bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with advanced colorectal cancer (aCRC): A real-world (RW) analysis.
Authors: Kasi Pashtoon Murtaza , Weipert Caroline , Nguyen Tim , Liao Jiemin , Zhang Nicole , Forbes Shaun , Gordon Sean , Tan Benjamin R. 
Published: January 2023

246 Background: Data suggests that changes in ctDNA quantity correlate with response to therapy in patients with advanced solid malignancies. However, there is little consistency on how to calculate and interpret such changes. Here, we apply a clinically-validated molecular response algorithm to a RW cohort of patients with aCRC to further evaluate its ability to assess treatment outcomes. Methods: We queried the Guardant INFORM database, which comprises aggregated commercial payer health claims and de-identified records from patients with comprehensive ctDNA testing via Guardant360 (G360) from September 2018-March 2022. Patients with aCRC who received G360 within 15 weeks prior to new treatment initiation (any line of therapy) and a second test 3-15 weeks after treatment initiation were retrospectively evaluated using the G360 Response algorithm. Cox proportional hazards (CPH) were used for RW time to next treatment (TTNT), time to treatment discontinuation (TTD), and overall survival (rwOS) analyses. Patients categorized as molecular responders had a >50% decrease in mean variant allele fraction (VAF) ratio from pre-treatment to on-treatment. Gender, age, line of therapy (LOT) and comorbidities were included as covariates. Median TTNT, TTD, and rwOS were calculated by Kaplan Meier. Results: Of 185 aCRC patients with eligible MR results, 65% received chemotherapy +/- VEGF, 21% received regimens containing anti-EGFR monoclonal antibodies, and 14% received other therapies. 43% of aCRC patients were classified as molecular responders, 42% were non-responders, and 15% were not evaluable by the algorithm due to no/low ctDNA at one or both timepoints. 16% of patients cleared their ctDNA on treatment (i.e., ctDNA became undetectable). Molecular responders had significantly longer TTNT (median 10.1 months vs 6.1 months; HR p < 0.005), TTD (median 5.2 Months vs 3.9 months, HR p=0.041), and rwOS (not reached vs 17.8 months, HR p=0.017). Conclusions: Patients with aCRC classified as molecular responders, as calculated by this algorithm, had prolonged time on treatment and overall survival. Compared to tumor markers, ctDNA has a short half-life, which can allow for early response assessment, as shown by our study. These findings are relevant for clinical care, with future potential to allow for adaptive clinical trial design. [Table: see text]
Plasma-only multiomic minimal residual disease (MRD) testing in 2,000 consecutive patients with colorectal cancer (CRC).
Authors: Pedersen Katrina Sophia , Tan Benjamin R. , Zuo Xiaotong , Kiedrowski Lesli A. , Bucheit Leslie 
Published: January 2023

28 Background: Use and impact of circulating tumor DNA (ctDNA) testing for MRD detection has been infrequently reported outside clinical trials. We report clinical use of a validated plasma-only multi-omic MRD assay in a large, unselected CRC cohort, including clinically annotated cases. Methods: The first 2,000 US patients (pts) with documented stage (stg) and Guardant Reveal MRD test results since clinical launch in Feb 2021 were queried; all tests per pt were analyzed (data cut-off: July 2022). Pts could be enrolled in a post-operative program (POP, up to 3 tests 3-16 weeks post-resection) or a surveillance program (SP, after treatment) for recurrent tests; pts could also have one-time tests. Programs were analyzed for stg II/III only. Clinical factors were extracted from test requisition forms; pts from Siteman Cancer Center had additional data extracted from medical records. Results: 1994 pts met criteria for analysis with median age of 64 (range 21-95); 1,112 (56%) were male. ctDNA was detected in 27%, with detection increasing by stg (Table). 30% of positive samples were detected by methylation only, a 43% increased detection over genomic only analysis. 505/544 positive pts had >1 test: 20% had ctDNA first detected on a subsequent test, a 25% increase when testing serially. Most stg II/III pts were tested in the SP. Stg II pts tested POP had a median turnaround time of 10 days (range 6-42); 96% had results prior to 12 weeks post-resection. In the annotated subgroup of 28 pts (65 tests), 8/28 (28%) had ctDNA detected. 13 pts had rectal- and 15 had colon cancer. 11/28 (39%) were stg II, 13 (46%) stg III, 4 (14%) stg IV. 26/28 had surgery, 7/13 rectal pts had neoadjuvant chemotherapy and/or radiation prior to ctDNA testing. 8 (29%) pts recurred. At data cut-off, assay sensitivity to predict or confirm recurrence was 80% (95%CI: 44.4-97.5%), specificity 100% (95%CI: 81.5-100%), PPV 100%, NPV 90% (95%CI:72.26-96.9%). Two pts with recurrence and negative ctDNA had their last test >6 months prior to recurrence. Testing informed clinical decision-making in 11 (39%) pts to proceed with systemic therapy (5), repeat scans sooner (2), proceed with biopsy (1), or confirm recurrence (3). Conclusions: Through real-word data, we confirm prior studies showing multi-omic plasma-only MRD testing has high sensitivity and specificity for recurrence and now show use of the assay in clinical decision-making. Notably, methylation analysis and serial testing both improved detection of MRD and impacted clinical care. These findings should continue to be studied in larger cohorts and randomized trials. [Table: see text]
Neo-AEGIS (Neoadjuvant Trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Final primary outcome analysis.
Authors: Reynolds John V. , Preston Shaun R. , O'Neill Brian , Lowery Maeve Aine , Baeksgaard Lene , Crosby Thomas , Cunningham Moya , Cuffe Sinead , Griffiths Gareth Owen , Roy Rajarshi , Falk Stephen , Hanna George , Bartlett Frederick R. , Parker Imelda , Alvarez-Iglesias Alberto , Nilsson Magnus , Piessen Guillaume , Risum Signe , Ravi Narayanasamy , McDermott Raymond S. 
Published: January 2023

