bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilizing quantitative pathologic analysis of digitized images of rectal cancer (RC) to predict response to neoadjuvant therapy (NAT).
Authors: Walden Daniel , Eslinger Cody , Emiloju Oluwadunni Eunice , Storandt Michael H. , Hagen Catherine E. , Pfeiffer Ashlyn , Sonbol Bassam Bassam , Ahn Daniel H. , Bekaii-Saab Tanios S. , Ness Andrew , Wu Christina , Pai Reetesh , Ou Fang-Shu , Pai Rish , Hubbard Joleen M. 
Published: January 2024

200 Background: We developed and validated a quantitative segmentation algorithm (QuantCRC) to predict disease recurrence in stage I-III colorectal cancer patients (pts) based on the analysis of digitized hematoxylin and eosin (H+E) stained pathology slides. In this study, we aim to determine if QuantCRC analysis on pre-treated RC biopsies can predict pathological complete response (pCR) after NAT which include total neoadjuvant therapy (TNT), chemoradiation (CRT) and others. Methods: Stage II-IV RC pts treated with curative intent modalities between 2005-2023 at Mayo Clinic and University of Pittsburgh were evaluated. Eligible pts had pre and post-treatment tissue available for analysis. Clinical characteristics, treatment, and outcome data were extracted from the medical record. QuantCRC extracted 15 features: %tumor, %stroma, tumor:stroma ratio, %TB/PDC, %mucin, %necrosis, %high-grade, %signet ring cells, tumor-infiltrating lymphocytes (TILs) per cm2 of a tumor, %immature stroma (tumor bed), %inflammatory stroma (tumor bed), %mature stroma (tumor bed), %immature (stromal region), %inflammatory (stromal region), and %mature (stromal region). The associations between the QuantCRC features and pCR were evaluated using Wilcoxon rank-sum tests and logistic regression models while adjusting for primary tumor location and NAT. Results: The identified 288 pts had the following demographics: median age 60, 59% male, 52% distal tumor, 42% TNT. Pts who achieved pCR had smaller pre-treatment tumors (p=0.03), higher TILS, and lower %immature (stroma) (Table 1). After multivariable adjustment, higher TILS and lower %immature (stroma) remain to be significantly associated with a higher likelihood of pCR. A higher %mature (stroma) and %mature stroma (tumor bed) were also identified, in multivariable models, to be associated with a higher rate of pCR. NAT protocol and tumor location (proximal vs. distal) were not associated with pCR. Conclusions: The ability to integrate pathological features with AI may allow for personalized treatment. Using this technology, we recognize that patients who harbor a more mature stromal archetype and inflammatory tumor predisposition, are more likely to achieve pCR to conventional NAT. These pathological features are not currently incorporated into risk stratification in RC. Additional validation and integration into current risk stratification methods is warranted. [Table: see text]
Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer using a multi-marker panel and a machine-learning approach: Final results of the prospective multicenter PERMAD trial.
Authors: Kestler Hans A. , Ettrich Thomas Jens , Stein Alexander , Arnold Dirk , Prager Gerald W. , Kasper Stefan , Niedermeier Michael , Müller Lothar , Kubicka Stefan , Koenig Alexander , Buechner-Steudel Petra , Berger Andreas , Wille Kai , Kestler Angelika , Kraus Johann M. , Werle Silke , Perkhofer Lukas , Lausser Ludwig , Seufferlein Thomas 
Published: January 2024

204 Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Methods: 15 German and Austrian centers prospectively recruited 154 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results: Using random forest machine learning, we developed a predictive model that discriminated between the situations of ”no progress within 100 days before radiological progress” and ”progress within 100 days before radiological progress”. Into this we incorporated a combination of ten out of the 102 CAF markers, which fulfilled this task with 81% accuracy, 72% sensitivity, and 88% specificity. Conclusions: Using artificial intelligence we identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress. Further studies are required to show its clinical value. Clinical trial information: NCT02331927 .
