bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant KRAS and TP53 with high mutation allelic frequency in ctDNA as poor outcome predictors in metastatic pancreatic cancer.
Authors: Guan Shasha , Shi Yan , Han Quanli , Li Jie , Lv Yao , Yan Huan , Han Lu , Chen Yang , Qian Niansong , Wang Zhikuan , Shi Huaiyin , Dai Guanghai 
Published: May 2019

e15763 Background: This study was to investigate the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in metastatic pancreatic cancer (MPC). Methods: From 2015 to 2018 in our center, 40 MPC patients treated with nab-paclitaxel based first-line chemotherapy were prospectively collected both tumor tissue and blood samples, in which the genomic profiling of 425 genes was identified by next-generation sequencing. High mutation allelic frequency (MAF) was defined > 30% and > 5% in tumor tissue and blood, respectively. Kappa statistics were used to compare mutant (mt) genes in tissue and ctDNA. Progression-free and overall survival (PFS, OS) were assessed with Kaplan-Meier and Cox methods. Results: Among 40 MPC patients, tumor tissue and blood samples were available in 34 and 38 patients for somatic and germline alternation test, respectively. The most commonly mutant gene were KRAS (31/34 in tissue with a median MAF of 29.4%, 29/38 in ctDNA with a mMAF of 8.2%), and TP53 (28/34 in tissue with a mMAF of 31.1%, 25/38 in ctDNA with a mMAF of 7.4%). Moderate agreement was seen between ctDNA and tumor tissue (mt KRAS: κ = 0.54, P = 0.001; mt TP53: κ = 0.74, P < 0.001). Mutation in CDNK2A and SMAD4 genes were detected in 8 and 6 patients in tissue and ctDNA, respectively. Germline alternation was found in 7 genes in 9 patients (9/40). High MAF of mt KRAS (r = 0.51, P = 0.005) or mt TP53 (r = 0.50, P = 0.005) in ctDNA was correlated with high CA199 levels (> 5000 u/ml) at baseline. MT KRAS in tissue with high MAF was associated with poor OS (high 7.5m vs low 10.1m, P = 0.001) in univariate and multivariate analyses (HR 3.87, 95%CI 1.47 to 10.19). Univariate analyses showed mt KRAS and mt TP53 in ctDNA with high MAF were associated with poor PFS ( KRAS and TP53: high 3.4m and 3.0m vs low 6.1m and 5.7m, P = 0.001 and P = 0.004, respectively) and OS ( KRAS and TP53: high 5.3m and 5.3m vs low 12.6m and 10.1m, P < 0.001, respectively). The presence of ctDNA in any above four mt driver gene with high MAF was associated with poor PFS (HR 3.79, 95%CI 1.71 to 8.42) and OS (HR 7.21, 95%CI 2.69 to 19.34) in multivariate COX model, when adjusted by age, sex, tumor differentiation, and baseline CA199 level. Conclusions: The presence of mt KRAS and mt TP53 with high MAF in ctDNA was associated with worse PFS and OS in MPC patients. Peripheral ctDNA testing demonstrated an alternative promising prognostic biomarker for MPC patients before treatment.
Pancreatic cancer: Assessment of neoadjuvant chemotherapy outcome based on radiomics of pretreatment computed tomography.
Authors: Li Xiang , Tang Tianyu , Bai Xueli , Liang Tingbo 
Published: May 2019

e15767 Background: The objective response rate to neoadjuvant chemotherapy (NAC) was limited to around 35% in pancreatic cancer and as more as 30% patients show no benefit to NAC. In this instance, predicting the response to NAC may play an important role in individual treatment for pancreatic cancer patients. We aim to evaluate contrast enhanced-computed tomography (CE-CT) features in predicting treatment response and survival after neoadjuvant chemotherapy (NAC) for patients with borderline resectable and locally advanced pancreatic cancer. Methods: Sixty-one pancreatic cancer patients receiving NAC were enrolled and underwent abdominal CE-CT before treatment. All patients were divided into groups according to the changes of tumor size after treatment. 396 radiomics features were extracted from three-dimensional ROIs (region of interest) based on pretreatment CE-CT images of each patient. The optimal features were selected and three supervised machine learning classifiers were developed. Finally, univariate and multivariate analyses were performed to evaluate the capability of the selected features in predicting histopathologic response and outcomes. Results: Nine, seven and five radiomics features were selected as optimal features for three experiments respectively. Two features, Haralick Entropy and Histogram Entropy, were found consistent in experiments and were both higher in patients with tumor enlargement. Moreover, lower Histogram Entropy was significantly associated with a better histopathologic response (p = 0.008) and smaller tumor size (p = 0.041) in patients with tumor resection. In univariate Cox regression analysis, lower Histogram Entropy (P = 0.006) and lower Haralick Entropy (P = 0.001) predicted a better prognosis. Meanwhile, lower Haralick Entropy (p = 0.048) was independent predictor for longer survival time in multivariate Cox regression analysis. Conclusions: Radiomics features are strongly correlated with NAC treatment response and prognosis in pancreatic cancer, suggesting the great potential of imaging radiomics to help tailoring the treatment into the era of personalized medicine
Validation of lymphocyte to monocyte ratio in resected small bowel adenocarcinoma as a predictor of survival.
Authors: Huffman Brandon M. , Jin Zhaohui , Yadav Siddhartha , Patel Shruti , Mahipal Amit , Halfdanarson Thorvardur Ragnar 
Published: May 2019