295 Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) remains controversial, specifically whether multimodal therapy or perioperative chemotherapy is superior. Neo-AEGIS was designed as the first randomized clinical trial (RCT) to directly compare the multimodal CROSS regimen (carboplatin/paclitaxel, 41.4Gy radiation therapy) with a modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) regimen (pre-2018) and more latterly the FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin) regimen. Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5% for peri-operative chemotherapy. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade. Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 34.2 (0.43-111.8) months, there were 186 deaths, 91 CROSS and 95 MAGIC/FLOT arm, with 3-year estimated survival probability of 57% (95% CI 49,64) and 55% (95% CI 47,62), respectively [(HR 1.03 (95%CI. 0.77-1.38))]. Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy in the primary outcome of overall survival, notwithstanding greater proxy markers of local tumor response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in clinical decision making in modern practice. Clinical trial information: NCT01726452 . [Table: see text]
Analysis of concordance between microsatellite instability by next generation sequencing (NGS-MSI) and mismatch repair deficiency by immunohistochemistry (IHC-MMR) in >28,000 colorectal tumors.
Authors: Ali-Fehmi Rouba , Oberley Matthew James , Kraus Harris , Herzog Thomas J , Karnezis Anthony , Antonarakis Emmanuel S. , Kasi Pashtoon Murtaza , Farrell Alex Patrick , Xiu Joanne , Swensen Jeffrey , Spetzler David , Abraham Jim , Korn Wolfgang Michael , Bryant David 
Published: January 2023

30 Background: The use of immune checkpoint inhibitors (ICI) in MSI-H/MMRd CRC patients has profoundly changed the treatment landscape in the metastatic setting; the most recent NICHE-2 trial showed 100% response rate in MSI-H/MMRd locally advanced CRC patients treated with neoadjuvant ICI, further highlighting the importance of identifying these patients accurately to enhance patient care. Here we report the concordance of NGS-MSI and IHC-MMR from a very large cohort of CRC tumors and study the molecular characteristics and clinical outcomes of these patients. Methods: A total of 28,105 CRC tumors were analyzed by NGS (592 genes, NextSeq or WES, NovaSeq) and IHC. MMRd was defined as complete loss of ≥1 IHC stains (MLH1, MSH2, MSH6, or PMS2) and proficient (MMRp) as any positive staining for all four proteins. MSI status was determined from over 7,000 target microsatellite loci covered by NGS. Central pathology review (CPR) of MMR IHC was done on 73 cases with discordant MMR/MSI results. Real-world overall survival was obtained from insurance claims and calculated from either tissue collection or treatment start to last contact; Kaplan-Meier estimates were calculated for molecularly defined patients. Results: For CRC tumors with NGS and IHC, 28031/28105 were concordant (99.74%), 0.09% were MMRd/MSS, and 0.2% were MMRp/MSI-H. After CPR, 23/24 (96%) of MMRd/MSS cases and 46/49 (94%) of MMRp/MSI-H were confirmed. Of the 46 post-CPR MMRp/MSI-H CRC samples, 52% had ≥1 pathogenic missense mutation in including MLH1/PMS2/MSH2/6 or MLH3, MSH3, PMS1 or POLE. Of the 23 post-CPR MMRd/MSS CRC samples, 38% had MLH1 loss, 91% PMS2 loss, no MSH2 loss and 9% MSH6 loss. When comparing clinical outcomes with concordant MSS/MMRp tumors, concordant MSI-H/MMRd patients had significantly longer OS (HR=1.131 [95% CI: 1.02-1.254], p<0.001) and post-ICI survival (HR= 2.695 [95% CI: 1.932-3.76], p<0.001). Compared to MSS/MMRd tumors (N=21), MSI-H/MMRp (N=29) trends to have longer OS (HR=2.163, [95% CI: 0.939-4.983], p=0.064) and insufficient ICI-treated patients were available for analysis. Conclusions: Here we report from >28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy. [Table: see text]
Real-world outcomes with front-line doublet versus triplet chemotherapy in advanced gastroesophageal adenocarcinoma.
Authors: Sama Shashank , Nevala-Plagemann Christopher Duane , Smith Jarrod , Pappas Lisa M. , Haaland Benjamin , Garrido-Laguna Ignacio 
Published: January 2023

