bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-free DNA analysis in renal cell carcinoma: Comparison with tumor sequencing and correlation with response to therapy.
Authors: Hamieh Lana , Nassar Amin , Lasseter Kathryn , Ogorek Barbara , McKay Rana R. , Thorner Aaron , Nag Anwesha , Lee Gwo-Shu Mary , Bhatt Rupal Satish , Pomerantz Mark , Freedman Matthew L , Kwiatkowski David J. , Choueiri Toni K. 
Published: March 2019

655 Background: Massively parallel sequencing (MPS) of circulating-free DNA (cfDNA) is seeing increasing use in multiple cancer types. There is little data on its use in metastatic renal cell carcinoma (mRCC) as a tool for prognostication and disease monitoring. Methods: cfDNA was extracted from 63 blood samples of 40 metastatic RCC patients (pts). Serial samples were obtained in 12 of 40 (30%) pts (median = 1, range = 1-7). cfDNA was used for targeted MPS using a custom bait-set of 27 genes commonly mutated in RCC. Variants observed in at least 3 reads, in both read directions, and at an allele frequency (AF) of ≥0.5% for single nucleotide variants (SNV), or in 2 reads and AF of ≥0.2% for small indels, were candidate variants validated by Sanger sequencing or amplicon MPS (aMPS). All mutations identified in cfDNA were also assessed in matched patient WBC DNA using aMPS and Sanger sequencing. Tumor specimens from 23 pts were also sequenced in parallel using our institutional OncoPanel assay that assesses 275-447 cancer-associated genes and results were compared with those seen in the cfDNA. Results: Thirty-one of 38 (82%) candidate variants were validated in 17 of 40 pts. Ten of those (32%) from 10 pts were also detected in WBC DNA, 3 of which were germline and 7 were at low mosaic frequency and likely reflected clonal hematopoiesis (CH). The remaining 21 variants validated in cfDNA were in TP53 (6), PBRM1 (3), SETD2 (3), VHL (2), ATM (2), NF2 (2), PTEN (1), PIK3CA (1), and MTOR (1). Two of 17 (12%) pts without tumor mutation analysis had 4 validated variants seen in cfDNA only. 10 of 23 (43%) pts with tumor mutation analysis had one or more variants seen in both tumor DNA and cfDNA. Three of the 23 had mutations seen only in cfDNA. Pts with any mutation in cfDNA (n = 14) had a significantly shorter overall survival in comparison to those without a finding (p < 0.001). Among 12 pts with serial samples, 5 had cfDNA variants identified. Response to therapy correlated with variant prevalence in all 5, including 2 with significant partial responses. Conclusions: This study suggests that paired tumor–cfDNA analysis has value in the assessment of response to therapy in RCC. Further analysis is proceeding.
A multigene expression score for predicting response to anti-PD-1/PD-L1 therapy for clear cell renal cell cancer patients.
Authors: Choudhury Yukti , Tan Kai Wei , Tan Hui Shan , Hong Jian Cheng , Tay Miah Hiang , Tan Min-Han , Tan Puay Hoon , Tan Wan Ling , Ng Quan Sing , Toh Chee Keong , Kanesvaran Ravindran 
Published: March 2019

