bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penile and uterine cervical squamous cell carcinomas: A comparative genomic profiling study.
Authors: Jacob Joseph , Pinkhasov Rubin , Shapiro Oleg , Liu Nick , Gay Laurie M. , Alexander Brian Michael , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Venkataprasanth P. , Miller Vincent A. , Corona Robert John , Ross Jeffrey S. , de La Roza Gustavo , Bratslavsky Gennady 
Published: March 2019

514 Background: Metastatic penile (mPSCC) and uterine cervical squamous cell carcinoma (mCSCC) are aggressive forms of malignancy with limited treatment options. We used comprehensive genomic profiling (CGP) to compare the genomic alterations (GA) and their potential impact on targeted and immunotherapy options of mPSCC and mCSCC. Methods: 78 metastatic mPSCC and 604 mCSCC underwent CGP using a hybrid-capture-based next-generation sequencing assay with a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median age of mPSCC men was higher than mCSCC women. The HPV+/CDKN2A- status was more frequent in the mCSCC than mPSCC. The GA/tumor were similar for both tumor types (table). TP53 mutations were more common in mPSCC likely linked to loss of original HPV+ status. TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC. MSI-High status was extremely rare in all cases, but the relatively high frequencies of TMB ≥ 10/20 mut/Mb in both mPSCC and mCSCC were noteworthy. Examples of patients with mCSCC and mPSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC and mPSCC share a variety of genomic features, the 2 tumor types can nonetheless be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with viral identification much higher in the mCSCC group. There are opportunities for targeted therapies in both groups predominantly identified in the MTOR pathway. Numerous cases with significantly elevated TMB in both mPSCC and mCSCC suggest that immunotherapies might be of benefit in a subset of patients. [Table: see text]
PD-L1 and p16 expression in penile squamous cell carcinoma from an endemic region.
Authors: De Bacco Mateus Webber , Fay Andre P. , Carvalhal Gustavo , Copetti Josenel , McGregor Bradley Alexander , Sonpavde Guru , Wagner Mario 
Published: March 2019

515 Background: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited treatment option in advanced stages. Brazil has one of the highest incidences of PSCC in the world, and different biology has been postulated across distinct populations. We evaluate PD-L1 and p16 expressionand its association with clinical outcomes in PSCC patients from an endemic region. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 35 patients with PSSC. PD-L1 and p16 expression were evaluated by immunohistochemistry. PD-L1 tumor positivity (PD-L1+) was defined as ≥1% tumor cell membrane staining using ZR3 antibody. Any tumor cell membrane staining of p16 was considered positive (p16+). Baseline characteristics including tumor size, stage, grade, subtype, and survival data were collected. Comparisons between PD-L1 and/or p16 expression and clinicopathological features were evaluated using fisher exact testor wilcoxon rank sum tests. Cox model tested the association of PD-L1 and/or p16 expression and 5-year-survival. Results: Clinical features were summarized in table1 according to PD-L1 expression. PD-L1 positivity was significantly associated with larger tumor size ( p=0.027), and p16 expression, a surrogate for HPV infection ( p=0.002). There was a non-statistically significant trend to a shorter 5-year-survival for PD-L1+/p16+ vs. PD-L1-/p16- patients (30.8% vs. 60.6% HR: 2.27 95% CI - 0.61-8.42 p=0.22). Conclusions: PD-L1 expression appears to be associated with p16 expression, larger tumors, higher proliferative rate and worse clinical outcomes in patients with PSCC. provide additional rationale for PD1/PD-L1 inhibitors alone or in combination with chemotherapy foradvanced PSCC in endemic regions. Clinical features. [Table: see text]
Comprehensive and epidemiological characterization of urachal adenocarcinoma: A pan-Canadian collaboration.
Authors: Wiam Belkaid , Hamilou Zineb , Soulieres Denis , Canil Christina M. , Zalewski Pawel , Heng Daniel Yick Chin , Da Silva Vitor , Castonguay Mathias , Routy Bertrand , Blais Normand 
Published: March 2019

