bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adapted physical activity in patients (Pts) with advanced pancreatic cancer (APACaP): Results from a prospective national randomized GERCOR trial.
Authors: Neuzillet Cindy , Bouché Olivier , Tournigand Christophe , Chibaudel Benoist , Bouguion Lucile , Bengrine-Lefevre Leila , Lopez-Trabada Ataz Daniel , Mabro May , Metges Jean-Philippe , Péré-Vergé Denis , Conroy Thierry , Lievre Astrid , Andre Morgan , Desseigne Françoise , Goldwasser François , Henriques Julie , Anota Amélie , Hammel Pascal 
Published: June 2022

4007 Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences > 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]
Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial.
Authors: Fietkau Rainer , Ghadimi Michael , Grützmann Robert , Wittel Uwe A , Jacobasch Lutz , Uhl Waldemar , Croner Roland S. , Bechstein Wolf Otto , Neumann Ulf Peter , Waldschmidt Dirk , Boeck Stefan Hubert , Moosmann Nicolas , Reinacher-Schick Anke C. , Golcher Henriette , Adler Werner , Semrau Sabine , Kallies Annett , Hecht Markus , Tannapfel Andrea , Oettle Helmut 
Published: June 2022

4008 Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p<0.01) than for CRM+ R0 surgery with 66.7 ± 0.15% (1y) and 41.2 ± 0.1% (2y) as well as for patients without or incomplete surgery with 68.5 ± 0.03% (1y) and 26.4 ± 0.03% (2y). Conclusions: The addition of radiotherapy after IC improves the R0 CRM - resection and pCR rate without significant change in R0 resection rate (primary endpoint). Pts with R0 CRM - resections had a better prognosis compared to patients with either R0 CRM+ or incomplete or without surgery. However, this effect on resectability did not translate into a statistically significant PFS or OS benefit in the whole cohort. Clinical trial information: NCT01827553. [Table: see text]
Effect of neutrophil extracellular traps on tumor lymph nodes.
Authors: SU Xin , Brassard Ariane , Dhoparee-Doomah Iqraa , Rohanizadeh Ramin , Giannias Betty , Bourdeau France , Sangwan Veena , Rayes Roni , Spicer Jonathan , Ferri Lorenzo , Cools-Lartigue Jonathan 
Published: June 2022

4033 Background: In most human cancers, regional lymph nodes (LNs) are the first sites of metastasis. In addition to being an important part of the tumor staging system, with the advent of novel therapies, lymph node metastasis has become a crucial clinical intervention point before distant metastasis, the leading cause of cancer-associated deaths. To initiate metastasis, the conditions of LNs need to be optimized for tumor cell deposition and growth. This process is believed to be mediated by the activation of immune cells including polymorphonuclear neutrophils (PMNs). However, the cellular mechanism is not well defined. Our early observations suggest that PMNs and neutrophil extracellular traps (NETs), DNA comprising structures that are extruded in response to inflammatory cues, are associated with adverse oncologic outcomes. Thus, one potential mechanism of increased LN metastasis is that tEVs recruit PMNs and propend NETs formation. Methods: Human tissue micro-arrays (TMAs) of gastroesophageal (GEA) cancer patients were stained with PMN and NETs markers and quantified by HALO software. C57BL/6 or pad4-/- mice were injected with B16F10 or H59 cells alone or treated with neutrophil elastase inhibitor (NEi) or PMN depletion antibody. LN sections were stained with NETs markers and quantified by ImageJ (NIH). Results: In the study of 175 GEA cancer patients, lymphatic NET deposition was observed in both tumor infiltrated lymph nodes and tumor negative lymph nodes. We also demonstrated high LN NETs deposition was associated with reduced survival, even in the absence of overt metastasis ( p=0.03). Next, we sought to investigate the dynamic and the consequence of LN NETs deposition using animal models. We found that LN Neutrophil Recruitment and NET deposition happens in a pre-metastatic manner. Moreover, LN metastasis was abrogated through different kinds of NETs inhibition (neutrophil depletion, pad4 knockout and NEi treatment, n=10, p<0.001), demonstrating the consequences of LN NETs deposition and its potential as a treatment target. Finally, we showed that the LN PMN recruitment and NETs formation was mediated by increased production of IL-8 by Lymphatic Endothelial Cells (LEC). Conclusions: Together, we demonstrated that NETs can contribute to LN metastasis, and can serve as a potential therapeutic targets. By further investigating the detailed mechanism, this project will lead to major advances in the management of cancer patients.
Perioperative chemotherapy with LP002, an anti-PD-L1 antibody, in patients with resectable gastric and gastroesophageal junction cancer: A prospective, open-label, phase Ib trial.
Authors: Tang Jialin , Huang Jing , Zhang Bo , Qi Ling , Dao Xin , Wang Lin , Li Yong , Tian Yantao 
Published: June 2022

