bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enabling accessibility to the CellScape spatial biology workflow for researchers using standard histology protocols and pre-slided specimens.
Authors: Berigan Benton , Braubach Oliver , Ingalls Matthew , Meshik Xenia , Schwarz J. Spencer , Cashion Kayla , Northcutt Adam , Jackson Charles 
Published: June 2024

e15185 Background: Solid tumor specimen collection during clinical trials often follows a standard histology protocol, ending in the generation of FFPE sections mounted onto 1 mm histology slides. Though a common sample format for researchers developing tissue-based biomarkers, slides present a data quality challenge for multiplexed spatial biology workflows. Here we present data describing an innovative flow cell design fully compatible with pre-slided tissue specimens. We collected spatial biology data using this slide-compatible flow cell and compared it to the gold standard direct mounting on coverglass. Several rounds of marker staining and imaging demonstrate equivalency in method outcomes including image resolution, signal to noise, and re-interrogation capacity. Methods: FFPE biopsy tissue specimens (tumor punch biopsies and a tonsil section) were mounted on standard histology slides. These specimens were incorporated into flow cells using a new glass coverslip and porting device, CellScape™ Slide, that pairs with a standard histology slide to form a microfluidic chamber. After mounting, each sample was probed for consensus CD markers (CD45, CD3, CD4,CD8,CD20, etc.) through several rounds of iterative immunofluorescence staining using CellScape™ Precise Spatial Multiplexing. The resulting multi-layered whole slide image dataset was then interrogated for spatial resolution and signal-to-noise using digital image analysis. Results: Spatial resolution and signal-to-noise ratio (SNR) were assessed through comparison to data collected from similar samples using the existing CellScape microfluidic chip. The lowest intensity signal collected with at least a 30:1 SNR (acceptable for image analysis) was equivalent or lower in the CellScape Slide preparation (equivalent sensitivity). The highest intensity signal collected was equivalent between the two flow cell designs. Comparing stain quality (specificity, sensitivity) among markers stained through multiple rounds of iterative staining, imaging, and signal remove via photoinactivation showed that the CellScape Slide flow cell is on par with or better than the existing CellScape chip. Further, the usable clear window of the CellScape Slide flow chamber, measuring 16 mm x 44 mm, was found to be greater than twice that of the existing chip. Literature review determined this to also be the largest imaging window available among commercially available spatial biology platforms. Conclusions: Assessment of the CellScape Slide flow cell, innovative in providing access to the CellScape spatial biology workflow for pre-mounted FFPE tissue, determined that the optical performance of the new flow cell is at least on par with the existing flow cell. Further, the usable window is over twice the area, and the new flow cell is fully capable of supporting re-interrogation of the sample.
Preliminary results of atezolizumab and pirfenidone in non-small cell lung cancer.
Authors: Huang Chao Hui , Wick Jo , Komiya Takefumi 
Published: June 2024

e15197 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis improved outcomes for stage IV non-small cell lung cancer (NSCLC). Poor response to PD-L1 antibody has been linked to increased cancer-associated fibroblasts (CAF), which interact with cytotoxic T cells (CTLs) similarly to regulatory T cells (Tregs). CAFs, through cytokine production, impair antitumor immunity by affecting CTL function (TGF beta) and inhibiting CTL recruitment into tumors, suggesting that CAFs could be a therapeutic target in CPI-resistant NSCLC. Pirfenidone (P) exhibits anti-fibrotic effects by blocking fibroblast differentiation into CAFs and suppressing TGF beta production and associated signaling pathways/collagens. Atezolizumab (A) targets PD-L1, inhibiting its interaction with PD-1 and B7-1 (CD80) receptors on T cells. We initiated a phase I/II trial to test the combination of AP in recurrent NSCLC after CPI progression. The phase I study aims to determine the maximum tolerated dose (MTD) of AP and assess its safety and tolerability. The phase II study will evaluate its efficacy. The Exploratory Objectives are to measure circulating levels of TGF beta and investigate the expression of CAF-related proteins. Methods: phase I will enroll 3 patients using P at 801 mg PO TID and A at 1200mg IV every 3 weeks. If there is ≤ 1 Dose Limiting Toxicity (DLT), the study will proceed to phase II. If there are ≥2 DLTs, P will be reduced to 534 mg TID. If there is ≤ 1 DLT at this dose, we will proceed to phase II. If there are ≥2 DLTs, then the study will be terminated. Phase II will enroll 16 patients to assess efficacy. The main inclusion criteria are patients with recurrent NSCLC without actionable mutation, after progression with first-line therapy CPI with or without platinum-based doublet chemotherapy, no more than 2 lines of therapy, measurable disease, ECOG 0-2, and adequate organ function. Results: The study enrolled a total of 5 patients (4 males, 1 female), median age of 63.4; 5 were white; 3 patients did not complete the required 21 days of therapy for evaluation (1 non-compliance, 1 disease progression,1 unrelated Urinary Tract Infection); 2 patients were evaluable for toxicity, without DLT; 1 exhibited a partial response to cutaneous metastatic disease, with overall stable disease, 1 had disease progression. Adverse events (AE) in more than 5% of patients included blood disorders, cardiac, gastrointestinal, administration site, metabolic, musculoskeletal, psychiatric, respiratory, and skin disorders. Serious AEs were noted in 2 patients: one experienced gastrointestinal bowel perforation due to disease progression resulting in death, and the other had a respiratory disorder. Conclusions: The combination of AP did not produce unexpected side effects or reach the dose-limiting toxicity threshold. After the phase I portion is completed, the study will proceed to phase II expansion to enroll patients with recurrent NSCLC. Clinical trial information: NCT04467723 .
