bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.
Authors: Coveler Andrew L. , Reilley Matthew , Zalupski Mark , Macarulla Teresa , Fountzilas Christos , Castanon Alvarez Eduardo , Nagrial Adnan , Uboha Nataliya Volodymyrivna , Frentzas Sophia , Overman Michael J. , Noonan Anne M. , Messersmith Wells A. , Pavlakis Nick , Mettu Niharika B. , Smith Paul , Murtomaki Elina , Bragulat Veronique , Cooper Zachary A. , Kumar Rakesh , Spigel David 
Published: June 2023

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]
Nationwide implementation of best practices in pancreatic cancer care (PACAP-1): Stepped-wedge cluster randomized trial.
Authors: Mackay Tara , Latenstein Anouk EJ , Augustinus Simone , van der Geest Lydia G. , Bogte Auke , Bonsing Bert A. , Bos Hendrik , Bosscha Koop , Brosens Lodewijk , Cirkel Geert A. , Hol Lieke , Busch Olivier R.C. , Creemers Geert-Jan , Curvers Wouter L. , Derks Sarah , van Hooft Jeanin E. , Van Eijck Casper H.J. , Wilmink Johanna , Van Laarhoven Hanneke W.M. , Besselink Marc G. ,   for the Dutch Pancreatic Cancer Group
Published: June 2023

4152 Background: Implementation of new treatment strategies in cancer care is often inadequate and slow. We aimed to implement best practices in pancreatic cancer care using a nationwide stepped wedge design and assess the impact on overall survival. Methods: Nationwide multicenter stepped-wedge cluster randomized controlled trial comparing implementation of best practices with usual care (May 22, 2018 – May 29, 2020). Best practices included adequate use of perioperative and palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), and metal biliary stents. The 6-week implementation period in all 17 Dutch pancreatic centers and their regional referral networks included monitoring, return visits, and provider feedback in combination with education and reminders. Primary outcome was one-year overall survival for all disease stages and secondary outcomes included guideline compliance and quality of life. Results: Overall, 5580 patients diagnosed with pancreatic cancer were included; 2939 after implementation of best practices versus 2641 before. One-year survival did not differ among the groups (HR 0.98, 95 CI 0.88-1.08). Overall use of perioperative chemotherapy (neoadjuvant and adjuvant) did not significantly differ, but use of palliative chemotherapy significantly increased (23.9% to 30.3%, OR 1.38, 95 CI 1.10-1.74). Also the use of PERT (34.2% to 45.2%, OR 1.64, 95 CI 1.28-2.11); and metal biliary stents (74.1.% to 83.3%, OR 1.78, 95 CI 1.13-2.08) significantly increased. The Global Health Score did not differ (AUC 43.8 to 42.7, median difference -1.12, 95 CI -3.13-0.80, n=655). Conclusions: This nationwide population-based trial to enhance implementation of best practices in pancreatic cancer care showed successful implementation of most best practices, but no increase in one-year survival and quality of life. Clinical trial information: NCT03513705 .
First in class TLR7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiation therapy in patients with advanced pancreatic adenocarcinoma: Results from the AGADIR study.
Authors: Pernot Simon , Sargos Paul , Rochigneux Philippe , Ghiringhelli François , Palmieri Lola Jade , Cousin Sophie , Guégan Jean Philippe , Fumet Jean David , Bourbonne Vincent , Bessede Alban , Metges Jean Philippe , Italiano Antoine 
Published: June 2023

