bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of appendiceal cancer treated at a state peritonectomy service.
Authors: Strach Madeleine Cornelia , Ansari Nabila , Koh Cherry , Solomon Michael , Horvath Lisa , Mahon Kate 
Published: June 2022

3629 Background: Appendiceal cancers (AC) are rare with varied prognosis. Nomenclature refined by the WHO 2019 classification is: appendiceal mucinous neoplasms (AMNs), adenocarcinomas (AA) including mucinous (MAC), not otherwise specified (ANOS), signet ring (SRC) and goblet cell (GCA), and neuroendocrine tumours (NET). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS+HIPEC) is the definitive treatment. The role of chemotherapy remains unclear with conflicting outcomes and there is need to delineate the optimal regimen in different disease settings. The aim of this study was to evaluate AC treatment and clinical outcomes by the WHO 2019 classification and analyse the impact of perioperative chemotherapy. Methods: We reviewed prospective data from the database at an Australian state peritonectomy service, Apr 2017-Dec 2021. Variables included demographics, tumour characteristics, treatment details and survival outcomes. Analysis was by the Kaplan-Meier method using the log-rank test for statistical comparison (SPSSv27). Results: 115 patients (of 207 referred) with confirmed AC proceeded to CRS. Histopathology comprised 49 AMNs (43%), 62 (63%) AA, 3 SRCs and 1 NET. The mean age was 56y (21-78), 53% female. 94% had CRS+HIPEC (Mitomycin 85%). 70% had cytoreductive score 0. The median peritoneal cancer index was 23 (0-39). 20 (17%) had localised (M0) disease, 10 acellular mucin (M1a) and 85 (74%) metastases (M1b/c). 71% were lymph node negative (N0). 40% had chemotherapy (oxaliplatin/5-fluorouracil 57%). 8 of 15 who had molecular testing had a KRAS mutation. Median follow-up was 26m (1.9-167). The table shows univariate survival analysis. Conclusions: This is the first study evaluating outcomes of perioperative chemotherapy for AC in a cohort of patients since the WHO 2019 classification. MAC have worse survival compared to ANOS, but similar to GCAs. Peritoneal acellular mucin has a similarly improved prognosis to patients with no peritoneal disease compared to those with cellular disease. Chemotherapy demonstrated worse survival compared to no chemotherapy, also seen in the literature and likely influenced by selection of more aggressive disease. There is a need to develop biomarkers and better treatments to improve the survival of these patients. Further multivariate analysis for prognostic and predictive factors is planned.[Table: see text]
NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Swain Jayne , Craig Zoe , Sharma Rohini , Faluyi Olusola Olusesan , Wadsley Jonathan , Morgan Carys , Wall Lucy R. , Chau Ian , Reed Nick , Sarker Debashis , Margetts Jane , Krell Daniel , Cave Judith , Sharmila Sothi , Anthoney Alan , Patel Alkesh , Lamarca Angela , Hubner Richard A , Valle Juan W. 
Published: June 2022

4005 Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m2 free base)/5-FU (2400 mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of <15% would give grounds for rejection. Intention was to show that the regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and toxicity. Based on futility analysis, the DSMB recommended closure of recruitment in Dec 21. Results: Of 58 patients in 15 UK centres (Nov 18-Dec 21), 29 in ARM A, 29 in ARM B, 57% were male, median age (range): 63.5 years (22-85), 90% ECOG PS 0/1, 10% PS 2, 90% Ki-67≥55%, 33%/38%/29% small/large cell/unknown morphology, primary site: 69% gastrointestinal, 12% unknown, 9% genitourinary, 5% head & neck, 3% gynae, 2% breast, 60% had liver mets, 91%/7%/2% were resistant/sensitive/intolerant to 1L platinum-based treatment. At a median follow up of 6.6 mo, the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented (Table). Adverse events ≥ grade 3 occurred in 51.7% and 55.2% in ARM A and B and there were 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Data cleaning is on-going. Conclusions: nal-IRI/5-FU, but not docetaxel, met the primary endpoint (exceeding the threshold for efficacy), with manageable toxicity, and warrants evaluation in a phase III trial. Clinical trial information: 03837977. [Table: see text]
Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.
Authors: Chau Ian , Ajani Jaffer A. , Doki Yuichiro , Xu Jianming , Wyrwicz Lucjan , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez Freitas Melro , Holtved Eva , Blum Murphy Mariela A. , Abdullaev Sandzhar , Soleymani Samira , Lei Ming , Kato Ken , Kitagawa Yuko 
Published: June 2022