Application and evaluation of fecal SDC2 gene methylation in the diagnosis and treatment of colorectal cancer.
Authors: Xie Rongjia , Liu Zhuqing , Xu Qing 
Published: June 2024

e15541 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by regulating cell adhesion, tissue differentiation and angiogenesis. The aim of this study is to verify the sensitivity and specificity of fecal SDC2 gene methylation in the detection of colorectal cancer, find the dominant population who can benefit from this detection, expand its clinical application scenarios, and explore its role in the evaluation of the efficacy and prognosis of patients with advanced colorectal cancer. Methods: A total of 72 patients diagnosed with colorectal cancer were included in the study. The methylation level of SDC2 gene in feces of patients was detected by fluorescence PCR. We evaluated sensitivity and specificity and assessed associations between fecal SDC2 methylation levels, fecal occult blood tests, characteristics of the lesions on colonoscopy, and clinical practice. The critical value of reaction solution A was 10.0, and the critical value of reaction solution B was 10.5. When the Ct value of any tube of reaction solution A or B was less than the critical value, it was judged as "positive". Results: Data from 72 patients were evaluated, with a sensitivity of 89.1% (41/46 95%CI 0.798 to 0.985) for patients with untreated colorectal cancer. The sensitivity of SDC2 methylation detection was 46.2% (12/26 95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference in the detection rate of SDC2 methylation between the two groups was statistically significant (P < 0.001). Among the 46 untreated patients with colorectal cancer, 32 patients with positive SDC2 gene methylation received radical surgery, and 30 of them (93.75%) turned to SDC2 gene methylation negative after surgery. Patients who achieved clinical benefit (CR+PR+SD) found reduced SDC2 gene methylation levels in the stool.There was no significant difference in the methylation level of SDC2 gene between colorectal cancer patients with different fecal occult blood test results (-, +, ++, +++) (P = 0.564)、different lesions (ascending colon, transverse colon , descending colon , sigmoid colon, and rectal) (P = 0.179)、different stages (stage I, II, III, IV) (P = 0.828)、different types (infiltrative, ulcerative, protruding) (P = 0.629), and different sizes of lesions (≤ 5cm, 6-9cm, ≥10cm) (P = 0.644). Conclusions: The high sensitivity of fecal SDC2 gene methylation in detecting untreated CRC patients may help make colonoscopy a screening method only for those at high risk of developing CRC. It may help to evaluate the efficacy of radical surgery, predict the recurrence of colorectal cancer and monitor the efficacy of palliative treatments for colorectal cancer. This work was supported by Shanghai Shenkang Project (No.SHDC2022CRT009).
The effect of HER2-targeted inhibitors as second-line or later-line regimens in the treatment of HER2-positive advanced colorectal cancer: A systematic review and meta-analysis.