656 Background: Anti-PD-1 inhibitor nivolumab and combination checkpoint inhibition (nivolumab and ipilimumab) are approved for advanced clear cell renal cell cancer (ccRCC), with objective response rates between 25% to 40%. PD-L1 expression is a poor predictor of anti-PD-1/PD-L1 therapy response in ccRCC. Better predictive biomarkers are required. The CLEAR score (CS) is a multigene prognostic expression score for ccRCC (Eur Urol 2015) previously associated with TKI outcomes. Given association of prognosis and clinical benefit, CS was explored as a biomarker for response to anti-PD-1/PD-L1 therapy in this study. Methods: CS is derived from the expression of 8 genes in ccRCC tumor tissue and intervening stroma and includes components of chemokine signaling. Based on this, immunohistochemistry of ccRCC tumor tissue (n = 24; matched CS also derived from same tissue), was done for tumor-infiltrating lymphocytes (CD8+) and PD-L1. Staining intensity was also correlated to CS. In another set of RCC patients who received nivolumab or pembrolizumab after progression on anti-angiogenic therapy (n = 12), correlation of their tumor CS and response outcome to anti-PD-1 therapy was done. Results: CS was significantly higher for ccRCC tumors with higher intratumor and/or stromal CD8+ cell infiltration (p < 0.001). A similar correlation with PD-L1 staining was not observed. Among RCC patients receiving anti-PD-1 therapy, clinical benefit (stable disease or partial response) was characterized by higher CS, regardless of treatment line. When analysis was limited to ccRCC histology, CS were significantly higher (p < 0.05) for responders (n = 2) compared to non-responders (n = 4) to nivolumab treatment. Conclusions: This is the first study reporting the correlation of a multi-gene score (CS) with immune phenotypes in ccRCC. CS correlates well with intratumor/stromal CD8+ cell infiltration, and is a potential biomarker for response to anti-PD-1 therapy. Consistent with clinical trial data, high CS (associated with poor prognostic tumors) correlated with better responses. Studies with a larger cohort of patients are underway to establish the utility of CS in predicting response to anti-PD-1/PD-L1 therapy.
Ten year treatment complication outcomes of radical prostatectomy versus external beam radiation therapy versus brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Goy Barry W. , Burchette Raoul J. 
Published: March 2019

67 Background: To compare 10 year treatment complication outcomes of radical prostatectomy(RP) vs external beam radiation therapy(EBRT) vs brachytherapy(BT) for patients with intermediate risk prostate cancer(IRPC). Methods: A retrospective analysis was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007, using univariate comparisons. 819 underwent RP, 574 underwent EBRT, and 110 underwent BT using iodine-125. Urinary and rectal complications for RP were graded as severe if patients required ≥ 3 pads/diapers per day, required chronic use of condom catheter or penile clamp, daily self-catheterization, placement of sling or artificial urinary sphincter, or developed rectal fistula/incontinence. Complications for EBRT and BT were graded as severe if they were classified as grade 3 or 4 on the Radiation Therapy Oncology Group grading system for late effects. For erectile dysfunction, the prevalence of patients requiring injections, pumps or penile implants were calculated after a minimum of 1 year of follow up. Results: Median follow up was 10.0 years for RP, 9.6 for EBRT, and 9.8 for BT. Neoadjuvant androgen deprivation therapy was given in 0.6% for RP patients vs 58.9% of EBRT vs 12.7% of BT, p < 0.0001. Median age for RP vs EBRT vs BT was 62.1, 70.8, 65.3, p < 0.0001. The 10-year prevalence of severe urinary complications for RP vs EBRT vs BT was 10.1%, 12.5%, 4.6%, p = 0.04. The percentage of patients having a pre-treatment American Urological Association(AUA) urinary score for RP vs EBRT vs BT was 7.3%, 11.5%, 97.3%, p < 0.0001. The 10-year prevalence of severe rectal complications for RP vs EBRT vs BT was 0.5%, 1.6%, 0.0%, p = 0.06. The 10-year prevalence of erectile dysfunction devices for RP vs EBRT vs BT was 24.3%, 6.6%, 8.2%, p < 0.0001. Conclusions: After 10 years of follow-up, BT had the lowest rate of severe urinary complications, which may due to using the AUA score to avoid implanting those who had significant baseline obstructive voiding symptoms. EBRT had a higher rate of severe rectal complications. RP had the highest probability of undergoing treatment using erectile dysfunction devices, despite having younger patients.
Factors linked with receiving a lymph node dissection during surgery for nonmetastatic renal cell carcinoma.
Authors: Radadia Kushan Dilip , Rivera-Nunez Zorimar , Kim Sinae , Farber Nicholas , Sterling Joshua , Modi Parth K. , Sharad Goyal , Rahul Parikh , Weiss Robert E. , Kim Isaac , Elsamra Sammy , Jang Thomas , Singer Eric 
Published: March 2019