Association of pathologic nodal status with minimal residual disease after neoadjuvant treatment and resection of locally advanced rectal cancer.
Authors: Uppal Abhineet , Bhutiani Neal , Shen John Paul Y.C. , Alfaro Kristin , Kell Robert J. , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Konishi Tsuyoshi , Holliday Emma , Morris Van K. , Dasari Arvind , Willis Jason , Newhook Timothy E. , Bednarski Brian K. , You Y. Nancy , Peacock Oliver , Messick Craig , Das Prajnan , Chang George J. , Kopetz Scott 
Published: January 2024

205 Background: Studies have shown that minimal residual disease (MRD) identified by detection of circulating tumor DNA (ctDNA) is associated with recurrence after surgical resection of colorectal cancer. Though multiple trials are evaluating the use of ctDNA to guide adjuvant therapy, data on the utility of ctDNA after neoadjuvant therapy is limited. In this study, we evaluated the associations between ctDNA and recurrence after neoadjuvant treatment and resection of rectal cancer (LARC). Methods: Consecutive patients with primary rectal cancer treated with neoadjuvant systemic therapy and/or chemoradiotherapy followed by resection between 12/2020-4/2023 were identified. Patients were tested for ctDNA via the MD Anderson INTERCEPT platform using a high-sensitivity patient informed assay. Patients with metastases or a first ctDNA test more than 3 months after resection were excluded. MRI-determined stage, extramural vascular invasion (mrEMVI), pelvic sidewall adenopathy (PSW), pathologic lymphovascular invasion (LVI), perineural invasion (PNI) and tumor regression grade (TRG) were collected. Associations between these factors and ctDNA status were analyzed with Fischer’s exact test. Recurrence free survival (RFS) was analyzed with the log-rank test. Results: Sixty-seven patients (3 treated with chemoradiotherapy alone, 15 with systemic therapy alone and 49 with total neoadjuvant therapy) were identified. Positive ctDNA was identified in 6 (8.9%) within 3 months after resection, all of whom received total neoadjuvant therapy, and 3/6 recurred within 12 months. Clinical T status (p=0.146), N status (p=0.842), mrEMVI (p=0.475) and PSW (p=0.318) were not associated with MRD. TRG was not associated with MRD (TRG0-1: 4% vs TRG2-3: 11.3%, p=0.547). Pathologic N status was associated with MRD (ypN0: 4.4% vs ypN+: 18%, p=0.049). MRD was associated with a median RFS of 3.2 months (HR 39, 95% CI: 4.1-380, p=0.0015). 1-year RFS was 98% for patients without MRD. Conclusions: Minimal residual disease after multi-modality treatment of LARC is associated with early metastatic recurrence. The patient informed MRD assay appears both sensitive and specific for detection of relapse. Advanced clinical stage and high-risk radiologic features were not associated with MRD, while post-treatment pathologic N status was. Given the high relapse rate for MRD+ patients, MRD detection after resection warrants additional investigation for metastases and/or enrollment on MRD treatment clinical trial. Methods to predict MRD prior to resection are urgently needed.
Identification of somatic alterations associated with brain metastases from a colorectal origin.
