bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of TAS-102 in patients with colorectal cancer with ctDNA-defined minimal residual disease post-adjuvant therapy: Results from the MD Anderson INTERCEPT Program.
Authors: Pellatt Andrew Jared , Bent Alisha Heather , Parseghian Christine Megerdichian , Johnson Benny , Huey Ryan W , Raghav Kanwal Pratap Singh , Morris Van K. , Overman Michael J. , Morelli Maria Pia , Willis Jason , Le Phat , Shen John Paul Y.C. , Lee Michael Sangmin , Alfaro Kristin , Aziz Kathryn , Kell Robert J. , Sun Ryan , Kopetz Scott , Dasari Arvind 
Published: January 2024

136 Background: Circulating tumor DNA (ctDNA) has emerged as a novel marker with high specificity and positive predictive value for identifying radiographically occult microscopic or minimal residual disease (MRD) in colorectal cancer (CRC) patients (pts). An additional widely acknowledged unmet need is the development of therapeutic strategies to eradicate MRD and increase the cure rate of the disease. Ongoing trials are evaluating MRD as a biomarker for determining the intensity of post-operative adjuvant therapy. However, the feasibility and efficacy of therapy in pts who are MRD+ during surveillance (after all curative intent treatments including adjuvant chemotherapy) is unknown. Methods: In this proof-of-concept phase II study, pts with stages II-IV CRC noted to be MRD+ during surveillance (ctDNA+ but no radiographic evidence of disease on imaging in last 30 days) received 6 months (m) of TAS-102. Pts were identified through the MD Anderson INTERCEPT program that integrates MRD testing with a tissue informed assay (Signatera) into standard of care for CRC pts. The primary endpoint was 6-m ctDNA clearance and secondary objectives included 3-m ctDNA clearance, and disease-free survival (DFS). Assuming H0 = 5% spontaneous, HA = 30% ctDNA clearance with TAS 102 & 1-sided α = 0.05, 15 patients are required for β = 85%. Results: Between 7/22/22 and 9/7/23,15 pts with MRD were enrolled. Baseline characteristics included a median age of 62 years (range: 37-73), Caucasian (77%), male (77%), resected Stage IV (92%) and median ctDNA level of 1.55 MTM/ml (range 0.04-28.72). At data cutoff, 11 pts had 3-m ctDNA levels and 10 had a decrease in their ctDNA level (91%) including 5 with undetectable levels (45%). At 6-m, 60% of patients had ctDNA levels at or below prior levels; three maintained undetectable ctDNA at 6-m: of those, two pts had subsequent radiographic progression following therapy completion. Median DFS was 9.4-m in the full cohort. Conclusions: We demonstrate the feasibility of identifying and enrolling MRD+ pts through screening during surveillance onto therapeutic trials and show the ability of an experimental therapy to convert patients to MRD negative status, a necessary but not sufficient step for disease eradication. Preliminary results suggest that treatment with TAS-102 is effective in inducing ctDNA clearance in the short term in most pts, but with no evidence of persistent clearance. Updated results including 6-m ctDNA levels and survival data will be presented. Clinical trial information: NCT05343013 .
Results of a prospective phase II study of total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Ma Huiying , Tang Yuan , Zhang Wenjue , Zhou Haitao , Liu Zheng , Zhang Haizeng , Cai Yong , Li Yongheng , Wei Lichun , Liu Shixin , Wang Wenling , Song Yongwen , Chen Bo , Lu Ningning , Qi Shunan , Liu Yueping , Wang Shulian , Wang Xishan , Li Yexiong , Jin Jing 
Published: January 2024