516 Background: Urachal cancer is a rare form of urothelial cancer representing 0,1-0,2% of bladder cancers. The exact underlying cause of urachal cancer is still widely unknown and there is much speculation on multiple factors such as genetic and environmental ones that may play a role. Moreover, given the lack of treatment consensus, we proposed the first study that assesses the clinical, genetic and molecular features of this disease in Canada. Methods: This ongoing study is recruiting in Canadian centers from the year 2005 onwards. The clinical database is constructed using the hospital electronic medical file. In addition, pathological tissues are centralized for molecular and genetic analysis. Results: To this date, 15 patients were included, 12 males and 3 females. Median age was of 49 years old with a disease distribution of Stage II (4), Stage III (3) and Stage IV (4). 8/15 patients developed metastasis after initial cystectomy in the lungs (n = 7), peritoneum (n = 2), lymph nodes (n = 4), and bone (1). Median survival of all patients was 23 months. Metastatic patients after cystectomy had a shorter overall survival (OS) of 21 months compared to non-metastatic patients (OS – not reached). The majority of metastatic patients (6/8) died of their underlying malignancy. Conclusions: This study is an ongoing country-wide effort to expand knowledge of this poorly studied disease. With ongoing accrual, the clinical features will be better defined and further molecular characterization will be performed to better predict response to therapy.
Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in patients with testis cancer in the salvage setting.
Authors: Albers Peter , Nini Alessandro , Hiester Andreas , Winter Christian , Lusch Achim , Lorch Anja 
Published: March 2019

524 Background: Although the use of PC-RPLND in testis cancer patients in the salvage setting has been reported, existing data characterizing histologic findings are poor. Methods: 179 PC-RPLNDs after salvage chemotherapy were selected from a prospective database of 504 RTRs (434 patients, 2003-2018). Uni- and multivariate analyses were used to assess the impact of preoperative positive markers, residual diameter, and type of salvage chemotherapy (either conventional salvage [CTX] or high dose chemotherapy [HDC]) on vital cancer histology (including teratoma with malignant transformation) at PC-RPLND. Results: Median age was 37 years (IQR 30-45). 11.5% of patients underwent thoraco-abdominal PC-RPLND and adjunctive surgeries were needed in 41.7%. Clavien-Dindo > II complications were registered in 5% of cases. After stratification for CTX and HDC, AFP only, β-HCG only, and both markers elevated were seen in 27.8%, 7.8%, and 2.2%, and 33%, 18.2% and 5.7% of patients, respectively. Overall, necrosis, postpubertal teratoma, and vital cancer were found in 30%, 29%, and 42%, respectively. Vital cancer was found in residual tumor sizes of < 2 cm and ≥ 2 cm in 41.2% and 32.9%, respectively. After stratification for CTX and HDC, patients after CTX had lower rates of necrosis (26% vs. 34%, p = 0.2) but not of vital cancer (42% vs. 42%, p = 0.9). The predictors of vital cancer were represented by the presence of AFP elevation only (OR 4.7, p = 0.001) and both markers elevated (OR 8.6, p = 0.02). Conclusions: In the salvage setting, the rate of vital cancer in residual tumor is three times higher as compared to the first-line setting. Presence of AFP elevation only or both markers elevated represent predictors of vital cancer. PC-RPLND has to be performed after salvage chemotherapy independent of the residual tumor diameter. [Table: see text]
Analysis of overall survival (OS) based on early tumor shrinkage in the phase III METEOR study of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC).
Authors: Duran Ignacio , Maroto Pablo , Suárez Cristina , Castellano Daniel E. , Garcia del Muro Xavier , Costa Luis , Martin-Couce Lidia , Benzaghou Fawzi , Thomas Stephane , Markby David W. , Choueiri Toni K. 
Published: March 2019