4153 Background: Pancreatic adenocarcinoma is refractory to immune checkpoint inhibitors such as PD1/PDL1 antagonists. Investigating alternative immunotherapeutic approaches is a crucial need for this devastating disease. The potent immunostimulatory effects of Toll-like receptor (TLRs) have spurred efforts aimed at the development of TLR agonists as new immune-oncology agents. Radiation therapy combined with TLRs agonists has been shown to enhance antitumor immunity in the preclinical setting. Methods: AGADIR is a multi-cohort, phase 2, multicenter, open-label study investigating the novel TLR 7/8 agonist BDB001 combined with atezolizumab and stereotactic body radiotherapy (SBRT) in patients with advanced cancers. Cohort A enrolled patients with advanced pancreatic adenocarcinoma. BDB001 was administered IV at the dose of 0.75 mg/m² on days 1, 8, and 15 of cycles 1, 2, and 3. Then from cycle 4 on day 1 every 3 weeks. Atezolizumab was given at the dose of 1200 mg every 3 weeks. SBRT of at least one metastatic lesion was started at least one week after the first administration of atezolizumab and at the latest before the Cycle 2 Day 1. The primary endpoint is disease control rate defined as the proportion of participants with complete response, partial response or stable disease, as per adapted RECIST v1.1, observed within 24 weeks of treatment onset. Secondary endpoints include objective response, progression-free survival, overall survival and safety. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 32 pts were enrolled in 3 centers (14 male, 18 female). Median age was 64 years (range 38 – 78). Median number of previous treatment lines was 1 (range 1 – 5). The most common treatment related adverse events were grade 1/2 asthenia, chills and fever. No death was related to the treatment. Among the 21 patients for whom central review was performed at the time of this writing, best tumor response was confirmed partial response, stable disease and progressive disease in 2 (9.5%), 6 (28.5%) and 13 (62.0%) patients respectively. The disease control rate was 38.0% (95%CI 18.1-61.5). Conclusions: The AGADIR study met its first endpoint for disease control rate in patients with advanced pancreatic cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03915678 .
Chemotherapy dose density and effect on prognosis for patients with resectable pancreas cancer: A secondary analysis of SWOG S1505.
Authors: Patel Sameer H. , Colby Sarah , Sohal Davendra , Guthrie Katherine A , Kachnic Lisa A. , Chiorean E. Gabriela , Lowy Andrew M. , Rocha Flavio G , Philip Philip Agop , Ahmad Syed 
Published: June 2023

4158 Background: Chemotherapy is an integral part of multimodality treatment for resectable pancreatic ductal adenocarcinoma (PDAC). Assessing the impact of chemotherapy dose reductions or missed cycles on survival is difficult as few trials prospectively address the prognostic value of this important metric. Methods: SWOG S1505 (NCT02562716) was a randomized, phase II study of perioperative (12 weeks neoadjuvant and 12 weeks adjuvant) chemotherapy with mFOLFIRINOX or gemcitabine/nab-paclitaxel for resectable PDAC. Dose density (DD) was defined as the estimated percent of chemotherapy dose received of the total planned per protocol. Thresholds were based on published analyses and balance in sample size across treatment arms. Cox regression analysis of overall survival (OS) according to DD was performed in patients alive at two landmark time points: after surgery (among those who completed surgery) and at 40 weeks (when protocol therapy was to be completed). Results: Of the 103 eligible patients enrolled, median age was 64 years, 81% underwent pancreaticoduodenectomy, 15% distal pancreatectomy, and 3% a total pancreatectomy. In the 73 patients who underwent surgery, median neoadjuvant chemotherapy DD was 89%. Patients with ≥ 85% DD had higher median OS from surgery (38.1 v. 17.2 months, p = 0.039) compared to patients with < 85% DD. Of the 82 patients who survived to 40 weeks post randomization, 67 underwent surgery and 58 started adjuvant chemotherapy. The median DD for all perioperative chemotherapy was 67%; DD was significantly higher for neoadjuvant compared to adjuvant therapy (83% vs. 58%, p < 0.001). In this cohort, DD ≥ 70% was associated with better median OS from 40 weeks post randomization (32.2 v. 14.0 months, p = 0.017). DD was not significantly associated with pathologic response, margin status, or lymph node negativity. There were no significant differences in DD between the mFOLFIRINOX and gemcitabine/nab-paclitaxel arms. Conclusions: This is the first study to identify a prognostic role for chemotherapy DD in patients undergoing perioperative chemotherapy for resectable PDAC. Patients who received ≥ 85% DD preoperatively and/or ≥70% DD perioperatively had significantly higher mOS than those receiving a smaller proportion of protocol therapy. With greater survival benefit in patients who received higher chemotherapy DD, and higher DD being likelier in preoperative vs. postoperative treatment, these data support use of neoadjuvant chemotherapy for resectable PDAC. Moreover, these findings suggest that DD should be considered in prospective studies for localized PDAC to optimize therapy to be received.
Meta-analyses of factors associated with long-term survival after resection of pancreatic ductal adenocarcinoma.
Authors: Fatimi Asad Saulat , Javed Ammar Asrar , Mahmud Omar , Habib Alyssar , Grewal Mahip , He Jin , Wolfgang Christopher Lee , Besselink Marc G. 
Published: June 2023