Authors: Strong James S. , Drebin Harrison M. , Walch Henry S. , Gui Chengcheng , Pike Luke Roy George , Moss Nelson S. , Sanchez-Vega Francisco , Smith Jesse Joshua 
Published: January 2024

210 Background: Colorectal brain metastases (cBM) confer a devastating prognosis with survival of less than 13 months. Identifying genomic signatures to predict and guide treatment for these patients would be a valuable adjunct. This study evaluated genomic and clinicopathological features specific to cBM. Methods: cBM patients from the MSK-MET cohort were evaluated in comparison to other colorectal cancer patients with extracranial metastases (cOM). Clinicopathologic features and genomic alterations were analyzed with MSK-IMPACT, a targeted DNA sequencing panel for solid tumors and matched blood specimens. We considered mutations, copy number alterations, and fusions. Analyses of genomic features were restricted to microsatellite stable (MSS) patients. q-values were computed using Benjamini-Hochberg correction to account for multiple hypothesis testing. Patient record review identified patients with sequenced matched samples from the primary colorectal tumor and the brain metastases, which were then examined for loss and gain of assessed genetic alterations. Results: Of 130 patients with cBM identified from the cohort, 20 samples were from brain metastases, 52 from the primary CRC, and 58 from other metastatic sites. Average time to diagnosis of cBM was 3.5 years after primary colorectal cancer diagnosis and average time to death was 10 months after cBM diagnosis. Compared to the 3,383 cOM patients, cBM patients had significantly higher rates of both MSS CRC primaries (p<0.001, 122/130 cBM were MSS vs. 3,038/3,382 cOM) and primaries that originated in the rectum (p<0.002, with 38/130 cBM primaries from the rectum vs. 695/3,382 cOM rectal primaries). Somatic alterations in the KRAS, BRCA2, CDK8 and ERCC5 genes were significantly more frequent in patients with cBM compared to cOM patients (all p<0.001) (Table 1). Of the 9 patients who had matched primary and metastatic brain tissue sequenced, KRAS alterations were shared between the primary and brain metastasis in 2/9, ERBB3 and ERCC5 in 2/9, p53 in 6/9, and APC in 6/9 patients. In addition, newly acquired private alterations found only in the brain metastasis samples of matched patients included PIK3RI, ARID5B, NOTCH4, CYLD and SMAD4. Conclusions: We identify new genomic and clinical factors in cBM patients, including somatic alterations in potentially clinically actionable targets. To further explore potential clinical utility, these findings require validation in an independent cBM clinicogenomic dataset.[Table: see text]
Correlation of exploration of immune profile and genomic with microsatellite stable/tumor mutational burden-low colorectal cancer.
Authors: Abushukair Hassan Mohammed , Saeed Azhar , Sahin Ibrahim Halil , Saeed Anwaar 
Published: January 2024

213 Background: Microsatellite stable/tumor mutational burden-low (MSS/TMB-L) tumors, represent the majority of colorectal cancer (CRC) patients and derive limited benefit from immune checkpoint inhibitors (ICI). Given the vast heterogeneity of this population, some patients may be candidates for ICI. Herein, we study the tumor immune microenvironment (TIME) and genomic correlates associated with favorable immune response in MSS/ TMB-L CRC patients. Methods: Using The Cancer Genomic Atlas Colorectal Adenocarcinoma (TCGA-COAD) cohort (n = 594), MSS patients (MSI Mantis score < 0.4) with TMB-L (<10 mutations/megabase) were identified. The CIBERSORT algorithm was used to calculate the fraction of 22 immune cells using RNA-seq data. Relevant immune expression signatures from the CRI iAtlas were used to assess TIME profiles. An antitumor immune activity (AIA) score was constructed using CD8+ T cells, T regulatory cells, and M1 & M2 macrophage fractions. Enriched mutations in MSS/ TMB-L patients with favorable antitumor immune scores were identified and used to stratify patients into favorable and unfavorable immune profiles (FIP & UIP). Comparisons were made using the Mann-Whitney U T-test and Fisher’s exact test. Results: We identified 430 (72.4%) MSS/TMB-L patients among the TCGA-COAD cohort. The AIA score ranged from – 0.44 to 0.62 (higher scores denote favorable AIA activity). The majority of patients (77%) had scores < 0. Top enriched mutated genes associated with higher scores included HMX2, BBS12, IFNLR1, SLC30A2, WDR48, ZNF329, H4C11, PARD3B, ENAM, ASCC1, CCDC88B, CMKLR1, IL21, KLHL11, and OTOP2. Patients harboring a mutation in one or more of these 15 genes were categorized in the FIP group (n=50, 11.6%) and patients with no mutations were categorized in the UIP group (n=360, 88.4%). The FIP group had significantly (p < 0.05) higher levels of TMB, CD8+ T cells, activated NK cells, M1 macrophages, immunogenic SNV mutations, and cytotoxic activity while patients with UIP had higher levels (p < 0.05) of M2 macrophages, neutrophils, and a trend for higher regulatory T cells and TH17 cells. Gene set enrichment analysis showed upregulation of T cell proliferation, interferon signaling, and Fanconi anemia pathway in FIP. Compared to UIP, FIP patients had a trend for better disease-specific survival after adjustment for CC subtype (colon vs. rectum) and age (HR: 0.26, 95% CI: 0.06-1.09, p = 0.066). Conclusions: Findings from this analysis highlight a subset of MSS/TMB-L CRC patients, with features of favorable anti-tumor immune response and unique mutation profile, that might derive benefit from immunotherapy. Further investigation is underway to further explore the genomic correlates in this subset of patients.
