bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of G-CSF during neoadjuvant therapy on outcomes of operable pancreatic cancer.
Authors: Murthy Pranav , Zenati Mazen S , AlMasri Samer S. , Singhi Aatur D. , DeSilva Annissa , Paniccia Alessandro , Lee Kenneth K. , Simmons Richard L. , Bahary Nathan , Lotze Michael T. , Zureikat Amer H. 
Published: June 2021

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.
Circulating cell free tumor DNA detection as a prognostic tool in advanced pancreatic cancer.
Authors: Botrus Gehan , Uson Junior Pedro Luiz Serrano , Raman Puneet , Kaufman Adrienne , Kosiorek Heidi E. , Sonbol Mohamad Bassam , Borad Mitesh J. , Ahn Daniel H. , Chang Isabela , Drusbosky Leylah , Starr Jason S. , Mody Kabir , Bekaii-Saab Tanios S. 
Published: June 2021

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.
Impact of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC).
Authors: Mehdi Maahum , Kamgar Mandana , George Ben , Szabo Aniko , Annunzio Kaitlin , Taylor Bradley W , Shreenivas Aditya Varnam , Chakrabarti Sakti , Thomas James P. , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Clarke Callisia , Hall William Adrian , Erickson Beth , Ahmed Gulrayz , Thapa Bicky 
Published: June 2021

4136 Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]
Genetic and immune divergence in pancreatic cancer lesions at the time of metastatic relapse compared to primary tumor.
Authors: Gebregziabher Bereket , Oldridge Derek A. , Furth Emma E. , Feldman Michael D. , Rech Andrew J. , Vonderheide Robert H. 
Published: June 2021

4140 Background: Relapse of pancreatic ductal adenocarcinoma (PDA) is common even after complete resection and adjuvant therapy. Compared to the resected tumor, the biological characteristics of metastatic tumors at the time of first relapse are poorly understood. Methods: Whole-exome sequencing (WES) (250x) and bulk RNA sequencing were performed on samples from 30 patients with PDA. Paired primary tumor samples were obtained after R0 or R1 resection, and metastatic tumor samples were obtained by biopsy at the time of first relapse. 74.1% of patients had received adjuvant chemotherapy and radiation therapy, 7.4% had received adjuvant chemotherapy only, and 3.7% had received adjuvant radiation therapy only. Most common metastatic sites were liver and lung. The cohort was 60% male with a median age at diagnosis of 64 years. The vast majority of patients had stage IIA or IIB disease at diagnosis. Median disease-free survival was 481 days. Analysis used Freebayes (somatic variant calling), Kallisto (transcript quantification), Danaher et al. (cell type deconvolution), and antigen.garnish (neoantigen prediction). Results: High-quality WES and/or RNA sequencing were available for 27/30 patients. Among these were 16 pairs of primary and metastatic samples for WES and 15 paired samples for RNA sequencing. Median tumor purity was 32% (primary) and 42% (metastatic). KRAS mutations were present in 43/48 evaluable samples, with conserved KRAS mutations in 14/16 primary-metastatic pairs. Tumors were otherwise highly variable, with 13/16 patients developing oncogenic mutations in metastatic tumors that were undetected in primary tumors (BRCA1 [3/16], AKT3 [3/16], TP53 [2/16], ROS1 [2/16]). Overall, primary and metastatic tumors had similar tumor mutation burden and neoantigen production rate. However, neoantigens were highly variable at the peptide and gene level, with conservation rates of 2.73% and 11.57%, respectively, across primary-metastatic pairs. PDA transcriptomic subtype also differed across primary-metastatic pairs in all cases. Furthermore, metastatic tumors contained lower immune suppressive signal by transcripts and deconvolution (CTLA4: p = 0.0012, FOXP3: p = 0.0026, PDCD11: p = 0.012, regulatory T cells: p = 0.012), while myeloid cells were higher (CD33: p = 0.0067). Conclusions: With the exception of KRAS, metastatic PDA tumors at relapse contain new oncogenes, distinct neoantigens, and lower immune-suppressive signal compared to primary PDA tumors. These data suggest a potential clinical utility for tumor biopsies at the time of first metastatic relapse and caution against clinical decisions for relapsed, metastatic patients based solely on sequencing of the originally resected tumor.
Association of total neoadjuvant therapy with major pathologic response and survival in localized pancreatic cancer: A multi-institutional analysis of 504 patients.
Authors: Datta Jashodeep , Collier Amber , Kronenfeld Joshua , Wilson Gregory , Maduekwe Ugwuji , Snyder Rebecca A , Weber Sharon M. , Hawkins William G. , Kim Hong Jin Jin , Parikh Alexander A. , Hammill Chet , Kooby David A. , Abbott Daniel , Maithel Shishir K. , Hosein Peter Joel , Ahmad Syed A. , Merchant Nipun B. 
Published: June 2021

