bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automated computed tomography (CT)-derived skeletal muscle mass determination as a significant prognostic factor in colorectal cancer patients using deep neural network model.
Authors: Seo Dongjin , Kim Han Sang , Park Yu Rang 
Published: June 2021

3534 Background: Although recent evidence suggests skeletal muscle depletion predicts the survival of patients with cancer, the retrieval and manual measurement of the computed tomography (CT) images hinder clinical application in routine clinical practice. The advent of recent deep learning applications enables highly accurate noninvasive longitudinal evaluation of skeletal muscle mass (SMM) changes. Here, we evaluated the prognostic impact of DNN-measured skeletal muscle changes in colorectal cancer (CRC) patients. Methods: A total of 6,196 newly diagnosed CRC patients were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2010, and Sep 30, 2020. SMM is measured by the Skeletal muscle index (SMI). The formula used was: L3 skeletal muscle cross-sectional area (cm2)/height2 (m2). Patients’ SMI patterns were grouped by difference ratio of initial and last SMI. Patients were also classified by BMI pattern with the result of K-means clustering. Association of baseline SMI, baseline body mass index (BMI), SMI changes, BMI changes, and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test the predictive accuracy of survival models. Results: Fully automated UNet architecture-based deep learning algorithms were applied for the third lumbar transverse CT detection, skeletal muscle segmentation, and skeletal muscle area quantification in CRC patients undergoing abdominal CT between at the time of diagnosis and one year after the diagnosis. Baseline BMI distribution was 28% obese, 26% overweight, 42% normal weight, and 4% underweight. Patients in all SMI categories varied widely in BMI. Changes in SMI were categorized into three groups: SMI increase (33%), steady (45%), and decrease (22%) group. Similarly, BMI changes were categorized into three groups: BMI increase (24%), BMI stable (57%), and BMI decrease (19%) group. Low baseline SMI, low baseline BMI, SMI decrease, and BMI decrease were independently prognostic of survival. Intriguingly, BMI and SMI changes had a different prognostic impact in men and women. For women, the SMI increase group (hazard ratio [HR], 0.4; 95% CI, 0.3-0.7; P= 0.001) was associated with longer OS, while the SMI decrease group (HR, 1.2; 95% CI, 0.6-2.2; P= 0.619) was not associated with shorter OS, both compared with SMI steady group. Conclusions: Automated CT-derived SMM depletion had a negative prognostic impact independent of BMI and age in CRC patients. A noninvasive automatic deep learning algorithm provides a unique opportunity to apply to routine clinical practice and understand how and when cachexia impacts cancer prognosis.
Are current family-history based colorectal cancer screening guidelines adequate for early detection and potential prevention of young-onset cases?
Authors: You Y. Nancy , Rodriguez-Bigas Miguel A. , Chang George J. , Bednarski Brian K. , Skibber John Michael , Mork Maureen E , Moskowitz Julie B , Nguyen Sa Thi , Thirumurthi Selvi , Lynch Patrick M. , Kopetz Scott , Vilar Sanchez Eduardo 
Published: June 2021