Impact of somatic genomic alterations in patients with metastatic colorectal cancer in a minority-rich academic medical center.
Authors: Jang Jessica , Khanimov Moisey , Johnson Devin , Zhang Chenxin , Moon Jee-Young , Bernabe Carolina , Kuang Chaoyuan 
Published: January 2024

215 Background: Genomic alterations in metastatic colorectal cancer (mCRC) play a pivotal role in the clinical manifestations of the disease. Mutations have been associated with the age of onset of mCRC, tumor location, and metastatic sites. We conducted a retrospective study to explore the relationship between the genomic profile and clinical phenotype in a distinct patient population predominantly comprised of Hispanic and Black patients with mCRC. Methods: Patients with mCRC with available next-generation sequencing (NGS) treated at Montefiore Einstein Comprehensive Cancer Center (MECCC) who were diagnosed from January 2000 - January 2023 were included. Molecular testing was collected from: Perthera, Guardant, Caris, and Foundation One. The following parameters were collected: race, ethnicity, age of CRC diagnosis, age of metastatic diagnosis, metastatic sites, NGS profile, tumor location, and lines of treatment. Mutations were categorized into one of eight distinct pathways: cell cycle, MAP Kinase, WNT, homologous recombination, DNA damage repair, epigenetic modifications, transcription, & cell death. The primary endpoint was to examine the relationship between individual genetic alterations or any of these eight pathways and the clinical parameters. Results: 169 patients with microsatellite stable (MSS) mCRC were included (median age at diagnosis 59 years, 42% Hispanic, 38% Black). 148 distinct genetic alterations were discovered across our population, of which roughly half fit into one of eight clinical pathways. In concordance with previously published data, we found a significant association between PTEN and right-sided tumors (38% mutated in right-sided vs. 16% mutated in left-sided, p<.001). Cell cycle pathway mutations and SMAD4 mutations were associated with an earlier age of both primary CRC (p=.001 & p=.042, respectively) and metastatic diagnosis (p=<.001 & p=.013, respectively). CDK8 mutations were associated with atypical sites of metastases (p=.045). Conclusions: This analysis sought to deepen the understanding of how genomic alterations impacted the clinical phenotype in our population of mCRC patients. We identified previously undescribed associations between mutations in the cell cycle pathway and SMAD4 versus age of CRC diagnosis. As molecular sequencing in CRC continues to advance, these relationships may be further elucidated, which can potentially help guide treatment and identify higher-risk patients.
“Choosing wisely” in oncology: The example of surveillance positron emission tomography-computed tomography (PET-CT) for patients with colorectal cancer (CRC) treated with curative intent.