4145 Background: Despite increased utilization of neoadjuvant therapy for pancreatic cancer (PC), a substantial proportion of patients never receive adjuvant therapy. We examined if total neoadjuvant therapy (TNT) would facilitate delivery of all prescribed (≥6 months) non-surgical therapy (NST: chemotherapy ± radiation) to improve oncologic outcomes. Methods: Patients receiving neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ±radiation followed by pancreatectomy at 7 centers were reviewed. Patients receiving TNT (≥6 months NST pre-resection) were compared to those receiving < 6 months ( < TNT). Primary outcomes were major (complete/near-complete) pathologic response (MPR) and overall survival (OS). Results: Of 504 patients, 105 (21%) were selected for TNT. TNT and < TNT patients had similar performance status and rates of borderline resectable/locally advanced disease (82% vs. 80%). TNT patients were significantly more likely to receive ≥6 months NST (100% vs. 31%; p < 0.001) vs. < TNT. While selection of chemotherapy regimen (FOLFIRINOX or gemcitabine/nab-paclitaxel) did not differ between TNT and < TNT cohorts, TNT patients were more likely to receive neoadjuvant radiation (44% vs. 25%, p < 0.001). Rates of vascular resection, postoperative complications, and mortality were similar between groups. TNT was associated with decreased rates of lymphovascular/perineural invasion (p = 0.002) and nodal positivity (p = 0.001), and increased rates of MPR (41% vs. 23%; p = 0.001) and pathologic complete response (13% vs. 6%; p = 0.02). TNT was associated with improved OS compared with < TNT (median 38 vs. 30 months; p = 0.039). Both MPR (median 38 [MPR] vs. 28 [limited response] months; p = 0.002) and ≥6 months NST (TNT or peri-operative) (median 38 [≥6m] vs. 26 [ < 6m] months; p = 0.001) were associated with improved OS. Addition of radiation was not associated with MPR or OS. Conclusions: The TNT approach allows more patients with localized PC to receive ≥6 months NST and is associated with improved rates of MPR and OS. TNT should be considered for all patients with operable PC when possible.
Vorolanib, everolimus, and the combination in patients with pretreated metastatic renal cell carcinoma (CONCEPT study): A randomized, phase 3, double-blind, multicenter trial.
Authors: Sheng Xinan , Ye Dingwei , Zhou Ai-Ping , Yao Xin , Luo Hong , He Zhisong , Wang Zengjun , Zhao Yingchao , Ji Zhigang , Zou Qing , He Chaohong , Guo Jianming , Tu Xinhua , Liu Ziling , Shi Benkang , Liu Ben , Chen Peng , Wei Qiang , Zhou Fang-Jian , Guo Jun 
Published: June 2021