4165 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Long-term survival (>5 years, LTS) is rarely seen even after ‘curative-intent’ resection. With improved systemic control via effective systemic therapies, LTS is now being reported more frequently. However, our understanding of LTS in PDAC remains limited. The aim of the current study was to perform a systematic review and meta-analysis to quantify the associations between various clinicopathological factors and LTS following resection of PDAC. Methods: The PubMed, Embase, Scopus, and Cochrane CENTRAL databases were systematically searched for articles reporting actual patient survival data. Two reviewers independently screened and reviewed articles, extracted relevant data, and assessed the risk of bias in included studies using the Newcastle-Ottawa scale (NOS). Data that compared patients who achieved LTS after resection with those who did not were extracted from the included studies. Meta-analyses using a random effects model were conducted to identify associations between LTS and various patient, tumor, and treatment related factors. Results: Overall, 33 studies with 46,981 patients after resection of PDAC were included. Most articles received a ‘good’ NOS assessment, indicating acceptable risk of bias. The median rate of LTS was 15.27% (IQR: 9.47-20.72). Multiple clinicopathological factors were found to be associated with LTS, including tumor grade (OR: 0.40, 95%CI: 0.31-0.52), tumor stage (OR: 0.36, 95%CI: 0.31-0.41), and margin status (OR: 0.43, 95%CI: 0.36-0.50). Factors that were not associated with LTS included patient age, tumor size, tumor location, or genetic mutations. Notably, adjuvant therapy (OR: 1.68, 95%CI: 1.24-2.28) but not neoadjuvant therapy (OR: 1.08, 95%CI: 0.62-1.87) were associated with LTS. Conclusions: This meta-analysis revealed that 15% of patients achieved LTS after resection of PDAC. Multiple clinicopathological factors are associated with LTS whereas presence of ‘traditional’ negative prognostic factors does not rule out LTS. Further studies are required to identify robust predictors of LTS in resected PDAC. [Table: see text]
Mutation-site localized non-B DNA burden and survival heterogeneity in early-stage pancreatic cancer.
Authors: Xu Qi , Kowalski-Muegge Jeanne 
Published: June 2023

4166 Background: Pancreatic cancer is a highly aggressive disease with a poor prognosis, and one in which most measure of genomic instability (e.g., tumor mutation burden (TMB), fraction of genome altered (FGA)) have thus far, not proven informative in differentiating survival. Non-B DNA are alternative DNA forms that deviate from the canonical B-DNA structure with potential to increase susceptibility to mutations, leading to the development of cancer. The role of non-B in pancreatic cancer has not been fully explored. Herein, we investigate the relationship between gene mutation sites co-localized with non-B DNA motifs in terms of survival and B-DNA features. Methods: Using TCGA data, we derived a genome-wide mutation signature on 104 early-stage pancreatic patients. We introduced a metric, mutation-localized non-B burden (MLNB) by the number of non-b motifs containing mutation sites, normalized to the number of mutations and motif library size. We applied MLNB to patient-specific mutation signatures to derive an MLNB burden for non-B DNA structure motifs: G-quadruplexes (G4), Z-DNA, inverted repeats (IR), mirror repeats (MR), direct repeats (DR), and short tandem repeats (STR). We performed a cluster analysis on MLNB and compared groups based on overall survival (OS) in months (mos) using a log-rank test. Comparisons of B-DNA-derived molecular features among clusters were performed using a Kruskal-Wallis and Fisher Exact test. Results: Among the 104 early-stage pancreatic patients with a mutation signature, MLNB clustering resulted in six patient clusters that differentiated by non-B DNA structure, with DR burden the longest OS cluster (n=23, median OS=30mos), significantly (p < 0.05) differing as compared to IR (n=23, median OS=15 mos), STR (n=20, median OS=16mos), MR with lack of IR (n=14, median OS=13mos) and MR with IR (n=16, median OS=8mos). A mix of Z-DNA and G4 burden defined a cluster with shorter OS (n=22, median OS=14mos) as compared to DR, though not significant. Patients with the longest OS, MLNB-DR burden cluster had mutation signatures enriched in MAPK and Notch signaling pathways, as compared to the other clusters enriched with double-stranded break and mismatch repair (IR), hedgehog and WNT signaling (STR), and interleukin-4 signaling (MR) pathways. Among all clusters, CDKN2A deletion was most prevalent except for MLNB-DR burden cluster. No Significant differences were found between the MLNB clusters with age, race gender, KRAS and TP53 mutations, FGA, TMB, tumor purity, Bailey and Moffit subtypes. Conclusions: Our results point towards the potential use of MLNB as an emerging marker of site-structure genomic instability. Considering that triplex DNA is emerging as a marker genomic instability, and that we distinguish between two MR groups based on IR burden, our results may provide insights into various instability mechanisms associated with poor survival in pancreatic cancer.
The five periampullary cancers: Not just different siblings but different families—An international multicenter cohort study.
Authors: Uijterwijk Bas , Cabus Santiago , Mavroeidis Vasileios K. , Pessaux Patrick , Korkolis Dimitris , Berger Adam C. , Björnsson Bergthor , Suárez Miguel , Vladimirov Miljama , Kleeff Jorg , Boggi Ugo , Soonawalla Zahir , Zaniboni Alberto , Serradilla Mario , Mazzola Michele , Ghorbani Poya , Wellner Ulrich , Besselink Marc G. , Abu Hilal Mohammed 
Published: June 2023