313 Background: Current guidelines recommend an upfront cytotoxic doublet with or without targeted therapy or immunotherapy for the management of patients with advanced gastroesophageal adenocarcinoma (aGEA).While evidence for the superiority of combination chemotherapy over single agent chemotherapy has been well established, the comparison of two drug versus three drug regimens has been less definitive. This study analyzed a large real-world database to compare clinical outcomes between doublet and triplet approaches in the frontline setting. Methods: The nationwide de-identified Flatiron Health electronic health record (EHR)-derived database was reviewed for patients with aGEA treated with a first line (1L) cytotoxic doublet or triplet irrespective of combination targeted therapy between 2011 and 2022. Patients who received non-standard chemotherapy combinations or did not have a visit or medication order within 90 days of advanced stage diagnosis were excluded. Kaplan Meier and Cox proportional hazards models were used to compare overall survival outcomes between groups. Overall survival was considered as time from the 1L therapy to death with censoring for loss to follow up. Results: 5375 patients with aGEA who met inclusion criteria, 4415 (82%) received doublet chemotherapy and 960 (17%) received triplet in the 1L. Median OS (mOS) for those receiving a doublet was 11 months (95%CI 10-11) similar to those receiving a triplet (11 months, 95% CI 10-12). A Cox proportional hazards model controlling for potential confounding variables of gender, race, smoking status, disease site, as well as HER2 and PDL1 status did not show a significant difference in outcomes between the two groups (HR 0.9, 95%CI 0.8-1). A subgroup analysis comparing FLOT with FOLFOX/CapeOx demonstrated an improved mOS with FLOT (13 mo vs 10 mo; 95%CI 11-15 vs 9-10). This benefit was sustained in a multivariable analysis which demonstrated an increased risk of death with FOLFOX/CapeOX compared to FLOT (HR 1.2, 95% CI 1-1.4). Conclusions: Consistent with prior studies, this real-world study did not identify a significant difference in survival outcomes with 1L triplet compared to doublet chemotherapy in aGEA. When limiting analysis to modern chemotherapy regimens however this data does suggest that a survival benefit may exist with the use of FLOT when compared to FOFOX/CapeOX. This finding would need to be further evaluated in prospective trials incorporating immunotherapy and targeted therapy prior to widespread recommendation.
Treatment selection and outcomes of locally advanced esophageal cancer in octo- and nonagenarians: Is a curative intent multimodal approach feasible?
Authors: Ahmed Nabeel , Tankel James , Asselah Jamil , Alcindor Thierry , Alfieri Joanne , David Marc , Najmeh Sara , Cools-Lartigue Jonathan , Spicer Jonathan , Mueller Carmen L. , Ferri Lorenzo 
Published: January 2023