4041 Background: Immune checkpoint inhibitors were effective, either alone or in combination with chemotherapy, in pts with metastatic gastric or gastroesophageal junction (GEJ) cancers, but their role for resectable disease remained unknown. We report the safety and pathological response of gastric/GEJ cancer pts receiving LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in a phase Ib trial. Methods: We enrolled pts with previously untreated, PD-L1 positive, resectable (cT2-4a, any N, M0) gastric/GEJ cancer. Eligible pts received three preoperative and six postoperative 2-week cycles of intravenous LP002 900mg on day 1, intravenous cisplatin 50 mg/m2 on day 1, and 2000 mg/m2 5-fluorouracil as 48-h infusion starting on day 1. The standard surgery was scheduled 4-6 weeks after completion of 3 cycles of preoperative treatment. The primary endpoint was safety. Secondary endpoints included proportion of pts with R0 resection and pathological complete response (pCR), disease-free survival, and overall survival. With pre- and post-treatment samples, we also characterized genomic changes in tumor tissue with next generation sequencing (NGS), and alterations in the tumor immune microenvironment (TIME) using multiplex immunofluorescence staining. Results: From September 2020 to July 2021, 30 pts were enrolled into this study. The median age was 64.5 years (range, 50-74). Most primary tumors were in the GEJ (N=28, 93.3%). 29 pts (96.7%) had adenocarcinoma, and 1 had small cell neuroendocrine tumor. The median follow-up duration was 7.9 months (range: 5.1-10.6) as of data cut-off (November 1, 2021). All pts completed the planned preoperative treatment, and 27 pts (90.0%) proceeded to surgery. Reasons for surgery not being performed were metastatic disease in 1 patient, and patient request in 2 cases. 24 pts had R0 resection, while 3 underwent R1 resection. 1 patient achieved pCR (TRG 1 per the Mandard’s tumor regression grading system) and 5 pts (18.5%) reached TRG 2-3. Treatment-related adverse events (TRAEs) were observed in 27 pts during perioperative treatment. Most of the TRAEs were of grade 1 to 2. The most common grade 3 toxicities were nausea (23.3%), neutrophil count decreased (16.7%) and anorexia (6.7%). 11 pts had immune-related adverse events, mostly grade 1 hyperthyroidism (45.5%). There were no grade 4-5 TRAEs. NGS analysis revealed that the mutation frequencies of the 733 genes in the sequencing panel decreased after preoperative treatment in pts with TRG 2-3. The analysis of TIME is undergoing. Conclusions: LP002 plus cisplatin and 5-fluorouracil was safe in pts with resectable gastric or GEJ cancer, and could be a new perioperative treatment option for PD-L1 positive disease. Pts are followed-up for survival outcomes. Clinical trial information: NCT04755543.
Cellworks singula therapy response index (TRI) predicts clinical outcomes for esophageal adenocarcinoma: MyCare-004.
Authors: Smyth Elizabeth Catherine , Watson Drew , Nutzinger Barbara , Castro Michael P , Kapoor Shweta , Prasad Samiksha Avinash , Rajagopalan Swaminathan , Cheah Calvin , Nair Prashant Ramachandran , Alam Aftab , Devonshire Ginny , Grehan Nicola , Suseela Rakhi Purushothaman , Tyagi Anuj , Agrawal Ashish Kumar , Azam Humera , Sauban Mohammed , Pampana Anusha , Macpherson Michele Dundas , Fitzgerald Rebecca C. 
Published: June 2022

4064 Background: Computational biological modeling reveals many dysregulated signaling pathways responsible for hallmark behaviors of cancer and variable drug response in the population. A mechanistic model created for each patient using comprehensive genomic inputs can biosimulate downstream molecular effects of cell signaling and drugs for each patient’s personalized in silico virtual disease model. Singula TRI is designed to predict the outcome of specific therapies with a continuous TRI Score, 0 to 100, for each patient’s unique genomic network. Methods: TRI’s ability to predict Overall Survival (OS), Disease Free Survival (DFS) and Mandard – tumor regression grade (TRG) was prospectively evaluated in a retrospective cohort of gastroesophageal adenocarcinoma (GEA) from UK OCCAMS consortium. Random sampling stratified by clinical factors was used to split the data into independent training (N = 140) and validation (N = 131) subsets. Multivariate Cox Proportional Hazard (PH) and Proportional Odds models were used to predict survival and pathological response as a function of the pre-defined TRI and clinical thresholds compared with standard clinical factors. Results: 271 GEA patients were selected who had pre-chemo treated biopsies with 50x whole genome sequencing from the OCCAMS International Cancer Genome Consortium study. The median age was 65.6 years, 234 male and 30 female, with deceased median OS of 21.9 months and living of 49.9 months. There were 35 T2, 215 T3, 70 N0, 126 N1, 62 N2 and 266 M0. Patients were treated with physician prescribed chemotherapy treatments (PPT) according to UK clinical guidelines (SC). Biosimulation revealed that 99% of these tumors had deficiency in DNA repair genes. Other pathways included amplification of multi-drug resistance pumps, TP53 mutations and aberrations of the PI3K/AKT pathway genes. The table shows that TRI provides additional predictive information for OS and DFS beyond PPT and standard clinical factors. TRI was also predictive of TRG in univariate analysis. TRI scores were also generated for 82 alternate therapies for each patient enabling selection of optimal therapies with estimates of improvements in median OS and DFS compared to SC. Conclusions: In this cohort of patients, Cellworks Singula TRI was predictive of survival and TRG beyond clinical factors. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA and validation in prospective clinical studies is warranted.[Table: see text]
Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): A prospective, single-arm phase II trial.
Authors: Liu Dongming , Mu Han , Liu Changfu , Zhang Weihao , Cui Yunlong , Wu Qiang , Zhu Xiaolin , Fang Feng , Zhang Wei , Xing Wenge , Li Qiang , Song Tianqiang , Lu Wei , Li Huikai 
Published: June 2022