4167 Background: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC) and ampullary adenocarcinoma (AAC). Based on histopathology, the AAC is currently subdivided in the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype. Despite close anatomical resemblance, it is unclear how the ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. Methods: This is an international multicenter cohort study, including patients after curative intent resection for periampullary cancer retrieved from 45 centers (from Europe, USA, Asia and Canada) between 2010 and 2021. Pre-operative CA19-9, differences in pathology and postoperative pancreatic fistula (POPF, grade B/C), 8-year overall survival (OS) and disease-free interval (DFI) were compared between DAC, AmpIT, AmpPB, dCCA and PDAC. Results: Overall, 3809 patients were included of which 348 DAC, 774 AmpIT, 848 AmpPB, 1036 dCCA and 803 PDAC. The best 8-years overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, p<0.001), dCCA (26.4%, p=0.020) and last, PDAC (12.9%, P<0.001). The best 8-years DFI was measured for AmpIT (62.7%) and the worst for both dCCA and PDAC (24.9% and 21.8%). This pattern correlated with the height of the pre-operative CA19-9 but not with the pathology, in which the largest and most progressed tumors were found in DAC. The incidence of POPF was lower in the pancreas-related tumor types (AmpPB 18.5%, PDAC 8.3%) compared to the non-pancreas related types (DAC 27.3%, AmpIT 25.5%, dCCA 27.6%). Conclusions: Despite the close anatomic relation of the five periampullary cancers, this study shows that there are prognostic and clinically relevant differences in terms of preoperative blood markers, pathology, complications, long-term survival, and recurrence. More characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for “periampullary cancers”, this study emphasizes the need for individual evaluation of each histopathological periampullary subtype with the ampullary subtypes as individual entities in future studies.
Tumour factors and the variation in non-muscle invasive bladder cancer recurrence after transurethral resection surgery between sites: Results from the RESECT study.
Authors: Gaba Fortis , Gallagher Kevin M. , Bhatt Nikita R. , Clement Keiran D. , Zimmermann Eleanor F. , Khadhouri Sinan , Kulkarni Meghana , Anbarasan Thines , Ng Alexander , Light Alexander , Asif Aqua , Chan Vinson W. , Nathan Arjun , Ross Sabrina H. , O'Brien Tim , MacLennan Steve , Nielsen Matthew E. , Mariappan Paramananthan , Kasivisvanathan Veeru ,   RESECT Study Global Collaborators (BURST)
Published: June 2023

4510 Background: To determine if there is significant variation in early recurrence after transurethral resection (TURBT) surgery between sites taking part in the RESECT study (NCT05154084) after accounting for tumour characteristics. Methods: An international, multi-centre, observational study. A mixed effects logistic regression model with tumour size, tumour number, tumour grade, tumour stage as fixed effects and site as a random effect was fitted. Cases with first, presumed non-muscle invasive bladder cancer (NMIBC) undergoing TURBT were included. Cases were excluded if first check follow up had not been completed. Sites were excluded if they did not have at least 10 cases with first check follow up. Local and/or national approvals or ethical exemptions were obtained prior to commencing the study at participating sites. Results: After exclusions, 186 sites (UK: 80; Europe: 59; North America: 18; Asia: 17; Africa 7; South America: 3; Oceania: 2), contributing a total 4597 cases (average 25 cases) were included. Median recurrence rate per site was 12% (IQR 0-22) for low grade tumours and 27% (IQR 13-42) for high grade tumours. After controlling for tumour size, number, stage and grade (all significantly and independently associated with early recurrence) there was significant residual variation attributable to site (p<0.0001, intra-class correlation, 0.1). Adjustment for sites improved the regression model from an area under the receiver operating characteristic curve of 0.66 to 0.74. Initial analysis of surgical and peri-operative practice showed wide variation, mean 75% (IQR 66-92) cases per site had detrusor muscle resection and 42% (IQR 17-58) had use of single instillation of intravesical chemotherapy. Other differences in operative and perioperative practice were identified through surveys. Conclusions: There is significant variation in the early recurrence rate of NMIBC after TURBT surgery between sites that could not be explained by currently understood tumour features. We have identified differences in surgical technique and perioperative practice that may impact this and further investigation is warranted to understand how these factors impact recurrence rates. Clinical trial information: NCT05154084 . [Table: see text]