Authors: Zhang Qianyuan , Liu Haiyu , Zhang Suyun , Chen Jinghan , Luo Qiong , Xu Qian , Chen Xiangqi , Yang Sheng 
Published: June 2024

e15542 Background: To systematically evaluate and meta-analyze the efficacy and safety of Human Epidermal Growth Factor Receptor-2 Inhibitor (HER2 Inhibitor) as a second-line or later-line antitumor regimen in the treatment of HER2-positive advanced colorectal cancer and provides a new method to treat metastatic colorectal cancer who failed with first-line treatment. Methods: Literature focusing on the use of HER2-targeted inhibitors in the treatment of HER2-positive mCRC was downloaded from Pubmed, Web of Science, EMBASE and Google Scholar databases from January 1, 2019 to October 31, 2022, and the final included articles were determined by screening and relevant data were extracted, including Objective Response Rate (ORR), disease control rate (DCR), Progression-Free-Survival (PFS), Overall Survival (OS), and Serious Adverse Events (SAEs) (Grade 3/4 adverse events). Binary variables were compared using 95% confidence intervals (CI) and odds ratios (OR); for continuous variables, heterogeneity was checked using Cochran's Q Test (p values and I²) and Weighted mean difference (WMD) and 95% CI. P < 0.05 or I² > 50% denote statistical significance, and results were combined using a random-effects model. The efficacy and safety of adding HER2-targeted inhibitors in treating HER2-positive mCRC were further discussed using the above methods. Results: The systematic review and meta-analysis included 17 studies with a total of 267 patients, with an overall DCR of 57% (95% CI: 43%-70%), an ORR of 29% (95% CI: 21%-37%), a median OS of 13.11 months (95% CI: 10.57-15.64), a median PFS of 4.40 months (95% CI: 3.64-5.15), and SAEs of 20% (95% CI: 0.11-0.29). The efficacy of the second-line and later-line treatment was significantly better than that of the well-known EPIC study, ML18147 study, CONCUR study and FRESCO-2 study. Conclusions: Systematic review and meta-analysis show that HER2-targeted inhibitors as second-line or later-line regimens demonstrate ideal antitumor efficacy and safety in HER2-positive mCRC, which is better than the standard regimen without anti-HER2 therapy. Specifically, the new ADC drug (A antibody-drug Conjugate, ADC) should be able to improve the treatment effect of these patients more effectively. Therefore, HER2-targeted inhibitors can effectively improve the efficacy of second-line and later-line therapy for HER2-positive mCRC. Furthermore, it is still worth exploring its therapeutic effects application as first-line therapy, which is expected to offer new strategies for the clinical diagnosis and treatment of HER2-positive advanced colorectal cancer.
Predictors of survival outcome of TAS102 combined with bevacizumab compared to TAS102 alone in Saudi patients with metastatic colorectal cancer beyond second line of systemic therapy.
Authors: Elsamany Shereef Ahmed , Alghanmi Hosam , Tashkandi Emad M , Al-Shehri Ahmed Saleh , Hassanin Fayza , Abdulaziz Nashwa A. , Alhowari Mai , Mahrous Mervat , Alghamdi Mohammed Abdullah 
Published: June 2024

e15545 Background: Significant proportion of metastatic colorectal cancer (mCRC) patients receive systemic therapy beyond second line. This study aims to assess predictors of survival outcome in patients treated with TAS 102/bevacizumab compared to TAS102 alone beyond 2nd line. Methods: In this retrospective study, we assessed patients with mCRC treated with TAS102/bevacizumab or TAS102 alone beyond second line in 4 institutes in Saudi Arabia from January 2020 to December 2022. We checked progression-free survival (PFS) and overall survival (OS) of the study group and we assessed different parameters that may affect the survival outcomes. Results: We included 68 patients in this analysis (39 treated with TAS102/bevacizumab, 29 with TAS102 alone) with a median follow up of 20 months. Noteworthy, 39.7% of patients received treatment in third line (56.4% vs. 17.2%, respectively, p = 0.001) and 48.5% developed neutropenia with first cycle (51.3% vs. 44.8%, p = 0.59). Time from stage IV diagnosis to study treatment (TTAS102) was > 18 months in 56.4% vs. 44.8 %, respectively, p = 0.34. The two treatment arms were balanced for other parameters including site of primary tumour, tumour stage at diagnosis. Median PFS was significantly higher with TAS102/Bevacizumab compared to TAS102 alone (5 vs 3 months, HR = 0.59, 95% CI 0.35-0.98, p = 0.043). Similarly, median OS was significantly improved with TAS102/bevacizumab (15 vs 8 months, HR = 0.55, 95% CI: 0.30-0.98. p = 0.034). After adjustment of line of study treatment, TTAS102 and number of metastatic sites, PFS and OS were significantly improved with TAS102/bevacizumab compared to TAS102 alone (PFS: HR = 0.48, 95% CI: 0.26-0.89, p = 0.021), (OS: HR = 0.54, 95% CI: 0.26-0.91, p = 0.034). Survival outcomes were higher with TAS102/bevacizumab compared to TAS102 in patients with TTAS102 > 18 months (PFS: 5 vs. 3 months, HR = 0.27, 95% CI: 0.12-0.62, p = 0.002), (OS: 22 vs. 6 months, HR = 0.28, 95% CI: 0.11-0.68, p = 0.005) and in patients with neutropenia with first cycle (PFS: 6 vs 3 months, HR = 0.45, 95% CI: 0.21-0.98, p = 0.043), (OS: 26 vs 8 months, HR = 0.33, 95% CI: 0.13-0.81, p = 0. 0.016). No difference in survival outcomes in patients with TTAS102≤ 18 months and those with no neutropenia with first cycle. Conclusions: TAS102 with bevacizumab is associated with improved PFS and OS beyond 2nd line compared to TAS 102 alone especially in patients with longer TTAS102 and first cycle neutropenia.
Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial.
Authors: Stintzing Sebastian , Tabernero Josep , Satoh Taroh , Dasari Arvind , Lonardi Sara , Eng Cathy , Garcia-Carbonero Rocio , Elez Elena , Yoshino Takayuki , Sobrero Alberto F. , Yao James C. , Kasper Stefan , Arnold Dirk , Basic Edin , Granold Matthias , Petschulies Marco , Wu Liwen , Chen Lucy F. , Yang Zhao , Van Cutsem Eric 
Published: June 2024

e15554 Background: As mCRC and its treatment can adversely impact quality of life (QoL), maintaining QoL is an important treatment goal in addition to improving survival outcomes, particularly as patients progress through lines of therapy. In the global, randomized, double-blind, phase 3 FRESCO-2 trial (NCT04322539), fruquintinib (F) + BSC vs placebo (P) + BSC demonstrated significantly improved overall survival (OS) (median 7.4 months vs 4.8 months; HR 0.66, 95% confidence interval [CI] 0.55–0.80) and progression-free survival, with a manageable safety profile and without deterioration of QoL in heavily pretreated patients with refractory mCRC. The objective of this post-hoc Q-TWiST analysis was to assess the quality-adjusted survival benefit of F + BSC in the context of the FRESCO-2 trial. Methods: The Q-TWiST analysis was applied to all 691 randomized patients from FRESCO-2 (F + BSC n = 461 vs P + BSC n = 230). Survival time of each patient was partitioned into 3 health states: time spent with treatment-emergent adverse events of CTCAE grade 3 or 4 before disease progression (TOX), time before disease progression without toxicity (TWiST), and time between disease progression and death or censoring (REL). Assuming utility coefficients of 1 for TWIST and 0.5 for TOX and REL, Q-TWiST was calculated as the utility-weighted sum of the time spent in each health state. The mean time spent in each of the 3 health states was calculated for each treatment group using Kaplan-Meier analysis, and a 95% CI for the difference between treatment was calculated using the nonparametric bootstrap method. Results: Q-TWiST was 6.25 months for F + BSC and 4.21 months for P + BSC, a difference of 2.04 (95% CI 1.51–2.57) months longer with F + BSC vs P + BSC. This difference in Q-TWiST was mainly driven by the difference in the TWiST component (2.14 months [95% CI 1.78–2.49]; F + BSC 4.06 months vs P + BSC 1.92 months). The relative Q-TWiST gain, calculated as the difference in Q-TWiST divided by the mean OS time of the P + BSC group, was 31.4% in favor of F + BSC. Conclusions: In the FRESCO-2 trial, F + BSC demonstrated a clinically meaningful quality-adjusted survival benefit compared with P + BSC in heavily pretreated patients with refractory mCRC. Clinical trial information: NCT04322539 .
Regorafenib Plus for third-line treatment in metastatic colorectal cancer: A real-world study.