e15799 Background: Lymphocyte to monocyte ratio (LMR) has been described as a prognostic factor in many solid tumors including colorectal adenocarcinoma. LMR has not been investigated as a prognostic factor in small bowel cancers. In this study, we aimed to evaluate prognostic factors in resected small bowel adenocarcinoma including LMR. Methods: Two hundred forty-one patients who underwent resection for stage I-III small bowel adenocarcinoma were retrospectively identified utilizing the pathology database at a single tertiary referral institution from 1994 to 2015. All patients had complete follow up data and were included in the survival analysis. One hundred sixty-nine patients had preoperative peripheral blood counts available for analysis. Plot of martingale residuals against LMR were used to establish best cutoff points for LMR. A training set for LMR included consecutively identified patients from 2006 to 2015, and a validation cohort including patients identified from 1994 to 2005 was used. Overall survival was performed utilizing Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed and all tests were two sided. P value of < 0.05 was considered significant. Results: Median overall survival for the entire group was 54.5 months (95% CI: 37.2-81.2 months) with 5- and 10-year overall survival of 48% and 35%. The training set for LMR included 81 patients, and the validation set included 88 patients. The cutoff of 1.56 was chosen based on most significant p value (p = 0.002). When combined, the overall area under the curve (AUC) for LMR was 0.63, p < 0.01, (specificity 37.3%, sensitivity 90.1%, positive predictive value 33.1%, and negative predictive value 92.2%). There were 126 patients with LMR > 1.56 and 43 patients with LMR < 1.56 in the entire cohort. In multivariate analysis, LMR under 1.56 was a negative prognostic factor, HR = 2.20 (95% CI: 1.27-3.84, p < 0.01). In addition to LMR, age > 60 years and advanced T stage were independently negative predictors of overall survival in all patients. Conclusions: Lymphocyte-to-monocyte ratio < 1.56 is a validated negative prognostic factor in resected small bowel adenocarcinoma.
Validation of an artificial intelligence algorithm applied to a metabolic substrate analysis of urine for detection of urothelial cancer.
Authors: Kaludov Nikola , Siddiqui Mohummad Minhaj , Kates Max , Tripathi Hemantkumar , Salma Amatul Nasir , Lotan Yair , Steinberg Gary D. 
Published: May 2019

e16008 Background: Urine tests such as urine cytology are commonly used for the diagnosis and monitoring of urothelial cancer. These tests are often limited by issues related to sensitivity or specificity. It is well known that derangement of cellular metabolism is one of the hallmarks of carcinogenesis. As urothelial cancer is in constant contact with urine, we hypothesize that metabolite composition in the urine may provide insight into possible urothelial cancer presence in the urinary tract. In this study, we evaluated a metabolomics based urine test for the detection of urothelial cancer. Methods: In this prospective, multi-institutional IRB approved study, urine samples were collected from a total of 57 urothelial cancer patients and non-urothelial cancer controls. Gas chromatography profiles of urine small molecule metabolites were generated to yield over 2400 data points of metabolite peaks and troughs for every urine sample. A machine-learning based algorithm (Abilis Life Sciences) was constructed to predict urothelial cancer versus non-cancer controls through analysis of peaks and trough patterns of urine metabolomics profiles. Predictions were made in a blinded fashion and descriptive statistics of test sensitivity and specificity were generated. Results: The urine metabolite composition of 57 patients were analyzed and urothelial cancer predictions were generated. The test demonstrated an overall accuracy of 89.5% (51 out of 57 cases correctly predicted). The sensitivity of the test was 97.1% (34 out of 35) and specificity was 77.3% (17 out of 22). The Positive Predictive Value is 87.2%, while the Negative Predictive Value is 94.4%. The area under the curve for the receiver operating characteristic curve was 0.87. Conclusions: Urine based metabolic profile analysis using artificial intelligence algorithms is a promising potential diagnostic test for detection of urothelial cancer. Further testing is ongoing to increase robustness of the validation.
Assessment of treatment patterns of nonmuscle invasive bladder cancer patients in privately insured patients.
Authors: Tyson Mark , Guo Amy , Rotter David , Papademetriou Eros , Spigelman Samuel , Potluri Ravi C. 
Published: May 2019