333 Background: Neoadjuvant therapy followed by en bloc surgical resection affords the highest rates of survival from locally advanced esophageal cancer (LAEC) and represents the standard of care. However, patients of advanced age may not be offered this approach due to concerns over toxicity/tolerability. The outcomes of different treatment modalities for patients aged 80 and above with LAEC are not well described. Methods: A retrospective, single center, cohort analysis was performed on a prospectively maintained comprehensive esophageal cancer database. Between 2010-20, all patients ≥80yrs with locally advanced esophageal/GEJ cancer (cT2-4a, Nany, M0) were identified and outcomes stratified according to the following treatment categories: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery; definitive CRT (dCRT); upfront surgery; palliative CT or RT; or best supportive care (BSC). Data presented as median(range). Univariate analysis used for clinicopathological data (*p<0.05). Survival was compared with log rank analysis (Mantel Cox). Results: 79 patients ≥80 yrs with LAEC were identified. Median age was 83yr (80-97) and Charlson comorbidity index=7 (6-10). Most were cT3 (73%), cN- (56%) and adenocarcinoma (62%). Treatment approaches included: neoadjuvant (nCT(n=11)/nCRT(N=5)) + surgery (16/79(20%)); surgery alone (19/79 (24%)); dCRT (12/29(15%)); palliative RT or CT (24 + 3/79(34%)); BSC (5/79(6%)). Neoadjuvant consisted of nCT (FLOT=4; carbo-taxol =4; FOLFOX=2; CP+pembro=1) and nCRT (CROSS=5) and most received the intended full treatment/cycles (10/16:63%). Surgery was performed in 35 (age=82(80-96)), with major complications (grade 3-5) in 13/35 (37%) and 90-day mortality in 3/35(8.5%). Overall Survival for the entire cohort was 58% (1yr) and 19% (3yr), but highest with nCT/nCRT+surgery (94%/46%)*, followed by surgery alone (68%/39%), dCRT (58%/8%), palliative treatment (40%/4%), and BSC (0%/0%). Curative intent treatment (nCT/nCRT/surgery/dCRT) had significantly increased 1 and 3-yr survival compare to palliative treatment (76%/31% vs 34%/3.3%)*. Conclusions: Multimodal standard of care treatment, including surgical resection, of locally advanced esophageal cancer in octo/nonagenarians is feasible and safe in a subset of this high-risk population and associated with improved outcomes compared to other approaches. Age alone should not bias against curative-intent treatment in elderly patients with esophageal cancer.
Lower risk of metabolic syndrome and fatty liver in gastric cancer survivors: A propensity score-matched analysis.
Authors: Park Hyojin 
Published: January 2023

334 Background: With the recent development in cancer treatments, the number of cancer survivors is rapidly increasing. Thus, evaluation and management of accompanied comorbidities as well as survival itself have become important issues in cancer survivors. The aim of this study was to investigate the prevalence and risk of metabolic syndrome (MetS) and fatty liver in gastric cancer (GC) survivors compared with that in non-cancer (NC) subjects. We also analysed the risk for metabolic dysfunction-associated fatty liver disease in GC survivors compared with that in NC subjects. Methods: In this cross-sectional study, participants who visited Gangnam Severance Hospital from 2014 to 2019 for health check-ups were enrolled. After age- and sex-matched 1:4 propensity score matching, 119 GC survivors and 476 NC subjects were included. GC survivors were divided into operated gastric cancer survivors (OpGC) (n=95) and non-operated survivors (non-OpGC) (n=24). MetS was diagnosed by metabolic components and FL was assessed by ultrasonography. Results: MetS was observed in 21.0% of GC survivors and 30.5% of NC subjects, and in 13.7% of OpGC survivors and 50.0% of non-OpGC survivors. FL was observed in 25.2% of GC survivors and 37.6% of NC subjects, and in 21.1% of OpGC survivors and 41.7% of non-OpGC survivors. After adjusting for age, sex, MetS risk was significantly lower in OpGC survivors (odds ratio [OR] = 0.377, 95% confidence interval [CI]: 0.200-0.711, P=0.003). FL risk was significantly lower in OpGC survivors (OR = 0.467, 95% CI: 0.267–0.816, P=0.007), but not in non-OpGC survivors, compared with NC subjects. Risk of metabolic dysfunction-associated fatty liver disease was significantly lower in OpGC survivors (OR = 0.412, 95% CI: 0.233–0.729, P=0.002) compared with NC subjects. Conclusions: OpGC survivors showed a lower risk of MetS and FL compared with NC subjects. These associations can be explored to ensure timely medical intervention in GC survivors.
Nab-paclitaxel combined with oxaliplatin and S-1 as conversion therapy for advanced gastric adenocarcinoma.
Authors: Ji Ke , Bu Zhaode , Yang Heli , Wang Zhenning , Liu Funan , Liang Pin , Dong Yan , Zhang Jie , Zhao Qun , Liu Yang , Ji Jiafu 
Published: January 2023