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]
Phase II trial of perioperative chemotherapy of esophageal cancer: PIECE trial.
Authors: Nomura Motoo , Goto Masahiro , Watanabe Masayuki , Hato Shinji , Kato Ken , Baba Eishi , Matsubara Hisahiro , Mukaida Hidenori , Yoshii Takako , Tsuda Masahiro , Tsubosa Yasuhiro , Kitagawa Yuko , Hideki Ishikawa , Muto Manabu 
Published: June 2022

4038 Background: Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell cancer (ESCC) in Japan. The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in patients treated with NAC-S. Methods: Key eligibility criteria were as follows: ESCC of clinical stage IB-III (without T4 disease); aged 20 to 75 years; ECOG performance status 0 or 1; and performed neoadjuvant chemotherapy (5-FU + cisplatin). All patients registered before surgery. Patients received adjuvant therapy with 4 cycles of S-1 (80 mg/m2/day) that is administered orally for 4 weeks of a 6-weeks cycle. The primary endpoint was three-year relapse free survival (RFS). Results: A total of 52 patients were enrolled between January 2016 and January 2019. Two patients (one with small cell carcinoma and the other with synchronous malignancy) were excluded from analysis. Five patients were diagnosed as R1 or R2. Seven patients did not receive adjuvant S-1 due to adverse events of surgery in 5 patients, refusal to adjuvant S-1 in a patient, and forgot to start in a patient. Thirty-eight patients received adjuvant S-1, with 32 patients completing 4 cycles. The median relative dose intensity of adjuvant S-1 was 85.8%. Median follow-up time among survivors after surgery was 4.5 years (range 0.2-5.6). Three-year RFS in intention to treat population was 72.3% (90% confidence interval [CI] 59.9-81.5), suggesting that the primary endpoint was met, and 3-year overall survival was 85.0% (90% CI 73.9-91.6). Grade 3 or higher adverse event with an incidence 10% of greater were neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There was no treatment-related death. Conclusions: Adjuvant S-1 showed promising efficacy with manageable safety profile for patients with resectable ESCC after NAC-S, and warrants further evaluation in larger studies. Clinical trial information: UMIN000020204.
The adjudication rates between readers in Blinded Independent Central Review (BICR) of advanced esophageal cancer trials with or without immune checkpoint initiators as first-line therapy.
Authors: Liu Yan , Wang Yi , Iannessi Antoine 
Published: June 2022

4039 Background: It is challenging to use RECIST 1.1 for the response assessment in esophageal cancer, because it excludes certain examines such as the use of barium meal and endoscopy. In some esophageal trials, the study protocols also recommend not selecting the primary tumor as a target lesion, because esophageal lesion could be infiltrative in a cavity organ and difficult to measure reliable especially after treatment. Moreover, it can even be more difficult for independent central readers, as they are often blinded to patient clinical symptoms and outcomes. The aim of this study is to analyze a pool of advanced esophageal cancer trials which used RECIST 1.1, and to document the proportion of reader discrepancies, reader performance through monitoring procedures, and to provide suggestions for the reduction of read inconsistency. This study provides benchmarks of reader adjudication rate in novel esophageal cancer therapeutic trials with or without immune checkpoint inhibitors, which will help to trigger corrective actions, such as reader initial training and follow up re-training. Methods: We analyzed 4 esophageal cancer BICR trials that included 1,875 patients (8,501 time-points) involving 14 radiologists. We analyzed the adjudication rate of each trial as well as testing inter-trial differences. The analysis of adjudication allowed to compute trial and reader adjudication rate, readers endorsement rate, root causes of adjudications. Results: Trials had an average adjudication rate of 45.28% [42.60%-47.99%], while readers endorsement rates ranged [23.1%-81.6%]. The differences of target lesion selection (34.4%) and lesion measurement (40.3%) are the two main reasons that led to discordance per adjudicators’ assessment. The difference of new lesion determination and identification of non-target lesion progression contributed 17.8% and 7.5% of the discordance reasons, respectively. Conclusions: We provided benchmark performances for monitoring reader performance in trials with double reads. The discordances of baseline lesion selection and lesion measurement in follow up visits are the main reasons triggering adjudications in esophageal cancer central reading. Appropriate reader training and monitoring are solutions which can not only mitigate a large portion of the commonly encountered reading errors and help to reach more consensus on lesion selection and measurement between readers.
Non-invasive detection of esophageal carcinoma by integrative analysis of low-pass whole methylome sequencing of plasma cell-free DNA.
Authors: Liu Dan , Jiang Bin , Chen Weizhi , Nie Peiyao , Xie Hongyu , Han Tiancheng , Yang Shunli , Huang Yu S. , Lv Fang , He Shuying , Yang Ying , LI Yulong , Hong Yuanyuan , Yu Jianing ,   Genecast Biotechnology Co.,Ltd., Beijing, China
Published: June 2022