e16012 Background: 75–85% of bladder cancer patients present with non-muscle invasive disease (NMIBC). While transurethral resection of bladder tumors (TURBT) is the initial standard treatment for visible lesions, there is variation in the utilization of adjuvant intravesical treatments in the real world. This study aims to assess current treatment patterns in privately insured NMIBC patients. Methods: Bladder cancer patients were identified from Truven MarketScan Commercial and Medicare Supplemental databases using ICD-9/ICD-10 codes. In the absence of tumor staging information, patients were considered to have NMIBC based on diagnosis of CIS or an algorithm centered on the use of TURBT, intravesical treatments and absence of immediate progression to muscle invasive disease. Patients were included in the final cohort if they had one year of continuous insurance coverage prior to index diagnosis, and were without any bladder cancer treatment during this period. Results: 18,683 patients met the eligibility criteria and had a median follow-up of 23 months; the mean age was 68.6 years and 75% were male. The median time from diagnosis to TURBT was 8 days. 54% of the cohort had an intravesical treatment (35% specifically with Bacillus Calmette–Guérin (BCG), with median time from TURBT of 69 days). 77% of BCG-treated patients received 5 or more administrations during induction. However, only 22% of patients received maintenance BCG after induction. 16% of the total cohort developed a recurrence or progression during the available follow-up; five percent underwent a cystectomy, while seven percent were diagnosed with metastatic disease. Only 4% of patients with 5 or more BCG administrations during induction met the definition for being BCG-unresponsive; this is influenced by the low adherence to BCG maintenance protocol. Conclusions: Only a third of NMIBC patients are given intravesical BCG treatment. Adherence to BCG maintenance protocols is suboptimal. Rates of cystectomy/ exenteration are low, suggesting patients’ preference of bladder preservation and the unmet need for new bladder-sparing alternatives.
Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.
Authors: Nelson Ariel Ann , Wright Matthew David , Khaki Ali Raza , Diamantopoulos Leonidas Nikolaos , Kyasaram Ravi Kumar , Nezami Behtash , Dawsey Scott , Patel Krupen , Eitman Cheryl , MacLennan Gregory , Grivas Petros , Mendiratta Prateek , Ponsky Lee Evan , Hoimes Christopher J. 
Published: May 2019

e16016 Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p < 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.
Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.
Authors: Agarwal Archana , Nassar Amin , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , McGregor Bradley Alexander , Talasaz AmirAli , Lanman Richard B. , Sonpavde Guru 
Published: May 2019

e16027 Background: Penile cancer is a rare disease associated with HPV infection and is known to harbor recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. The median number of ctDNA alterations detected per sample was 2 (range 0-6). Overall, genomic alterations were detected in 15/16 patients (94%) across 21 genes (table 1). Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), TERT promoter (5/16, 31%), PIK3CA (3/16, 19%) and ERBB2 (3/16, 19%). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected with similar prevalences to previously described tumor tissue analyses. New alterations observed on serial ctDNA assays may provide insights regarding tumor biology and inform drug development. [Table: see text]
Association of immune gene expression profiling with vinflunine clinical benefit in metastatic urothelial cancer (mUC).
Authors: de Velasco Guillermo , Dueñas Marta , Bernardini Alejandra , Pinto Alvaro , Alonso-Gordoa Teresa , Puente Javier , González-Peramato María Pilar , Paramio Jesus , Castellano Daniel E. 
Published: May 2019

e16034 Background: There are limited treatment options for mUC after platinum-based chemotherapy failure. Immune checkpoint inhibitors (ICI) have shown a durable benefit but only in a minority of patients (20-25%). Vinflunine remains as a therapeutic option without validated biomarkers. In this study, we sought to analyze the molecular determinants of vinflunine response in mUC. Methods: mUC patients from 4 University Hospitals in Spain who received second-line vinflunine after platinum-based chemotherapy were classified in non-responders (NR: progressive disease ≤3 months; N = 10) or responders (R: response ≥ 6 months, N = 14). Targeted- sequencing of 275 cancer-related genes and a PanCancer Immune Profiling Panel were performed on pre-treatment tumors. Selected genes were evaluated by RT-qPCR and protein expression was detected by immunohistochemistry. Results: The most common alteration, TP53 mutations, had a similar frequency in R (7/14, 50%) and NR (4/10, 40%). Mutations in 5 genes: ERBB3 (4/14; 28,6%), KTM2C (4/14; 28,6%), PI3KCA (4/14; 28,6%), ARID2 (3/14; 21,4%) and FGFR3 (3/14; 21,4%) were identified only in R. Mutations in ERBB4 (3/10, 33,3%) and BCOR (2/10, 20%) were identified only in NR. Estimated TMBs were not significantly different among the R (13 per Mb) and NR (9 per Mb) samples. According to gene expression profiling, NR had high cytotoxic cells infiltrate and T cells as well as high counts of TILs compared to R. In addition, expression of IDO, MAGE A4, and SOCS1, that has been associated with response to ICIs, were down-regulated in R compared with NR. Conclusions: Gene profiling showed that low-expression levels of immune-related genes are significantly associated with clinical benefit from vinflunine. Validation and complementary studies are ongoing in patients treated with ICIs.
Neoadjuvant chemotherapy for muscle-invasive bladder cancer: Dana-Farber Cancer Institute (DFCI) experience.
Authors: Curran Catherine , Agarwal Archana , Nassar Amin , Abou Alaiwi Sarah , Kumar Vivek , Mossanen Matthew , Preston Mark A. , Steele Graeme , McGregor Bradley Alexander , Kilbridge Kerry L. , Sonpavde Guru 
Published: May 2019