4073 Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.
Organ-specific responses to atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma.
Authors: Cheon Jaekyung , Jung Sanghoon , Kang Beodeul , Kim Hyeyeong , Kim Chan , Chon Hongjae 
Published: June 2022

4076 Background: Anti-PD-1 monotherapy elicits various organ-specific immune responses. Although advanced hepatocellular carcinoma (aHCC) showed 20–40% objective response rates (ORR) for cases of extrahepatic lesions in sites such as the lungs or lymph nodes (LNs), only 10% of intrahepatic lesions responded to the monotherapy. The organ-specific responses were due to tumor heterogeneity and differential microenvironments, and may have contributed to the failure of the phase III trials of anti-PD-1 monotherapy for aHCC. Recently, the combination of atezolizumab and bevacizumab (Ate/Bev) as first-line systemic treatment has resulted in survival benefits for patients with aHCC. However, the organ-specific response for this treatment has not been explored. We aimed to evaluate the organ-specific response to Ate/Bev combination therapy in patients with aHCC. Methods: We enrolled patients who received first-line Ate/Bev treatment for aHCC. Eligible patients included those with Child-Pugh A liver function, measurable tumor lesions, and serial image studies available for response evaluation. An independent radiologist reviewed the tumors located in the liver, lungs, LNs, and other sites. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used. Results: Between May 2020 and June 2021, 124 patients from two Korean cancer referral institutions received first-line Ate/Bev treatment for aHCC. The patient baseline characteristics included: hepatitis B (n = 85, 68.5%), hepatitis C (n = 6, 4.8%), non-viral (n = 33, 26.7%); BCLC stage A/B/C (n = 2, 1.6%/n = 19, 15.3%/n = 103, 83.1%); macrovascular invasion (n = 39, 31.5%); extrahepatic metastasis (n = 75, 60.5%); and AFP >400 ng/ml (n = 39, 31.5%). The median age was 62 years (range: 34–90). With median follow-up duration of 10.1 months, median progression-free survival was 6.8 months (95% CI, 3.6–10.0) and median overall survival was 16.9 months (95% CI, range not available). The ORR was 29.8%. For 260 individual tumor lesions, the liver was the most commonly involved organ (n = 152, 58.5%), followed by the LNs (n = 42, 16.2%) and lungs (n = 24, 9.2%). Ate/Bev treatment induced potent tumor shrinkage in both intrahepatic and extrahepatic lesions: ORR for hepatic lesions was 28.3%; LN lesions, 40.5%; lung lesions, 29.1%; and other metastatic lesions, 19.0%. Further, the organ-specific response rate for intrahepatic tumors decreased as the tumor size increased (36.7%: ≤50 mm, 13.0%: >50 mm). Conclusions: Unlike anti-PD-1 monotherapy, Ate/Bev combination therapy showed favorable responses even in intrahepatic lesions, which are comparable to those in extrahepatic lesions. As such, Ate/Bev may overcome an immune-tolerant hepatic microenvironment in patients with aHCC. (NCT04862949).
Targeting HER2 mutation–positive advanced biliary tract cancers with neratinib: Final results from the phase 2 SUMMIT basket trial.
Authors: Harding James J. , Piha-Paul Sarina Anne , Shah Ronak H. , Cleary James M. , Quinn David I. , Brana Irene , Moreno Victor , Borad Mitesh J. , Loi Sherene , Spanggaard Iben , Ford James M. , DiPrimeo Daniel , Berger Michael F. , Eli Lisa DeFazio , Meric-Bernstam Funda , Solit David B. , Abou-Alfa Ghassan K. 
Published: June 2022

4079 Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.