550 Background: In the phase 3 METEOR study (NCT01865747), cabo improved OS (median 21.4 vs 16.5 mo; HR, 0.66; 95% CI, 0.53–0.83), progression-free survival and objective response rate compared with eve in patients (pts) with previously treated advanced RCC (Choueiri 2016). Retrospective studies have shown that early tumour shrinkage (eTS), based on target lesion reduction from baseline to first post-baseline scan, has predictive value for targeted therapies in RCC (Grunwald 2015; Grunwald 2016); here we evaluate its impact on OS in METEOR. Methods: In total, 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd), stratified by MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed by independent radiology review using CT/MRI scans at baseline, every 8 wk for the first 12 mo and every 12 wk thereafter. Median OS was estimated for pts with ≥30% eTS, any eTS or no eTS at first post-baseline scan (week 8); data cutoff, 2 October 2016 (Motzer 2018). Results: Median follow-up was 28 mo (IQR 25, 30). Median (range) time to objective response was 1.91 (1.6, 11.0) mo with cabo and 2.14 (1.9, 9.2) mo with eve, and corresponded to the time to the first post-baseline scan. A greater proportion of pts had ≥30% eTS with cabo (20%) than with eve (5%) and the rate of any eTS was higher in the cabo arm (73%) than with eve (47%; Table). Median OS with cabo vs eve for pts with ≥30% eTS was not reached (NR; 95% CI, 23.7–NR) vs 10.2 mo (95% CI, 3.9–NE), respectively (stratified HR, 0.45; 95% CI, 0.21–0.95; p<0.05). Median OS with cabo vs eve for pts with any eTS was 23.7 (95% CI, 21.7–27.7) vs 17.3 mo (95% CI, 15.4–20.8), respectively; (stratified HR, 0.62; 95% CI, 0.48–0.80; p<0.05). OS was similar for cabo and eve for pts with no eTS. Conclusions: Cabo demonstrated a higher rate and greater magnitude of eTS at first post-baseline scan compared with eve, and eTS was associated with prolonged OS in pts treated with cabo. Clinical trial information: NCT01865747. [Table: see text]
Molecular characterization of longitudinally tracked prostate cancer foci in men on active surveillance for low-risk disease.
Authors: Tosoian Jeffrey J. , Salami Simpa Samuel , Nallandhighal Srinivas , Jones Tonye A. , Plouffe Komal R. , Elkhoury Fuad F. , Morgan Todd Matthew , Liu Chia-Jen , Kunju Lakshmi Priya , Montgomery Jeffrey S. , Natarajan Shyam , Sisk Anthony , Tomlins Scott A. , Palapattu Ganesh S. , Marks Leonard S. 
Published: March 2019

56 Background: The biological trajectory of Gleason score 6 (GS6) prostate cancer (PCa) in men on active surveillance (AS) is unknown. We herein evaluate the potential for high grade PCa to arise clonally from GS 6 disease and determine the capacity of tissue-based biomarkers to predict grade progression. Methods: Men on AS with GS6 PCa who underwent magnetic resonance imaging/ultrasound (MRI/US) fusion biopsy on two occasions from 2012 through 2017 were enrolled. Tumor foci were tracked and re-sampled using the MRI/US fusion biopsy platform. ERG immunohistochemistry (IHC) and DNA/RNA next generation sequencing (NGS) were performed on formalin-fixed paraffin-embedded (FFPE) initial and repeat biopsy specimens to assess tumor clonality and evaluate candidate molecular markers of PCa grade progression. Results: Sixty-seven men of median age 64 years (IQR 59-69) and PSA 4.9 ng/ml (IQR 3.3-6.4) underwent repeat sampling of a single tracked tumor focus using MRI/US fusion biopsy. The median interval to repeat biopsy was 11 months (IQR 6-13). On repeat biopsy, 31 (46%) men progressed to high-grade (GS≥7) disease (n = 24, GS 3+4 = 7; n = 7, GS ≥4+3 = 7). Among the 67 subjects, ERG IHC status was concordant between initial and repeat biopsy in 64 (96%). Of 134 total specimens obtained (67 initial + 67 repeat biopsies), ERG status determined by NGS was concordant with ERG status by IHC in 132 (99%). Comparing the initial biopsy specimens in men who did versus did not undergo grade progression on follow up biopsy, derived cell cycle progression (CCP) scores (median 57.3 vs. 44.0, p = 0.11) and genomic prostate scores (GPS; median 73.8 vs. 64.4, p = 0.15) were not significantly different. Similarly, expression of FOLH1, PCAT4, SCHLAP1, and SPINK1 on initial biopsy did not significantly differ among men who did and did not undergo grade progression. Conclusions: Use of MRI/US fusion biopsy facilitated resampling of the same clonal focus of cancer over time, with high concordance of ERG status determined by both IHC and NGS. Derived genomic classifiers and candidate individual gene expression markers measured on initial biopsy tissue were not significantly different between patients who progressed and those who did not.
Evolving patterns of metastatic renal cell carcinoma: A meta-analysis.
Authors: Lin Justin , Oh William K. , Liaw Bobby Chi-Hung , Galsky Matt D. , Tsao Che-Kai 
Published: March 2019

