauze Andra V. , McMahon Sheri , Rauchhorst Myrna , Couvillon Anna , Falk Martin H. , Eggleton Peter , Choyke Peter L. , Dahut William L. , Schlom Jeffrey , Gulley James 
Published: March 2017

30 Background: Endorectal(er) MRI is an emerging tool in assessing intraprostatic tumors. Immunotherapy development in prostate cancer has been limited due to the lack of intermediate (bio)markers of response. Methods: Untreatedpts with high-risk prostate cancer were randomized in a trial (NCT01496131) of standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25). Pts had erMRI at baseline and after 2 months of ADT+/- biweekly immunotherapy. Low dose (300 mg/m2, maximum 600 mg) cyclophosphamide for regulatory T-cell depletion preceded first immunotherapy. Multiparametric MRI included evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments utilized flow cytometry to evaluate immune cell subsets. This analysis focuses on the 2 month neoadjuvant period of ADT+/-immunotherapy before radiation. Results: 28 pts (n = 14/arm) with high risk prostate cancer (Gleason 8-10, PSA > 20, or stage T3) were enrolled. PSA declined in all pts 2 months after ADT. erMRI findings at 2 months indicated greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI suggests improvements in intratumoral diffusion and has been associated with decreased tumor density. This relative improvement between the groups occurred both per patient (p = 0.16) and per lesion (p = 0.031). Relative to baseline, pts receiving immunotherapy+ADT had increases in CTLA4+ CD8+ T-cells consistent with immune activation (p = 0.0134) and decreases in myeloid derived suppressor cells (MDSCs; p = 0.0353) during the neoadjuvant period corresponding to the erMRI changes. These immune findings were not seen in the ADT alone group. Conclusions: Pts who received immunotherapy+ADT for 2 months had greater improvements in ADC values on erMRI, consistent with decreased tumor density, relative to pts receiving ADT alone. Corresponding increases in activated CD8+ T-cells and decreases in MDSCs were seen in pts receiving vaccine+ADT. These preliminary findings suggest that ADC on MRI may be useful in assessing immunologic impact. Further study is warranted. Clinical trial information: NCT01496131.
Second primary lung cancer in the United States: 1992–2008.
Authors: Donin Nicholas , Kwan Lorna , Lenis Andrew T. , Alexandra Drakaki , Litwin Mark S. , Chamie Karim 
Published: March 2017

309 Background: Tobacco smoke is a known risk factor for both bladder and lung cancer. We hypothesized that bladder cancer survivors are at high risk for second primary lung cancers (SPLC), and sought to describe the incidence and mortality attributable to SPLC among survivors of bladder cancer as well as other common cancers in the United States. Methods: We identified adult patients diagnosed with a localized primary malignancy from 8 of the most common non-pulmonary cancer sites in Surveillance, Epidemiology, and End Results (SEER) data from 1992–2008. We explored factors associated with the incidence and mortality from SPLC using bivariable and multivariable models. Finally, we compared standardized incidence rates (SIRs) for SPLC in our cohort with the control arm of the National Lung Screening Trial (NLST), a large lung cancer screening trial in patients at high risk for lung cancer. Results: We identified 1,431,809 survivors of common non-pulmonary cancers, of whom 24,477 (1.7%) developed SPLC at a mean (SD) follow-up of 5.7 (3.6) years. Bladder cancer survivors developed SPLC at twice the rate of other cancer survivors, with 10% developing SPLC in the 20 years following their bladder cancer diagnosis. Increasing age and male gender were independent risk factors for SPLC, irrespective of the primary cancer type. Of patients who developed SPLC, 19,059 (78%) died during follow-up. Lung cancer was responsible for 73% of these deaths, such that over half (57%) of the cancer survivors who develop SPLC ultimately died of lung cancer. Bladder cancer survivors demonstrated a SIR of 512 cases/100,000 person-years, which approaches the rate (572 cases/100,000 person-years) seen in the control arm of the NLST. Conclusions: Over half of patients who develop SPLC died of their disease. Almost 10% of bladder cancer survivors develop SPLC in the 20-years following their diagnosis. This rate approaches that seen in the control arm of the NLST, suggesting that the incidence in bladder cancer survivors could justify lung cancer screening in this population. Further efforts to better define the potential risks and benefits of lung cancer screening in bladder cancer survivors is warranted.
Does liposomal bupivacaine use intraoperatively decrease postoperative narcotic use in radical cystectomy patients?
Authors: Kukreja Janet Baack , Chang Courtney M , Seif Mohamed , Navai Neema , Kamat Ashish M. , Dinney Colin P.N. , Shah Jay Bakul 
Published: March 2017

311 Background: Bupivacaine liposome injectable suspension (LB) can be used to help control postoperative pain. It slowly releases bupivacaine for up to 96 hours after injection. This study sought to determine if the use of LB intraoperatively for radical cystectomy (RC) patients decreases postoperative narcotic use. Methods: A retrospective cohort study was performed. 281 patients underwent RC between November 2013 and May 2016, 203 received LB. LB was administered after fascial closure but before skin closure by performing suprafascial and subfascial injection with 20ml of LB. Patient demographics, BMI, renal function, operative characteristics, and the total postoperative intravenous morphine equivalents were reviewed. Where appropriate chi-squared, Mann-Whitney and t-tests were used for statical analysis. Multivariable analysis and linear regression models were performed. Because enhanced recovery principles were used simultaneously, enhanced recovery status was also used to adjust for predictors of post-operative opioid use. Results: There was no difference in baseline demographics, BMI, renal function or baseline opioid use between the LB and non-LB group. The operative time was longer in those who had LB administered and there were more open RCs performed in the LB group. Total morphine equivalents averaged to 8.0 mgs for the LB group and 50.7 mgs for the non-LB group, p-value <0.001. More patients had epidurals and IV PCA pumps in the non-LB group, (p=0.001 and <0.001, respectively). There were 42 patients whom did not require any IV morphine equivalents in the LB group compared to only 4 in the non-LB group (p=0.002). After adjusting for modality, and operative time, the linear regression model was predictive of less IV morphine equivalents in those with LB, p=0.044. Conclusions: The addition of LB to enhanced recovery principles increases the number of patients with zero narcotic use postoperatively. Irrespective of open or robotic modality and operative time, LB use decreases opioid use after RC.