e16037 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) extends overall survival in muscle invasive bladder cancer (MIBC) patients (pts) and pathologic complete response (pCR) is associated with improved survival. We conducted a retrospective study at DFCI to examine the impact of different chemotherapy regimens and renal function on pCR and tolerability. Methods: Pts who underwent RC for MIBC were retrospectively studied. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors (age, gender, chemotherapy regimen, creatinine clearance [Cr Cl] by Cockroft Gault formula) on pCR (ypT0), < ypT2N0 rate and early discontinuation for toxicities. Results: 196 patients treated with NAC were identified from 2002 -2018 (Table). Unconventional regimens (split dose cisplatin or carboplatin combined with gemcitabine) exhibited lower pCR rate (14%), but a moderate < ypT2N0 rate (36%). Among those receiving conventional cisplatin-based regimens, we did not identify an association between renal function (Cr Cl < 60 vs. ≥60 ml/min), age, gender and specific regimen (Cisplatin/Gemcitabine, MVAC, ddMVAC) with pCR or early discontinuation ( < 4 cycles) for toxicities, although the < ypT2N0 rate was numerically higher for MVAC/ddMVAC. The modest size of this cohort limited the analysis. Conclusions: pCR rates were similar with ddMVAC/MVAC and GC for MIBC, with potential superiority of MVAC/ddMVAC to GC for a subset of pts. If Cr Cl ≥50 ml/min, it may be reasonable to consider conventional cisplatin therapies as non-conventional NAC appeared to yield lower depth of benefit emphasizing need for evaluation of new tolerable regimens. [Table: see text]
Impact of facility patient volume on overall survival in patients with muscle invasive bladder cancer undergoing trimodality bladder preservation therapy.
Authors: Fischer-Valuck Benjamin Walker , Rudra Soumon , Gabani Prashant , Mueller Ryan , Gay Hiram Alberto , Michalski Jeff M. , Abraham Christopher , Baumann Brian Christopher 
Published: May 2019

e16039 Background: There is an association between higher hospital and urologist case volume and improved survival outcomes for patients with bladder cancer. Limited data on facility volume and outcomes exists following trimodality bladder preservation with TURBT followed definitive chemoradiation (CRT). Methods: The National Cancer Database was queried for patients from 2004-2013 with urothelial bladder cancer (cT2-4aN0M0) receiving definitive CRT after TURBT. High-volume bladder preservation case volume (BPCV) was defined as facilities in the > 70th percentile of trimodality bladder preservation cases per ten years examined. We compared OS between high- and low-BPCV using Cox proportional hazard models. CRT was defined as > = 5040cGy pelvic RT with chemotherapy given within 21 days. Propensity matching was performed to match high- and low-volume centers. Results: A total of 666 treatment facilities treating 1,635 patients with bladder preservation were identified with a median follow-up of 26 months (range 2-136 months). A 70th percentile cutoff identified 497 patients that received treatment at 64 high-volume facilities. Median OS of patients treated at high BPCV centers was 37.0 months (95% CI, 27.9-33.6) versus 32.3 months (95% CI, 27.3-46.7) for patients treated at low BPCV centers (P = 0.004). High BPCV facilities were independently associated with a decreased hazard of death (HR, 0.86, 95% CI, 0.75-0.98; P = 0.031). When BPCV was analyzed as a continuous variable, an increasing number of bladder preservation cases per institute was also independently associated with improved OS (HR: 0.98, 95% CI, 0.97-0.99; P = 0.044). In the propensity score matched cohort, median OS of patients treated at high BPCV was 36.1 months (95% CI, 26.5-45.8) versus 28.1 months (95% CI, 23.9-32.3) for patients treated at a low BPCV facility (P = 0.016). Conclusions: In this observational cohort, treatment at a high BPCV facility was associated with improved OS. Causal factors for this finding may include greater institutional expertise in multidisciplinary bladder cancer care and potential advantages in treatment technology.