563 Background: Advances in diagnostic and treatment modalities have resulted in better outcomes in metastatic renal cell carcinoma (mRCC) patients. With new therapies extending survival, we hypothesize that pattern of metastatic disease has evolved over time. We assessed the pattern of metastases as reported in baseline characteristics of prospective clinical trial patients between 1990 and 2018. Methods: This study identified all phase I-III mRCC therapeutic clinical trials published between January 1990 and July 2018 in PubMed and ClinicalTrials.gov. Studies that included patients with other cancers or did not report metastases were excluded. Data was stratified to examine differences in three listed treatment eras for first-line therapy. Linear regression models were used to evaluate temporal trends and subcategorized as either First Line Only treatments (FLO) or Second-Line and Beyond (SLB). Results: 127 clinical trials encompassing 16534 subjects were identified. Between 1990 and 2018, rates of lymph node metastases in the FLO population increased significantly at 1.03% per year ( P < 0.05). The rate of lung and liver metastases in FLO showed a trend of increase at 0.48% and 0.04% per year, respectively, but decreased -0.73% and -0.15% per year in the SLB population. Moreover, rate of bone metastasis showed a trend of increase in both populations, particularly between the VEGF/TKI and Immunotherapy/TKI eras in the SLB population (18.89% to 29.19%). Conclusions: Notable changes were found in the pattern of metastasis in patients with mRCC. Increasing rate of bone metastasis may warrant dedicated bone imaging for routine staging in patients with mRCC. These evolving patterns may have important implications in treatment selection and prognosis in this patient population. [Table: see text]
Impact of body mass index (BMI) on treatment outcomes to immune checkpoint blockade (ICB) in metastatic renal cell carcinoma (mRCC).
Authors: Lalani Aly-Khan A. , Xie Wanling , Flippot Ronan , Steinharter John A. , Harshman Lauren Christine , McGregor Bradley Alexander , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: March 2019

566 Background: An elevated BMI is associated with improved survival in mRCC patients treated with oral targeted therapies (TT); however, this relationship in the contemporary treatment landscape is unknown. We investigated the effect of BMI on outcomes in mRCC patients treated with PD-1/PD-L1 ICB. Methods: We analyzed 147 patients with mRCC who received ICB alone or in combination with VEGF or other therapies. The association of BMI with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic and Cox regression models, adjusted for known prognostic factors including International Metastatic RCC Database Consortium (IMDC) risk groups, line of therapy, ECOG (0 vs ≥1), and histology. Results: Median follow up was 25.5 (4.3-78.6) months (mos). Median time on ICB was 5.1 ( < 0.1-69.7) mos. Overall, most patients were male (71%), had clear cell histology (85%), and were intermediate risk (60%). 43% received first-line ICB and 45% received ICB in combination therapy (37% with VEGF inhibition, 8% with other therapies). At ICB initiation, 46 (31%) patients were considered underweight/normal weight (BMI < 25 kg/m2), 56 (38%) overweight (BMI 25-30 kg/m2), and 45 (31%) obese (BMI > 30 kg/m2). Patients with high BMI (≥ 25) had improved OS (median 34.3 vs 16.7 mos, 2-yr OS 61 vs 42%, p = 0.016) compared to those with low BMI ( < 25), with an adjusted hazard ratio (HR) = 0.74 (0.44-1.26). ORR (33 vs 28%, p = 0.7) and PFS (median 8.2 vs 5.9 mos, p = 0.4) did not statistically differ. Patients who experienced a BMI change from ≥ 25 at start of first-line TT to < 25 at start of subsequent-line ICB displayed shorter OS (adjusted HR = 2.25 (0.94-5.35)) compared to those with no change. Conclusions: High BMI appears to be associated with improved OS in mRCC patients treated with ICB. This contemporary data is consistent with the “obesity paradox” demonstrated in the TT era. Validation with the IMDC database and examination of underlying mechanisms are ongoing.
Efficacy of targeted therapy (TT) after checkpoint inhibitors (CPI) in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Kalirai Austin , Wood Lori , Lalani Aly-Khan A. , Heng Daniel Yick Chin , Ghosh Sunita , Iafolla Marco Adelmo James , Kollmannsberger Christian K. , Soulieres Denis , Castonguay Vincent , Bossé Dominick , Winquist Eric , Kapoor Anil , Basappa Naveen S. 
Published: March 2019