Authors: Tschernichovsky Roi , Razi Talish , Philosoph Keren , Menashe Idan , Arbel Ronen , Netzer Doron , Goldstein Daniel A 
Published: January 2024

216 Background: Healthcare overuse is a major challenge for healthcare systems. Professional guidelines, such as “Choosing Wisely”, have been put in place to mitigate specific areas of overuse. We examined whether the rate of unwarranted PET-CT in CRC patients treated with curative intent was successfully reduced following the adoption of “Choosing Wisely". Methods: We used the large Clalit Health Services dataset in Israel to identify patients with CRC who received adjuvant chemotherapy for localized disease between January 2017-December 2021. We then examined the number of PETCTs performed for each patient. Results: 1799 patients were included in our study (Table). We distinguished localized from metastatic cases based on specific drugs administered or not administered during the follow-up period (i.e. biologics). For the entire cohort, the median number of PETCTs performed per patient over the study period was 3. 364 (20.2%) patients underwent a single PETCT, 946 (52.6%) patients underwent ≥2 PETCTs, and 25 patients underwent ≥ 10 PETCTs. Assuming a single PETCT is considered “guideline concordant” during diagnosis and treatment of localized CRC, 52.6% (946/1799) of patients in our cohort underwent “guideline discordant” PETCT scans. Conclusions: Despite professional guidelines recommending against routine PETCT to monitor for recurrence following curative-intent treatment of CRC, there remains a large volume of “guideline-discordant” PETCTs in this space. Professional guidelines such as “Choosing Wisely” have largely failed to prevent this example of healthcare overuse. [Table: see text]
The power of glycobiology: Precision of polyp detection using glycoproteomic biomarkers.
Authors: Chandrasekar Dharini , Ding Nik Sheng , Wallace Michael B. , Norez Daniel , Guerrier Christina , Ramachandran Prasanna , Caval Tomislav , Desai Khushbu , Xu Gege , Serie Daniel , Hommes Daniel 
Published: January 2024

22 Background: Glycosylation plays a pivotal role in host immune response during cancer development. Recently, we have reported specific changes in blood-based glycoforms for the early detection of advanced adenomas (AAs) and colorectal cancer (CRC). This study aims to identify glycoproteomic biomarkers associated with various polyp types, as glycosylation abnormalities are linked to neoplastic transformation, and CRC risk varies by polyp histology. Methods: Samples from an observational study (NCT05445570) were used to identify three distinct histologic polyp groups: adenomatous (AP), hyperplastic (HP), or serrated (SP). Combining liquid-chromatography/mass-spectrometry and artificial-intelligence powered data processing, our glycoproteomic profiling platform assessed glycopeptide (GP) and non-glycosylated peptide quantification transitions from the serum samples. We used multi-nominal response logit models to examine the relationship between polyp types and biomarkers. An a priori biomarker panel was interjected as exposures in the model. Each marker is assessed independently for inclusion into our final model. The final model utilized biomarkers found to have a significant association with the presence of AP, SP, or HPs along with age, sex, and BMI. Results: We identified 1,035 subjects with distinct polyp histologies and 1,300 polyp-free controls. We found a significant increase in relative risk (RR) for polyp presence in patients who were: >60 years (AP RR 1.40), male (AP RR 1.74), or had a BMI> 25. From the GP biomarker panel, 15 GPs were associated with risk of polyp presence; however, only 7 GP markers were significantly associated after adjusting for age, sex, and BMI. Two biomarkers were found to have a protective effect for the risk of an adenomatous polyp (RR 0.37; RR 0.39). Three biomarkers increased the risk of an adenomatous polyp (RR 1.31; RR 1.42; RR 1.98). One biomarker was found to increase the risk of a hyperplastic polyp (RR 1.42). Two biomarkers were found to increase the risk of serrated polyps (RR 1.67; RR 2.08) and one biomarker was found to decrease the risk of serrated polyps (RR 0.77). Conclusions: This is a novel exploratory study using GP biomarkers as it relates to risk of polyp presence by distinct histology. The use of these biomarkers allows us to harness the power of glycobiology in the liquid biopsy domain for AAs/CRC detection. The exact function of these GP markers during the development of different polyp types needs to be further explored through future studies.