3549 Background: Strategies to detect and prevent young-onset colorectal cancer (YOCRC, diagnosed under age 50) are critical. Established high-risk screening guidelines (SGs) aim to detect/prevent YOCRCs arising from hereditary syndromes. For non-hereditary YOCRCs, average-risk screening is being considered at an earlier age, but family history (FH)-based increased-risk screening has been poorly studied. We aimed to define the proportion of non-hereditary YOCRC with a FH, and to determine whether existing SGs could have detected/prevented these cases. Methods: 394 consecutive YOCRC patients presenting for surgical resection were reviewed for tumor MMR status, pedigree and genetic testing. Those with known/suspected hereditary syndrome (by phenotype, MMR status, and/or germline mutation) were excluded (N = 65). Pedigrees (N = 329) were analyzed for first- or second-degree relatives (FDR, SDR) with CRC and the ages of diagnosis. The gap between the recommended age for FH-based CRC screening and the age of YOCRC diagnosis was calculated. Results: 89 (27%) non-hereditary YOCRC patients had a FH of CRC. The median age of diagnosis was 45; the tumors were mostly from the distal colon (22%) and rectum (60%), and stage III (48%) and IV (27%). Twenty-one (24%) patients had 22 FDRs with CRCs diagnosed at age 64 (median); and 71 (80%) patients had 92 SDRs with CRCs diagnosed at age 65 (median). Thirteen (15%) had a FH of YOCRC. The existing SGs consider 39 patients (44%) at increased-risk, and the remaining, average-risk (Table). Screening would have begun prior to the YOCRC diagnoses in 28 (31% [or 46, 52%]) patients. But YOCRC diagnosis preceded the recommended screening age in the remaining 61(69% [or 43, 48%]) patients by a median of 5.3 [or 3.9] years (Table). Conclusions: FH is found in 27% of the non-hereditary YOCRC patients; 15% has a FH of YOCRC. In nearly half of the patients, YOCRC was diagnosed several years earlier than the recommended age for FH-based screening, even assuming perfect SG adoption and starting average risk screening at age 45. Refining existing FH-based SGs can potentially be impactful.[Table: see text]
Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Fakih Marwan , Raghav Kanwal Pratap Singh , Chang David Z. , Bendell Johanna C. , Larson Timothy , Cohn Allen Lee , Huyck Timothy K. , Cosgrove David , Fiorillo Joseph A. , Garbo Lawrence E. , Ravimohan Shruthi , Potter Von , D'Adamo David , Sharma Neelesh , Wang Ying A. , Coppieters Sabine , Herpers Matthias , Soares Viana de Oliveira Carolina , Paulson Andrew Scott 
Published: June 2021

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]
Overall survival (OS) with encorafenib (enco) + cetuximab (cetux) in BEACON CRC: Effect of prior therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Aderka Dan , Grothey Axel , Van Cutsem Eric , Yaeger Rona , Wasan Harpreet Singh , Yoshino Takayuki , Desai Jayesh , Ciardiello Fortunato , Gollerkeri Ashwin , Golden Adele , Edwards Michelle L. , Tabernero Josep 
Published: June 2021

3583 Background: Enco + cetux (doublet) has been approved in the US, EU, and Japan for the treatment of BRAF V600E-mutant mCRC after progression on 1–2 prior regimens. In the BEACON CRC study (NCT02928224), median OS (95% CI) with the doublet was 9.3 months (8.0–11.3) compared with 5.9 months (5.1–7.1) with cetux + irinotecan or FOLFIRI (control) in patients (pts) with BRAF V600E-mutant mCRC (HR 0.61 [95% CI: 0.5–0.8]). This post-hoc analysis investigates OS by prior therapies to the doublet treatment in pts with BRAF V600E-mutant mCRC from the BEACON CRC study. Methods: OS of pts treated with the doublet or control were compared according to prior treatment with bevacizumab, oxaliplatin, or FOLFOXIRI and duration of prior anticancer therapy (ACT). Results: The proportion of pts in the doublet and control arms who received prior bevacizumab were 64% and 55%, respectively. Of pts who had one prior therapy, 95% and 88% received prior oxaliplatin and 20% and 14% received prior FOLFOXIRI, respectively. OS by prior treatment in the doublet and control arms is shown in the table. In the doublet arm, pts who had bevacizumab < 4 months before start of study treatment had a median OS of 8.3 months (95% CI: 6.2–11.2); those who had bevacizumab ≥4 months prior had a median OS of 10.7 (95% CI: 7.5–17.7). Within each treatment arm, OS was similar regardless of prior treatment with oxaliplatin or FOLFOXIRI. The duration of prior ACT was similar across study arms, ranging from 5.6–5.8 months for the first line of ACT. Conclusions: In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use. This exploratory post-hoc analysis provides data that reflect the prior treatment landscape clinicians may face when deciding subsequent treatment regimens for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT02928224. [Table: see text]
Association of plasma adiponectin with tumor infiltrating lymphocytes and survival in patients with stage III colon cancer (NCCTG N0147; Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Smyrk Thomas C. , Goldberg Richard M. , Cohen Steven J. , Gill Sharlene , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Jahagirdar Balkrishna N. , Jacobson Sawyer B. , Foster Nathan R. , Pollak Michael N. , Alberts Steven R 
Published: June 2021