568 Background: While the use of CPI has demonstrated clinical benefit in patients with mRCC, data showing the efficacy of subsequent TT is limited. This real-world analysis evaluated the efficacy of TT post CPI in mRCC patients. Methods: Data was collected and analyzed from CKCis. Patients with mRCC who received TT after CPI were identified and analyzed based on line of therapy. Time to treatment failure (TTF – time from starting first subsequent TT to stopping TT) and overall survival (OS) were calculated. Hazard Ratio (HR) calculations were adjusted for IMDC group and age. Results: 102 patients were treated with TT post CPI (table). Those who received first-line ipilimumab + nivolumab (I/N) versus a vascular endothelial growth factor inhibitor (VEGFi) + CPI combination prior to second-line TT had a median TTF of 8.0 vs 5.2 months (m) (HR=0.43, 95% CI: 0.13-1.44) and median OS of 16.5 m vs not reached (HR=0.76, 95% CI: 0.11-5.24). Patients who received a VEGFi versus a mammalian target of rapamycin inhibitor (mTORi) as third-line TT had a median TTF of 7.6 vs 4.4 m (HR=0.52, 95% CI: 0.24-1.10) and median OS of 21.7 vs 16.2 m (HR=0.41, 95% CI: 0.16-1.08). All third-line TT patients received first-line VEGFi and second-line nivolumab. Of the third-line VEGFi TT patients, 24 received axitinib (TTF 7.1 m, OS 21.7 m) and 22 received cabozantinib (data immature). Conclusions: Activity of TT in mRCC patients after CPI is demonstrated in multiple lines. In second-line, VEGFi TT had numerically better outcomes after I/N than after VEGFi+CPI combination. Efficacy of third-line TT was seen with a trend favoring VEGFi over mTORi. Axitinib in the third-line has notable activity after CPI, while data on cabozantinib and fourth-line TT are maturing. These results support the use of VEGFi after CPI in mRCC patients. [Table: see text]
Systematic review and REMARK scoring of renal cell carcinoma (RCC) prognostic circulating biomarker manuscripts.
Authors: Iafolla Marco Adelmo James , Picardo Sarah Louise , Aung Kyaw Lwin , Hansen Aaron Richard 
Published: March 2019

569 Background: No validated biomarkers exist to help guide prognosis of RCC patients. This study seeks to determine the current state of published prognostic RCC biomarker manuscripts and evaluate their quality using the REMARK criteria. Methods: The phrase “(renal cell carcinoma OR renal cancer OR kidney cancer OR kidney carcinoma) AND circulating AND (biomarkers OR cell free DNA OR tumor DNA OR methylated cell free DNA OR methylated tumor DNA)” was searched in Embase, Medline and PubMed during March 2018. One author (MI) selected all relevant manuscripts from the search results, and two authors (MI and SP) independently scored all relevant manuscripts using the REMARK guidelines (maximum 20 points comprised of 20 items subdivided into 48 criteria). Results: The search identified 525 publications: 73 were valid, 436 were rejected, and 26 were uncertain of their relevance. Amongst the valid publications, 33 were manuscripts of primary research (remainder: 26 review papers, 14 abstracts): manuscripts evaluating ≥ 2 biomarkers (n = 8) and novel biomarkers not published elsewhere (n = 7) comprised the majority. The median REMARK score was 10.6 (range 6.4-14.2). All manuscripts stated their marker, study objectives and method of case selection. The lowest scoring criteria were lack of: description of time between storage of blood/serum and marker assay (n = 2); flow or study profile diagram (n = 2); blinding of the person making the marker assessment to clinical outcomes (n = 3); and pre-specified hypotheses (n = 3). In total, only 8 studies reported a hazard or odds ratio. Using Pearson’s correlation, there was no association with either year of publication (median 2014; range 2004-2018; r2 = 0.14; p = 0.44) or impact factor (median 5.168; range 1.2-26.303; r2 = 0.24; p = 0.17) with REMARK score. Conclusions: Despite several published manuscripts on RCC prognostic biomarkers, most poorly adhere to the REMARK guidelines; this may be the cause for the paucity of a validated RCC biomarker to help supplement or supplant current clinical prognostic criteria. Better designed studies and appropriate reporting of methods, results and interpretation are required to address this urgent unmet need.