147 Background: Total neoadjuvant therapy is further accepted for the treatment of locally advanced rectal cancer, which is more valuable for patients with high-risk factors. Optimal schedule of radiotherapy and chemotherapy remains unknown and needs further exploration. Methods: We conducted a multicenter, randomized, phase II trial (ClinicalTrials.gov No.: NCT04543695). Patients aged 18-75 years with initial stage II / III rectal adenocarcinoma (At least one of high-risk factors should be included: mesorectal fascia involvement, T4, N2, positive lateral lymph node, or extramural vessel invasion) were assigned into three groups, 1) Chemoradiotherapy (50 Gy of radiation combined with oral capecitabine) followed by consolidation chemotherapy using six cycles of XELOX(CNCT group), 2) Induction chemotherapy before chemoradiotherapy (INCT group), or 3) Chemoradiotherapy alone (Control group). Then enrolled patients were required to undergo radical surgery after neoadjuvant therapy. Patients in Control group need six cycles of XELOX after surgery. The primary end point was proportion of yp0-II, and watch-and-wait strategy after complete clinical response (cCR) was allowed. Results: Of the 257 patients enrolled, 255 patients were evaluable (Control: CNCT: INCT= 84: 86: 85). Neoadjuvant treatment related grade 3 or 4 toxicity was higher in TNT approach (7.1%, 23.3% and 32.9% in Control, CNCT and INCT, respectively), of with myelosuppression being most common. Compliance of chemoradiotherapy was lower in INCT group (98.8%, 100% and 90.6% in Control, CNCT and INCT, respectively). As to CNCT and INCT, 60.0% and 74.1% of patients completed six cycles of chemotherapy, with 76.7% and 83.5% completing four cycles of chemotherapy, respectively. Proportions of downstage (yp0-II + sustained cCR) were achieved 75.6% in CNCT group and 74.1% in INCT group, respectively, compared to 56.0% in Control group. CR rates (pCR + sustained cCR) were achieved 43.0% in CNCT group and 38.8% in INCT group, respectively, compared to 20.2% in Control group. Both TNT approaches did not increase the incidence of surgical complications (6.0%, 8.1% and 10.9% in Control, CNCT and INCT, respectively), with anastomotic fistula and abdominal infection being of most common. Conclusions: Both TNT approaches increased the probability of ≥ G3 acute toxicities, but most patients could tolerate 4 cycles of neoadjuvant chemotherapy. Both TNT approaches could achieve a higher proportion of downstage and CR rate. Clinical trial information: NCT04543695 .
Comprehensive genomic analysis of molecular residual disease based on circulating tumor DNA in patients with postoperative colorectal cancer.
Authors: Hong Qingqi , Zhu Jingtao , Lin Hexin , Chen Yinan , Bai Haoyu , Yan Linghua , Xiao Li , You Jun 
Published: January 2024

156 Background: Despite receiving curative resection, a considerable percentage of colorectal cancer (CRC) patients still experience disease recurrence. The early detection of molecular residual disease (MRD) has the potential to improve risk assessment. Methods: A total of 104 patients with stage Ⅰ-Ⅳ CRC were enrolled, of which 259 serial plasma samples were collected. Multi-gene targeted sequencing was conducted on tumor and plasma samples to identify somatic variants. Results: Among the 104 patients, 14 cases had positive landmark MRD and 32 cases had positive longitudinal MRD. Patients with positive landmark MRD had significantly higher recurrence risk compared to those with negative landmark MRD (Hazard Ratio [HR]: 7.325; 95% CI, 2.877-18.647; P < 0.001). Similarly, positive longitudinal MRD was associated with increased recurrence risk (HR: 9.385; 95% CI: 3.085-28.556; P < 0.001), with a higher HR value. Positive MRD detection preceded CT confirmed recurrence in 85.7% of patients, with a median lead time of 198.5 days. In multivariate analysis, positive-MRD was the most significant prognostic factor for DFS. The combination of KRAS variant and MRD status improved the efficiency of prognostic prediction, the area under the curve value for the combination of MRD and KRAS was higher than MRD and KRAS. By analyzing the characteristic of cfDNA fragments, we found that mutation sites tended to be enriched in shorter cell free DNA (cfDNA) fragments. Conclusions: Our study demonstrated an excellent prognostic prediction potential of circulating tumor DNA-based MRD detection among postoperative CRC patients, especially the combination of KRAS variant and MRD improved the efficiency of risk stratification through MRD. This study may facilitate the incorporation of MRD and KRAS into prognostic prediction. Our study revealed that mutation sites tended to be enriched in shorter DNA fragments, providing valuable insights for future ctDNA detection method.
Rectal cancer disparities in a large, diverse health system in New York.
Authors: Naing Phyu Thin , Wu Vernon , King Daniel 
Published: January 2024