4067 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect esophageal carcinoma. Methods: Plasma cfDNA sampels from 85 patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 60 cancer patients and 398 healthy individuals and the independent testing cohort includes 25 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =96.25% in the discovery cohort and AUC =91.15% in the independent testing cohort. Under a specificity of 95.29% (CI: 87.64% - 100.00%), sensitivity was 72.00% (CI: 56.00% - 92.00%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect esophageal carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Regional subgroup analysis of the phase 3 TOPAZ-1 study of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC).
Authors: Vogel Arndt , Chen Li-Tzong , He Aiwu Ruth , Kim Jin Won , Chen Ming-Huang , McNamara Mairead Geraldine , Shimizu Satoshi , Gillmore Roopinder , Rey Felipe , Kim Hyosung , Xiong Julia , Makowsky Mallory , Rokutanda Nana , Cohen Gordon , Oh Do-Youn 
Published: June 2022

4075 Background: TOPAZ-1 (NCT03875235) is a randomized, double-blind, global, Phase 3 study evaluating the efficacy and safety of D + GC as first-line treatment for patients (pts) with advanced BTC. D + GC significantly improved overall survival (OS) versus placebo (PBO) + GC (Oh D-Y, et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Methods: A pre-specified subgroup analysis was performed for efficacy outcomes including OS for pts enrolled in Asia (China, Hong Kong, India, Japan, South Korea, Taiwan, Thailand) or the rest of the world (RoW; Europe [Bulgaria, France, Italy, Poland, Russia, Turkey, United Kingdom], North America [NA; USA], and South America [SA; Argentina, Chile]). Post hoc country level analyses were also performed to better characterize outcomes in different countries and regions. Pts with BTC were randomized 1:1 to D (1500 mg once every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on Days 1 and 8, Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from a Cox proportional hazards model. Results: Pt numbers were balanced across regions (Asia, n=374 [54.6%]; RoW, n=311 [45.4%]). Baseline characteristics were balanced between regions with the exception of modest differences in important pre-defined prognostic factors, including disease status: recurrent disease (Asia 23%; RoW 14.5%), ECOG performance status 1 (Asia 59.1%; RoW 41.2%), and metastatic disease (Asia 89.3%; RoW 82%). In the PBO arm, more pts in Asia received subsequent anti-cancer therapies than pts in RoW (53.6% vs 43.9%). Median duration of follow-up in censored pts was about 2 months (mo) longer in Asia versus RoW (14.8 vs 13.0 mo in D + GC; 13.8 vs 12.1 mo in PBO + GC). Regional level analysis (Table) showed outcomes were similar and approximated the overall population for Asia, Europe, and NA. Grade 3/4 adverse events were similar for Asia (D + GC 78.5%; PBO + GC 78.6%) and RoW (D + GC 72.7%; PBO + GC 76.7%). Conclusions: Despite some regional differences in prognostic characteristics, OS trends favored D + GC versus PBO + GC for pts enrolled in both Asia and RoW, supporting the use of D + GC as a potential new treatment option for all pts with BTC. Country-specific and regional outcomes continue to be explored. Clinical trial information: NCT03875235. [Table: see text]
A phase II study to evaluate the safety and efficacy of anlotinib combined with toripalimab for advanced biliary cancer.
Authors: Shen Jie , Kong Weiwei , Zhu Sihui , Liu Baorui 
Published: June 2022