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI > 30 kg/m2) [p < 0.001]. The level of adiponectin was significantly lower in men vs women (p < 0.001), in blacks vs whites or Asians (p < 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( < 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HRadj= 0.98, 95% CI 0.74-1.29, padj= 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HRadj= 1.12, 95% CI 0.85-1.47, padj= 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.
A novel clinical tool to estimate risk of false negative KRAS mutation in circulating tumor DNA testing.
Authors: Napolitano Stefania , Sun Ryan , Parikh Aparna Raj , Henry Jason , Parseghian Christine Megerdichian , Willis Jason , Raghav Kanwal Pratap Singh , Morris Van K. , Dasari Arvind , Overman Michael J. , Luthra Rajyalakshmi , Corcoran Ryan Bruce , Kopetz Scott 
Published: June 2021

3594 Background: Recently, in metastatic colorectal cancer (mCRC), the detection of RAS mutations by circulating tumor (ct) DNA has recently emerged as a valid and non-invasive alternative approach, overall showing a high concordance with the standard tissue genotyping, giving information on response to EGFRi treatment and resistant mechanisms. However, RAS mutations may be missed due to low levels of any ctDNA in the blood (false-negative), and it has been difficult to distinguish this from patients without a RAS mutation in the tumor (true-negative). We propose a methodology that can be applied to multi-gene ctDNA testing panels to accurately distinguish true- and false-negative tests. Methods: 357 subjects with tissue and multi-panel ctDNA testing from MD Anderson (MDACC) were used as a training dataset and 295 subjects from Massachusetts General Hospital (MGH) dataset as the testing dataset. CtDNA panels contained between 65 and 70 genes, allowing evaluation of tumor ctDNA shedding from variant allele fraction (VAF) levels in the plasma from other genes (such as APC and TP53). Based on the relationship between KRAS and the VAFs of other gene, we established a Bayesian model providing a posterior probability of false negative in the ctDNA test, using thresholds of < 5% (low), 5-15% (medium), and > 15% (high). This model was validated on the MGH database. Results: Across both cohorts, 431 patients were ctDNA wild type for KRAS. Of those, 29 had tissue documenting a KRAS mutation for a false negative rate of 8%. The model provides the posterior probability that a KRAS mutation is indeed present in the tissue given the observed values of allele frequencies for other mutated genes in the plasma. In the validation cohort, a predicted low false negative had no false negatives (0/62, 95% CI 0%-5.8%), while a predicted medium false negative rate was associated with 3% false negative (1/32, 95% CI 0%-16%). In contrast, a high predicted false negative rate was associated with 5% false negative (5/100, 95% CI 1.6%-11%). The results demonstrate the ability of our tool to discriminate between subjects with true negative and false negatives, as a higher proportion of false negatives are observed at higher posterior probabilities. Conclusions: In conclusion, our approach provides increased confidence in KRAS ctDNA mutation testing in clinical practice, thereby facilitating the identification patients who will benefit from EGFR inhibition while reducing the risk of false negative tests. Extension of this methodology to NRAS and BRAF is possible, with clinical application enabled by a freely available online tool.
H101 treatment of hepatic metastasis of colorectal cancer with recombinant human adenovirus 5 injection: A phase I clinical trial-TROJAN 021.
Authors: He Yang , Chen Jianhua , Zhu Zhongzheng , Gao Song , Wang Hui , Mao Wei , Qian Hong , Liu Weixing , Guo Xianling , Qing Huanlong , Xu Qing 
Published: June 2021