16 Background: The disproportionate burden of colorectal cancer among African American (AA) patients is striking, with 40% increase relative risk of death compared to non-AA White population (Seer Cancer Statistics Review, 2022). NAPRC aims to ensure equitable delivery of evidence-based treatment to ensure optimal outcomes for all patients. Our study investigated whether care delivery outcomes differed for AA patients in our NAPRC cohort of patients, and explored the reasons associated with the disparities. Methods: Rectal cancer patients were identified by pooling 2019 to 2022 data from NAPRC coordinators from 4 regional sites under Northwell Health, spread across a large geographical area in NY: Westchester and Phelps (Northern), Lenox Hill (Western), NSUH/LIJ (Central), and Huntington (Eastern). The primary outcome was time from biopsy (Bx) to treatment (Tx) initiation, where Tx was rectal cancer resection, chemotherapy, or radiotherapy. The secondary outcome was time from tumor board (TB) to first Tx. Social deprivation index (SDI) is a composite measure of 7 demographic characteristics collected in the American Community Survey (ACS) matched with zip codes of patients. SDI and the deprivation severity have a positive and linear correlation. Results: We collected data on 381 patients; 337 had documented race data: 42 AA and 295 non-AA (includes White, Asians and others). AA, compared to non-AA, patients had significantly longer median time from Bx to Tx in Western (66 vs 42 days, p<0.01) and Central (56 vs 41 days, p= 0.03) regions. AA patients also had higher time from TB to Tx in the Western (29 vs 17 days, p=0.01) and Central (26 vs 19 days, p= 0.05) regions, respectively. Longer time to treatment was associated with: AA patients, Medicare patients, and patients requiring social work assistance. SDI is positively correlated with time from Bx to Tx (p<0.01) and time from TB to Tx (p<0.01). Conclusions: There are significant disparities between AA vs Non-AA in both primary and secondary outcomes. These findings highlight the need for further exploration such as interviewing social workers and developing patient surveys to explore why the care disparities in AA population is more significant in certain regions than others. We need to account for race and social barriers in treating cancer patients. Taking a proactive approach by sending social work referrals for all AA patients may be a potential solution for these marginalized patients.
Development of an improved risk stratification scheme for stage II and III colorectal cancers through incorporation of the digital pathology biomarker QuantCRC.
Authors: Pai Rish , Wu Christina , Kosiorek Heidi E. , Banerjee Imon , Hagen Catherine E. , Hartley Christopher P. , Graham Rondell P. , Sonbol Bassam Bassam , Bekaii-Saab Tanios S. , Xie Hao , Sinicrope Frank A. , Patel Bhavik , Westerling-Bui Thomas , Shivji Sameer , Conner James , Swallow Carol Jane , Savage Paul , Cyr David Patrick , Kirsch Richard , Pai Reetesh 
Published: January 2024

162 Background: There is a need to improve current risk stratification of stage II and III colorectal cancer (CRC) to better inform risk of recurrence and guide adjuvant chemotherapy. The purpose of this study is to examine whether integration of QuantCRC, an AI-based digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Methods: ASCO and QuantCRC-integrated risk schemes were applied to an observational cohort of 1,068 stage II and III CRCs. The stage II integrated scheme utilizes pT3 vs. pT4 and QuantCRC-derived risk groups. The stage III integrated scheme utilizes pT1-3 vs. pT4, pN1 vs. pN2, and QuantCRC-derived risk groups. Performance metrics included log-rank test, hazard ratios and Somers’ Dxy rank correlation. Results: Integration of QuantCRC provides improved risk stratification compared to the ASCO scheme for stage II and III CRC. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared to the ASCO scheme (69.3% vs. 60.4%) without decreased 3-year RFS. The QuantCRC-integrated scheme provided larger hazard ratios (HR) for both intermediate-risk (3.04, 95%CI 1.81-5.10, P=2.8x10-5) and high-risk (4.62, 95%CI 2.02-10.61, P=0.0003) groups compared to ASCO intermediate-risk (2.09, 95%CI 1.21-3.63, P=0.008) and high-risk (3.08, 95%CI 1.57-6.01, P=0.001) groups. The QuantCRC-integrated scheme for stage III tumors identified a small group of 80/518 (15.4%) CRCs at very high risk of recurrence with HR of 4.08 (95%CI 2.68-6.23, P=6.5x10-11) compared to a HR of 2.42 (95%CI 1.72-3.38, P=3.1x10-7) for 228/518 (44.0%) high-risk CRCs in the ASCO scheme. QuantCRC-integrated risk groups remained prognostic in stage III CRCs when stratified by presence or absence of any adjuvant chemotherapy. No difference in RFS were seen in QuantCRC-integrated low-risk and intermediate-risk stage III CRCs stratified by 3 vs. 6-months of oxaliplatin-based adjuvant chemotherapy suggesting that these two groups can be treated with 3-months of adjuvant therapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance.
Liver steatosis and fibrosis as independent prognostic factors affecting survival in colorectal cancer with liver metastases.
Authors: Gupta Nikhil , Somasundaram Eashwar , Dhawan Andrew , Scott Jacob 
Published: January 2024