Authors: Yisilamu Patiguli , Yao Jiannan , Ge Yang 
Published: June 2024

e15562 Background: Regorafenib, approved as a monotherapy for refractory metastatic colorectal cancer (mCRC), is recognized for its potential immunomodulatory effects and ability to reverse chemotherapeutic resistance. In response to this, a combination regimen known as regorafenib Plus has been customized for specific patients. This study aims to evaluate the effectiveness and safety of regorafenib as a standalone treatment and in combination with other therapies (including concurrent/sequential chemotherapy, immunotherapy, transarterial chemoembolization [TACE]) in the real-world setting. The goal is to present viable treatment options for patients with mCRC. Methods: In this retrospective study, patients with chemo-refractory metastatic colorectal cancer (mCRC) who underwent regorafenib treatment at Beijing Chaoyang Hospital between January 2018 and October 2023 were stratified into two cohorts: monotherapy (Rego Mono) and concurrent/sequential combination therapy (Rego Plus). Index date was the initiation of regorafenib therapy in a sequence and median follow-up was 19.1 months. The clinical outcomes included progression-free survival (PFS), overall survival (OS), and 1/2-year OS rates. Results: A total of 67 pts were included (n = 39 Rego Mono; n = 28 Rego Plus). Baseline characteristics were comparable between cohorts. The median progression-free survival (PFS) was significantly extended in the Rego Plus group compared to Rego Mono (8.0 vs. 3.6 months, P = 0.000), and overall survival (OS) was also notably prolonged (24.4 vs. 19.1 months, P = 0.046). The 1/2-year OS rates were also improved by Rego Plus (63% vs 37.1%, 25.5% vs 11.4%). However, there were no statistical differences in PFS between concurrent and sequential combination therapies (8.4 vs 8.0 mont). Notably, under sequential therapy, after 3.7 months of PFS with regorafenib alone, an additional 4.7 months of PFS was observed when combined therapy was introduced. Regarding safety, Rego Plus was associated with an increased rate of adverse events (AEs) without an escalation in severity. Common AEs included rash, hand-foot syndrome, hypertension, and diarrhea. Conclusions: Rego Plus significantly prolonged PFS and OS in patients with chemo-refractory mCRC. Particularly when tumor stabilization is evident during monotherapy, the introduction of Rego Plus can offer a comparable or even longer PFS benefit, nearly doubling the PFS. Despite an elevated rate of AEs, the severity of these events did not increase, suggesting good tolerability. This approach has the potential to enhance the effectiveness of existing third-line therapies for mCRC, ultimately contributing to an improved prognosis for patients.
Chemotherapy plus EGFR antibody as conversion treatment in RAS wild type, right-sided metastatic colon cancer: A systematic review and meta-analysis.
Authors: Wang Jian , Wang Xiangling , Xia Pingtian , Wang Yanlei , Sun Dong , Guo Sen , Dai Yong , Hao Jing 
Published: June 2024

e15568 Background: The optimal conversion strategy for right-sided RAS wild type (WT) metastatic colorectal cancer (mCRC) remains a contentious issue, especially regarding the role of EGFR antibodies. EGFR antibody treatment might be an attractive option in patients with contraindications to bevacizumab or in hyperselected patients with microsatellite stable subtypes and without RAS/BRAF/HER2 alterations, potentially allowing a shorter time to conversion surgery. Methods: We performed a systematic search of PubMed/MEDLINE and EMBASE for randomized trials reporting the overall response rate (ORR) and resection rate following chemotherapy (CT) plus anti-EGFR agents (cetuximab or panitumumab) for right-sided mCRC. Studies were selected regardless of whether the resection rate was a study endpoint or not. We used a random-effects model with generic inverse variance to compute pooled ORR and resection rates and to compare CT regimens combined with anti-EGFR or anti-VEGF agents. Results: Ten randomized trials with a total of 4465 mCRC patients were included; seven trials reported the resection rate as a secondary endpoint. 828/4465 (18.5%) patients were right-sided, of whom 419/828 (50.6%) patients received CT doublet or triplet plus anti-EGFR, 263/828 (31.8%) treated with CT plus bevacizumab, and 146/828 (17.6%) patients with CT alone. The ORR was significantly higher in the anti-EGFR group compared to CT alone (50.89% vs 31.03%, OR: 2.23 [95% CI: 1.50-3.32], p < 0.01). No significant difference in ORR was observed between the CT plus anti-EGFR and CT plus bevacizumab groups (50.89% vs 53.32%, OR: 0.89 [95% CI: 0.65-1.21], p = 0.44). Resection rates were 8.08% for CT plus anti-EGFR, 4.79% for CT plus bevacizumab, and 12.24% for CT alone, with no significant differences among the three arms (χ2= 2.15, p = 0.34). Subgroup analysis of RAS/BRAF WT patients with right-sided tumors from the PARADIGM and PEAK trials showed no difference in progression-free survival (PFS) between the CT plus anti-EGFR or bevacizumab groups (11.01m vs 11.60m, HR = 1.04 [95% CI: 0.58-1.50]), but there was a trend toward improved overall survival (OS) with anti-EGFR treatment (30.66m vs 28.67m, HR = 0.81 [95% CI: 0.45-1.17]). Conclusions: The data indicate that augmenting chemotherapy with anti-EGFR could be a viable conversion therapy for patients with RAS/BRAF WT right-sided mCRC, underscoring its potential utility in this subset of patients.