3605 Background: Recombinant human adenovirus serotype 5 injection (H101), obtained through genetic engineering to delete the E1B domain and part of the E3 domain and then selectively replicated in tumor cells, has been approved in 2005 for the local treatment of nasopharyngeal carcinoma and head and neck cancers. This trial aimed to evaluate the safety and the preliminary treatment efficacy of H101 combined with standard treatments in patients with liver metastases from colorectal cancer. Methods: In this phase 1, dose-escalation trial (ChiCTR1900027922), 17-75 years old colorectal cancer patients with unresectable liver metastases that failed to first-line therapy were included at The Tenth People's Hospital Affiliated to Tongji University between 2018.9 and 2020.12. All patients received H101 combined with standard therapy (bevacizumab + mFOLFOX6/FOLFIRI). Ultrasound-guided injection of H101 into the liver metastases was performed for all patients, with one of the following doses: 5×1011 vp/injection for the low, 1×1012 vp/injection for the moderate, 2×1012 vp/injection for the moderate-high, and 3×1012 vp/injection for the high dose groups. Intravenous infusion of bevacizumab (5 mg/kg) and administration of standard-dose mFOLFOX6 or FOLFIRI within 48 h after the intratumor injection was performed. The primary endpoint of the trial was the maximum tolerated dose (MTD). The secondary endpoints included safety, tumor responses, and tumor marker CEA. The adverse events (AEs) were monitored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) and evaluated within 1 week after injection. Imaging examinations were performed for all patients to evaluate the tumor responses, according to the irRECIST. Results: Finally, 8 patients were included; the numbers of patients in the 4 groups were 1, 3, 3, and 1, respectively. MTD was not observed in this study. No grade >4 AEs were observed. The major AE included fatigue (5/8), fever (4/8), shiver (3/8), abdominal pain (3/8), and night sweat (3/8). The tumor responses included partial response in one patient (moderate dose group), stable disease in 6 patients (1, 1, 3, and 1 in the low, moderate, moderate-high, and high dose groups, respectively), and progressive disease in 1 patient (moderate group). No dose-effect response was found. The tumor marker CEA was reduced in 6 of the 8 patients, including 1 (1/1), 3 (3/3), 2 (2/3), and 0 patients in the low, moderate, moderate-high, and high-dose groups, respectively. Conclusions: The safety of H101 combined with standard therapy for liver metastases from colorectal cancer is acceptable, which also shows certain preliminary efficacy. The phase 2 trial is now ongoing. Clinical trial information: ChiCTR1900027922. [Table: see text]
Accurate early-stage colorectal cancer detection through analysis of cell-free circulating tumor DNA (ctDNA) methylation patterns.
Authors: Kinross James M. , Canal-Noguer Pol , Chersicola Marko , Knap Primož , Bitenc Marko , Perera-Lluna Alexandre , Roehrl Michael H. A. , Kruusmaa Kristi 
Published: June 2021

3606 Background: Colorectal cancer (CRC) screening programs suffer from poor uptake and biomarkers have limited diagnostic accuracy. The measurement of the methylation status of tumor-derived cell-free DNA in plasma may address these challenges. We used a targeted methylation panel, tumor-derived signal deduction and machine learning algorithm to refine a blood test for the detection of early-stage CRC. Methods: This was a prospective, international multicenter observational cohort study. Plasma samples were collected either prior to a scheduled colonoscopy as part of standard colorectal cancer screening or prior to colonic surgery for primary CRC. Differentially methylated regions (DMRs) were initially selected by analyzing CRC and control tissue samples with whole genome bisulfite sequencing. A targeted sequencing assay was designed to capture these DMRs in plasma ctDNA. Individual sequencing reads were evaluated for cancer-specific methylation signal and scores calculated for each DMR in a sample. A panel of methylation scores originating from 203 DMRs was used in a prediction model building and validated in a test cohort of patients. Results: Calculated scores were used to train a machine learning model on 68 ctDNA samples from 18 early stage (I-II) and 16 late-stage (III-IV) CRC patients and 34 age, BMI, gender and country of origin matched neoplasia-free controls (median age 63 [50-74], mean BMI 27 [19.5-37], female 50%, Spanish and Ukrainian population, distal cancers 50%). This model was then applied to an independent set of subjects from Spanish, Ukraine and Germany, including 36 stage I-IV cancer patients (median age 61.5 [55-82], BMI 28 [16-39], female 47%, 42% of the tumors were distal) and 159 age and sex matched controls. 87 of the control patients had a negative colonoscopy finding (cNEG), 19 had hyperplastic polyps (HP), 37 had small non-advanced adenomas (NAA) and 16 were diagnosed with other benign gastrointestinal diseases (GID). The model correctly classified 92% (33/36) of CRC patients. Sensitivity per cancer stage ranged from 83% (5/6) for stage I, 92% (11/12) for stage II, 92% (12/13) for stage III to 100% (5/5) for stage IV. Specificity of the model was 97% (154/159), with 100% (37/37) NAA, 94% (15/16) GID, 95% (18/19) HP and 97% cNEG patients correctly identified. Lesion location, gender, BMI, age and country of origin were not significantly correlated to prediction outcome. Conclusions: Methylation sequencing data analyzed using read-wise scoring approach combined with a machine-learning algorithm is highly diagnostic for early-stage (I-II) CRCs (89% sensitivity at 97% specificity). This method could serve as the basis for a highly accurate and minimally invasive blood-based CRC screening test with significant implications for the clinical utility of ctDNA in early-stage cancer detection.