672 Background: The benefit of a lymph node dissection (LND) in renal cell carcinoma (RCC) remains poorly defined. Despite this uncertainty, the American Urological Association (AUA) guideline on localized renal cancer recommends that LND be performed for staging purposes when there is suspicion of regional lymphadenopathy on imaging. Using the National Cancer Database (NCDB), we examined factors associated with the receipt of LND at the time of renal surgery. Methods: The NCDB was queried for non-metastatic patients who underwent partial nephrectomy or nephrectomy for RCC from 2010 to 2014. Patient socio-demographics, clinical characteristics, and treatment factors were extracted. Logistic regression models were used to examine factors associated with the receipt of LND. Results: We identified 110,963 patients who underwent surgery for RCC, of whom 11,867 (11%) had LND performed at the time of surgery. Clinical lymph node (cLN) and pathologic lymph node (pLN) information were available in 11,300 patients, of which 1,725 were preoperatively staged as having positive cLN. In the entire study population, patients who were cLN positive were approximately 19 times more likely to receive a LND at the time of surgery (OR: 18.68, 95%CI: 16.62-21.00). Factors associated with a LND in patients who are cLN negative (n = 106,370) were assessed. Clinical T (cT) stage was the strongest indicator of LND (cT2-4, OR range: 4.87-11.1). Among both cohorts, patients who received surgery at an academic/research institution or traveled farther ( > 31 miles) to a treatment center were more likely to undergo a LND. Patients from both cohorts who underwent robotic or laparoscopic surgery were less likely to receive a LND compared to open surgery. Conclusions: The greatest predictor of LND receipt is being cLN positive. Among patients who are cLN negative, the greatest predictor of LND is cT stage. Predictors of undergoing LND in all patients and those who are cLN negative include treatment center type and distance to the treatment center. Additional studies to determine the accuracy of clinical staging and assess novel preoperative imaging modalities that evaluate nodal involvement are indicated.
Moderately hypofractionated radiotherapy for localized prostate cancer: Long-term outcomes for 854 consecutive patients treated over 10 years (70 Gy in 2.5 Gy/fraction).
Authors: Mian Omar Y. , Abu-Gheida Ibrahim , Kotecha Rupesh , Weller Michael A. , Reddy Chandana A. , Kupelian Patrick , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Stephenson Andrew J. , Klein Eric A. , Shah Chirag , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D. 
Published: March 2019

78 Background: Moderately hypofractionated radiotherapy has been increasingly adopted in the management of localized prostate cancer (PCa). We report 10-year outcomes for patients treated with intensity modulation radiation therapy (IMRT) for localized PCa with 70 Gy in 28 fractions at 2.5 Gy/fraction. Methods: This retrospective study included 854 consecutive patients with localized PCa treated with image-guided moderately hypofractionated IMRT at a single institution between 1998 and 2012. Patients with a single intermediate-risk factor were considered to have favorable intermediate-risk (FIR) disease; multiple intermediate-risk factors were considered unfavorable (UIR). Biochemical relapse free survival (bRFS), clinical relapse free survival (cRFS), overall survival (OS) and PCa specific mortality (PCSM) were analyzed used Kaplan-Meier analysis. Grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded (CTCAE v4.03). Results: The median follow-up was 11.3 years (Max. 19 years). For patients with low-risk (LR, 31%), FIR (28%), UIR (12.5%), and high-risk (HR, 28.5%) disease the 10 year bRFS rates were 88%, 78%, 71% and 42%, respectively (p < 0.0001). The number of patients receiving no ADT, 1-6 months, or > 6 months of ADT were 39%, 50%, and 11%, respectively, reflecting practice patterns during this treatment period. The 10-year cRFS were 95%, 91%, 85% and 72% for patients with LR, FIR, UIR, and HR, respectively (p < 0.0001). The 10-year actuarial OS rate was 69% (95% CI 66-73%) and the 10-year PCSM was 6.8% (95% CI 5.1-8.6%) overall. For patients with LR, FIR, UIR and HR disease, the 10 year PCSM rates were 2%, 5%, 5% and 15%. 10-year cumulative incidence of grade ≥3 GU and GI toxicity was 2% and 1%, respectively. Multivariate analysis identified associations between clinical variables (ADT use, PSA nadir < 0.5ng/ml, and ISUP Grade Group) and bRFS, cRFS, and PCSM. Conclusions: Moderately hypofractionated IMRT with daily image guidance for localized PCa demonstrates favorable 10-year oncologic outcomes with a low incidence of toxicity for patients across all risk groups.
The molecular hallmarks and clinical consequences of tumor hypoxia in prostate cancer.
Authors: Vinayak Bhandari , Liu Lydia , Espirritu Shadrielle , Lalonde Emilie , Yamaguchi Takafumi , Heisler Lawrence , Livingstone Julie , Huang Vincent , Shiah Yu-Jia , Sabelnykova Veronica , Yousif Fouad , Fraser Michael , Chua Melvin , Van Der Kwast Theodorus , Liu Stanley K. , Boutros Paul Christopher , Bristow Robert G. 
Published: March 2019