343 Background: Conversion therapy can improve the survival of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. This study was conducted to evaluate the efficacy and safety of nab-paclitaxel combined with oxaliplatin and S-1 as a conversion therapy in gastric cancer. Methods: This was a single-arm, multicenter, open-label trial of patients with locally advanced unresectable or potentially resectable metastatic gastric adenocarcinoma. Eligible patients were administered nab-paclitaxel (150 mg/m2, day 1), oxaliplatin (85 mg/m2, day 1), and S-1 (80–120 mg/day, days 1–14) every 21 days for two or four cycles. Radiographic assessments were performed after two cycles of treatment. Subsequent treatment or surgery was decided by the investigator according to assessment results and patient's condition. The primary endpoint was R0 resection rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From January 2020 to September 2022, 62 patients (49 males/13 females) with a median age of 58.9 years (range: 36–73) were enrolled in this study. Sixteen (25.8%) of the 62 patients had distant metastasis. The overall response rate and disease control rate of 54 patients who underwent at least one assessment were 61.1% (33/54, 95% CI: 46.9–74.1%) and 94.4% (51/54, 95% CI: 84.6–98.8%), respectively. Of the 39 patients who underwent surgery, 33 (84.6%, 95% CI: 69.5–94.1%) patients had an R0 resection, two had an R1 resection, and four had exploratory laparotomies. The pathological complete response rate was 15.4% (6/39, 95% CI: 6.4–31.2%). After a median follow-up time of 8.4 months, the 1-year PFS rate was 68.6% (95% CI: 53.4–83.8%), whereas the median PFS and OS were not reached. Seven patients died because of disease progression (5 patients who did not undergo surgery), myocardial infarction (1 patient), and electrolyte disturbance (1 patient). Treatment-related adverse events occurred in 82.3% (51/62) patients, although most events were grade 1–2. Common hematological toxicities were leukopenia (61.3%), neutropenia (54.8%), anemia (41.9%), and thrombocytopenia (30.6%). Common non-hematological treatment-related adverse events were nausea (53.2%), fatigue (43.5%), hepatic function abnormal (33.9%), neurotoxicity (29.0%), and diarrhea (24.2%). Conclusions: Nab-paclitaxel combined with oxaliplatin and S-1 showed promising efficacy and acceptable toxicity in patients with locally advanced unresectable or potentially resectable metastatic gastric cancer. Clinical trial information: NCT04047953 .
Preoperative camrelizumab combined with chemotherapy for borderline resectable esophageal squamous cell carcinoma (BRES-1): A single-arm, open-label, phase II study.
Authors: Yang Hang , Zhang Guoqing , Li Xiangnan , Jiao Jia , Guo Yanan , Zhang Yan , Hou Zhichao , Huang Qi , Zhao Jia , Li Jindong 
Published: January 2023

360 Background: Patients with borderline resectable esophageal squamous cell carcinoma have poor prognosis and poor response to first-line therapy. The BRES-1 study aimed to assess the efficacy and safety of camrelizumab combined with chemotherapy in patients with borderline resectable esophageal squamous cell carcinoma. Methods: This single-center, single-arm prospective phase II clinical trial will enroll 30 patients with borderline resectable esophageal squamous cell carcinoma. The 30 enrolled patients will receive preoperative camrelizumab with chemotherapy regardless of programmed death ligand-1 status. Preoperative therapies will include camrelizumab, nab-paclitaxel and cisplatin. Surgery will be performed 3-4 weeks after the completion of the preoperative neoadjuvant therapy. Three weeks after surgery, two periods of maintenance therapy will be continued with camrelizumab combined with chemotherapy. Then, maintenance treatment will be continued with camrelizumab up to one year. Primary endpoints included pathologic complete response (pCR), major pathological response (MPR). Results: As of September 15, 2022, 19 patients who met the criteria were enrolled (63% males, median age 67), neoadjuvant therapy was completed in 18 patients and ongoing in 1 patients. Among the 19 patients, 11 patients were resected and all patients underwent an R0 resection. 5 patients (45%) reached major pathologic response, 3 patients (27%) reached pathologic complete response, 8 patients (8/11, 73%) with complete regression (TRG 1) or near-complete regression (TRG 2). No grade 3-4 immunotherapy related AEs were observed, no surgery related mortality. The most common treatment-related AEs were leukopenia (18/19, 95%), lymphopenia (18/19, 95%) and anaemia (15/19, 79%). Conclusions: Camrelizumab with chemotherapy for borderline resectable esophageal squamous cell carcinoma has shown good conversion rates. Its efficacy and safety will be further investigated in later trials. Clinical trial identification: ChiCTR2200056728.