4077 Background: To evaluate anlotinib combined with toripalimab for advanced biliary cancer that failed or without the will of standard first-line treatments. Methods: Open single arm phase II study were conducted, eligible patients (pts) were advanced biliary without the chance of operation and failed or without the will of standard first-line treatments. Pts received anlotinib 12mg po qd in 21-day cycles and toripalimab 240mg i.v. every 3 weeks. The main outcome measure was the objective response rate (ORR) of the target lesions evaluated by researchers based on the RECIST 1.1 standard, the secondary outcome measures were progress free survival (PFS) and treatment-related adverse event (TRAE). Results: As of Jan, 2022, 15 pts were enrolled including 9 the intrahepatic cholangiocarcinoma, 3 hilar Cholangiocarcinoma, and 3 the gall bladder carcinoma. 11 (73.3%) pts failed standard first-line treatments, and 4 pts were without the will of standard first-line treatments. The median follow-up was 254 days and 15 pts were all evaluated. 4PR, 9SD and 2PD were achieved. The ORR and DCR for irradiated target lesions was 26.7% and 86.7%, respectively. PFS for first line treatment was 139 days, and for second line treatment as 171 days. By this strategy, 1 ps was successfully transferred to operation after 3 cycle treatment. TRAEs (all grades) occurred in 14 (93.3%) pts. Grade 3 related AEs were fatigue (13.3%). Grade 1-2 related AEs were white blood cell count decreased (53.3%), hypertension (20.0%), thrombocytopenia (60.0%), fatigue (13.3%), hypothyroidism (6.7%), and fever asthenia (6.7%). Conclusions: The combination of anlotinib and toripalimab were demonstrated promising anti-tumor activity in advanced biliary cancer. Clinical trial information: ChiCTR2000037847.
High atezolizumab antidrug antibody levels are associated with unfavorable clinical outcomes and diminished T cell responses following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Chon Hong Jae , Kim Chan , Yang Hannah , Kim Ilhwan , Kang Beodeul , Kim Hyeyeong , Kim Hyunho , Lee Won Suk , Jung Sanghoon , Lim Ho Yeong , Cheon Jaekyung 
Published: June 2022

4105 Background: Systemic administration of humanized monoclonal antibodies can be immunogenic and trigger unwanted anti-drug antibody (ADA) responses. In the IMbrave 150 study, 29.6% of advanced hepatocellular carcinoma (HCC) patients developed atezolizumab ADAs after atezolizumab and bevacizumab (atezo/bev) treatment. ADAs could impair the action of the therapeutic antibody by reduction of serum concentration or neutralization. We determined the clinical and immunological implications of high ADA levels in advanced HCC patients after atezo/bev treatment. Methods: Advanced HCC patients (n = 132) treated with first-line atezo/bev were prospectively enrolled (discovery cohort: 50 from an institute; validation cohort: 82 from four institutes). Serum levels of atezolizumab ADA at baseline and three weeks (C2D1) and atezolizumab concentrations at C2D1 were measured by competitive ELISA. The effects of ADA on T cell immunity were examined by multiplex flow cytometry. Results: Strong ADA (≥ 1000 ng/ml) responses at C2D1 were observed in 17.4% of advanced HCC patients. ADA elevation after atezo/bev at C2D1 was evident in non-responders but not significant in responders. In the discovery cohort, patients with high ADA at C2D1 showed a decreased response rate (ADA-high: 11% and ADA-low: 34%) and shorter progression-free survival (PFS) and overall survival (OS) with atezo/bev compared to those with low ADA levels ( P = 0.004 for PFS; P = 0.009 for OS). In the validation cohort, patients with high ADA at C2D1 showed reduced response rate than those with low ADA (ADA-high: 7% and ADA-low: 29%). PFS and OS were worse in ADA-high group than in ADA-low group ( P = 0.001 for PFS; P < 0.001 for OS). In multivariate Cox regression analysis, the clinical significance of high ADA levels was independently associated with shorter PFS and OS after adjustment for age, sex, ECOG performance status, Child-Pugh score, AFP, macroscopic vascular invasion, extrahepatic spread, and neutrophil-to-lymphocyte ratio (PFS: HR 2.27, P = 0.006; OS: HR 3.04, P = 0.006). The atezolizumab serum concentrations were 29.8% lower in patients with high ADA levels than in ADA-negative patients. Atezolizumab concentration at C2D1 was inversely correlated with ADA levels. Moreover, patients with high ADA lacked CD8+ T cell proliferative responses to atezo/bev treatment. Furthermore, patients with high ADA had decreased secretion of effector cytokines such as IFN-γ and TNF-α from CD8+ T cells compared to those with low ADA. Conclusions: Highly elevated ADA at C2D1 is associated with unfavorable clinical outcomes in advanced HCC patients treated with atezo/bev. High ADA levels were associated with reduced atezolizumab exposure and could limit the drug’s anti-cancer efficacy.