81 Background: Localised prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumours. Prostate tumour cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumours with low levels of oxygen (hypoxia) have poor clinical outcomes. Methods: Hypoxia was measured using multiple mRNA-based signatures. We examined 548 patients with localised prostate cancer and statistically assessed the association of hypoxia with copy-number alterations (CNAs), single-nucleotide variants (SNVs), genomic rearrangements, focal genomic events ( i.e. kataegis, chromothripsis), telomere length, clinical indices ( i.e. grade, stage) and subclonal architecture. Results: Elevated hypoxia was associated with allelic loss of PTEN, higher rates of chromothripsis and intraductal and cribriform carcinoma (IDC-CA). To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumour microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups. Patients with localized prostate cancer that have polyclonal tumours with elevated hypoxia, allelic loss of PTEN and IDC-CA were at the highest risk of rapid biochemical failure (P = 3.48 x10-3, Logrank test) and metastasis (P = 4.61 x 10-3, Logrank test), even after controlling for T-category, Gleason score and pre-treatment PSA. Conclusions: These data suggest that the aggressiveness of prostate cancers is driven by the interplay of the tumour microenvironment, tumour evolutionary trajectories and its genomic mutational profile.
Concordance of systematic and fusion biopsy with surgical pathology.
Authors: Yu Alice , Yamany Tammer , Hanna Nawar , Nicaise Eduoard , Mojtahed Amirkasra , Harisinghani Mukesh , Wu Chin-Lee , Dahl Douglas M. , Wszolek Matthew , Blute Michael L. , Feldman Adam S. 
Published: March 2019

93 Background: Multiparametric MRI is increasingly used in prostate cancer detection. Previous studies have shown that detection rate of clinically significant cancer is higher in MRI targeted biopsy than systematic biopsy. However, the concordance between the Gleason score on fusion biopsy and radical prostatectomy is less well known. The objective of this study is to look for predictors of histopathologic concordance between biopsy (fusion and systematic) and radical prostatectomy. Methods: We used an institutional database of men who underwent mpMRI-ultrasound fusion targeted and systematic biopsy followed by radical prostatectomy. Gleason score on targeted, systematic and combination (targeted + systematic) biopsy were compared with Gleason score on radical prostatectomy, and concordance was recorded. The McNemar test was used to compare concordance and upgrade rates. Predictors of concordance and upgrade such as age, prostate volume, PSA, PSA density, Gleason score on biopsy, number of targets reported on mpMRI, and PI-RADS score were evaluated with Fisher’s exact test and logistic regression. Results: Surgical pathology was concordant with 47.4% of systematic biopsies, 52.0% of targeted biopsies and 58.4% of combination biopsies. There was no significant difference in concordance rates between systematic and targeted biopsy (P = 0.37). However, combination biopsy was superior to both systematic (RR 1.23, 95% CI 1.08-1.40, P = 0.03) and targeted biopsy (RR 1.12, 95% CI 1.02 – 1.24, P = 0.03) in predicting concordance with surgical pathology. Risk of upgrade to a higher Gleason score on surgical pathology was significantly lower with combination biopsy compared to systematic (RR 0.57, 95% CI 0.46-0.69, P < 0.001) or targeted biopsy alone (RR 0.72, 95% CI 0.61-0.84, P = 0.001). Upgrade rates were 43.9% for systematic biopsy, 34.7% for targeted, and 24.9% for combination. Lastly, we found no significant predictors of concordance or upgrade. Conclusions: Combination biopsy is associated with the highest concordance rate between biopsy and radical prostatectomy when compared with systematic or targeted biopsy alone. Performing targeted biopsy alone will underestimate tumour aggressiveness on surgical pathology.
Validation of a two-gene mRNA urine test for detection of high-grade prostate cancer in German men.
Authors: Tilki Derya , Hessels Daphne , Trooskens Geert , Mulders Susan , Brawer Michael , Van Criekinge Wim , Groskopf Jack , Haese Alexander 
Published: March 2019