4512 Background: The combination of agents targeting both VEGF- and mTOR-mediated pathways has been investigated in renal cell carcinoma (RCC). We conducted the CONCEPT study to assess vorolanib, everolimus, or their combination as second-line treatment in Chinese patients (pts) with metastatic RCC. Methods: Pts with cytologically or histologically confirmed RCC who had disease progression after one prior VEGFR-TKI were eligible for participation in the study. They will be randomized by 1:1:1 ratio to receive matching placebo plus vorolanib or everolimus, or the combination. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2016 and June 2019, 399 pts (133 pts in each group) were enrolled. At the data cutoff (October 23, 2020), the median PFS in combination group was significantly longer than that in single-agent everolimus group (10.0 months [95% CI, 8.2-10.4] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.70 [95% CI, 0.52-0.94]; P = 0.0171), while the median PFS was similar between single-agent vorolanib group and single-agent everolimus group (6.4 months [95% CI, 4.6-8.3] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.94 [95% CI, 0.69-1.24]; P = 0.6856). An objective response was achieved by 33 (24.8%) of 133 pts allocated vorolanib plus everolimus compared with 11 (8.3%) of 133 who received single-agent everolimus and 14 (10.5%) of 133 pts assigned single-agent vorolanib. OS was immature with no significant difference between pts assigned vorolanib plus everolimus (30.4 months [95% CI, 16.5-NE]) and those allocated single-agent everolimus (25.4 months [95% CI 19.4-NE]) or single-agent vorolanib (30.5 months [95% CI, 22.8-NE]). Treatment-related adverse event (TRAE) occurred in 132 (99%) of 133 pts with vorolanib plus everolimus, 127 (96%) of 133 pts with single-agent vorolanib and 131 (99%) of 133 pts with single-agent everolimus, respectively. Grade 3 or higher TRAEs occurred in fewer patients who received single-agent vorolanib (52 [39%]) than in those who received single-agent everolimus (71 [53%]) or vorolanib plus everolimus (96 [72%]). Safety profiles of both agents were consistent with previous studies. Conclusions: This is the first phase 3 study of combination of mTOR- and VEGF-targeted agents in second-line treatments. Vorolanib plus everolimus showed a PFS benefit for patients with metastatic RCC who have progressed after one previous VEGF-targeted therapy with a safe tolerance profile. Clinical trial information: NCT03095040.
Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.
Authors: Fallah Jaleh , Gittleman Haley , Weinstock Chana , Bloomquist Erik , Chang Elaine , Suzman Daniel L. , Agrawal Sundeep , Ibrahim Amna , Tang Shenghui , Pazdur Richard , Beaver Julia A. , Amiri-Kordestani Laleh 
Published: June 2021

4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]
Avelumab first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): Analysis of time to end of next-line therapy in JAVELIN Bladder 100.
Authors: Grivas Petros , Park Se Hoon , Voog Eric , Kopyltsov Evgeny , Gurney Howard , Muniz David Queiroz Borges , Rolland Frederic , Als Anne Birgitte , Valderrama Begoña P. , Wang Jing , Costa Nuno Matos , Laliberte Robert J , Di Pietro Alessandra , Powles Thomas , Bellmunt Joaquim 
Published: June 2021

4525 Background: Avelumab 1L maintenance is approved in various countries for patients (pts) with advanced UC that has not progressed with 1L platinum-based chemotherapy based on significantly prolonged overall survival (OS) seen with avelumab + BSC vs BSC alone in the phase 3 JAVELIN Bladder 100 trial. OS was prolonged despite the more frequent use of subsequent anticancer therapy in the BSC alone arm (42.3% in the avelumab + BSC arm vs 61.7% in the BSC alone arm), most commonly with immune checkpoint inhibitors (6.3% vs 43.7%, respectively). To further characterize the efficacy benefits of avelumab 1L maintenance, we report a post hoc analysis of the time to end of next-line therapy (for any reason) in the randomized trial population. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without disease progression with 4 to 6 cycles of 1L gemcitabine + either cisplatin or carboplatin. The primary endpoint was OS from randomization, assessed in 2 populations: all pts and pts with PD-L1+ tumors (Ventana SP263). In this exploratory analysis, time from randomization until end of next-line treatment received after first progression (due to death or discontinuation) was assessed. Results: A total of 700 pts were randomized 1:1 to avelumab 1L maintenance + BSC or BSC alone. Among all randomized pts, time to end of next-line therapy was prolonged in the avelumab + BSC arm vs the BSC alone arm (Table). Time to end of next-line therapy was also longer in the avelumab + BSC arm vs the BSC alone arm in pts with PD-L1+ tumors (n = 358) or PD-L1− tumors (n = 270). Conclusions: Pts who received avelumab 1L maintenance + BSC had prolonged time to end of next-line treatment compared with those who received BSC alone, irrespective of PD-L1 status. These data provide further evidence of the efficacy of a maintenance approach with avelumab in pts with advanced UC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]