96 Background: There is an unmet need for non-invasive methods that can accurately identify patients at increased risk for clinically significant prostate cancer (PCa). SelectMDx is a urine-based molecular test that has been clinically validated for the detection of high-grade PCa. We evaluated SelectMDx clinical performance in a cohort of German men undergoing initial prostate biopsy. Methods: The study population consisted of 443 men sequentially enrolled men who underwent initial prostate biopsy between July 2009 and December 2014 due to suspected PCa. Post-DRE urine was collected from all subjects prior to biopsy, and samples stored at -70C. Urinary HOXC6 and DLX-1 mRNAs were quantified by PCR in May 2018, and RNA results combined with clinical risk factors to determine the likelihood that biopsy would identify ISUP grade group (GG) ≥ 2 (Gleason Score ≥ 7) PCa. We assessed SelectMDx performance for detection of GG ≥ 2 PCa, compared to the PCPT Risk Calculator Version 2.0 (PCPTRC, http://myprostatecancerrisk.com , accessed Oct 7, 2018). Results: For the 443 subjects enrolled, average age was 66 years (median 66, interquartile range 61 to 71), and average serum PSA level 8.8 ng/mL (6.4, 4.8 to 9.7). Cancer was detected in 243/443 (55%) men biopsied (43% GG1, 36% GG2, 9% GG3 and 12% GG4-5). The prevalence of GG2-5 PCa in this population was 31.4% (139/443). For detection of GG2 or higher PCa versus GG1 or no PCa at biopsy, SelectMDx AUC was 0.82 (95% C.I. 0.78-0.86) and the PCPTRC yielded AUC 0.75 (0.70-0.80), P < 0.001. SelectMDx sensitivity was 94% (89-98%), specificity 46% (40-52%), positive predictive value 45% (42-47%) and negative predictive value (NPV) 95% (90-97%). If the initial biopsy had been performed based on SelectMDx results alone, 46% of potentially unnecessary biopsies and 34% of all biopsies would have been avoided, while 5.8% of men with biopsy-detectable high-grade PCa (seven GG2, one GG3) may have had their diagnosis delayed. Conclusions: In this first validation study of SelectMDx in German men, the test’s clinical performance was comparable to the published EU validation study, showing a high NPV for detection of GG2 or higher PCa. These results provide further evidence for the clinical validity of SelectMDx.
Preoperative trial of neoadjuvant abiraterone plus or minus cabazitaxel: Early results.
Authors: Herrera-Caceres Jaime Omar , Goldberg Hanan , Hansen Aaron Richard , Sridhar Srikala S. , Hamilton Robert James , Finelli Antonio , Zlotta Alexandre , Joshua Anthony M. , Fleshner Neil Eric 
Published: March 2019

98 Background: High-risk prostate cancer (PC) has a significant risk of recurrence when treated with unimodal therapy. The utility of neoadjuvant therapy, prior to RP has yet to be defined. The Princess Margaret Cancer Centres’ ACDC study investigates the application of agents used for castration resistant PC in the neoadjuvant setting by comparing the use of abiraterone (AA) + prednisone (P) + leuprolide (LHRH) with or without cabazitaxel (CA) prior to RP in 76 high-risk patients. Herein, we report early results and protocol modifications. Methods: This phase II trial will randomize patients to two treatment arms: Arm A (AA/P + LHRH + CA 25 mg/m2 with peg-filgrastim 6 cycles) or Arm B (AA/P + LHRH) for 6 months prior to RP. The primary objective is to compare the pathological complete response (CR) between the treatment arms. We present the RP outcomes and safety data for the first 13 participants. Results: Out of 13 randomized participants, 10 completed study procedures and underwent RP. One participant (Arm B) completed study drug treatment, but opted for radiation therapy, while 2 participants (both in Arm B) were discontinued due to hepatoxicity. At RP, 2 participants exhibited CR (1 in each group) and an additional 3 patients exhibited near CR (less than 5% tumor volume). The Table demonstrates patient characteristics, pathologic results and Grade 3 adverse events rates. Of note, 2 patients (both in CA arm) developed post-operative thrombo-embolic events post RP and two experienced febrile neutropenia. Conclusions: Early findings indicate significant tumor response with 50% of patients exhibiting CR or near CR. Reduction in dosage of Cabazitaxel to 20 mg/m2 as well as need for extended post-operative thromboembolic prophylaxis have been implemented. ACDC early outcomes. [Table: see text]