165 Background: Colorectal cancer is one of the leading causes of cancer-related death, and the liver represents the most common site of metastases. Greater depth of tissue invasion and lymph node metastases (more advanced T and N stage) are associated with increased risk of liver metastases, but how co-pathologies of the liver associate with disease progression and survival are not known. Further, prognostic factors associated with overall survival in patients with colorectal liver metastases (CRLM) remain poorly understood. Clinical factors affecting liver morphology and biomechanical properties, such as preexisting fibrosis or steatosis, may impact the pathogenesis of CRLM and thus the clinical prognosis. Current literature is mixed about whether prior steatosis and fibrosis contribute significantly to CRLM pathogenesis and prognosis. The purpose of this study is to evaluate whether liver steatosis and fibrosis impact outcomes in patients with CRLM. Methods: All CLRM cases (n = 197) that underwent resection between 2003 and 2007 from The Cancer Imaging Archive were included in our study cohort. For each clinical covariate, we generated a univariate model for overall survival and those meeting a modest predictive threshold (p < 0.15) were included in a multivariable model. These included: presence of major comorbidity, chemotherapy preceding resection of liver metastases, clinical risk score, presence of extrahepatic disease at time of diagnosis, presence of steatosis on CT imaging, percentage of residual tumor after treatment, and presence of fibrosis on CT. All statistics were performed in R (v.2022.12.0). Results: A multivariable Cox proportional hazards model identified four statistically significant clinical factors predictive of overall survival: clinical risk score (HR = 1.60, p = 0.026), presence of extrahepatic disease (HR = 2.33, p = 0.027), presence of steatosis (HR = 0.51, p = 0.0057), and fibrotic proportion of liver tissue less than 40% (HR = 2.63, p = 0.033). There were also four statistically significant clinical factors predictive of disease-free survival in the liver: chemotherapy preceding resection of liver metastases (HR = 2.28, p = 0.0011), presence of extrahepatic disease (HR = 2.18, p = 0.024), presence of steatosis (HR = 0.49, p = 0.0030), and fibrotic proportion of liver tissue less than 40% (HR = 2.74, p = 0.016). Conclusions: Our findings suggest that increased steatosis and fibrosis, as assessed by CT scans, are paradoxically protective in CRLM, showing longer disease-free survival and overall survival rates. We hypothesize that liver fibrosis and steatosis impact the microenvironment of the neoplastic cells in the liver, impairing tumor progression in this milieu. Further research is needed to assess how non-neoplastic co-pathologies resulting in biophysical changes affect tumor growth and overall survival.
The prognostic significance of extramural venous invasion detected via contrast-enhanced computed tomography colonography in colon cancer.
Authors: Kato Takeharu , Tsukamoto Shunsuke , Nagata Hiroshi , Takamizawa Yasuyuki , Moritani Konosuke , Kanemitsu Yukihide 
Published: January 2024

167 Background: The precise effects of extramural venous invasion (EMVI) and Spiculation on colon cancer recurrence remain poorly understood. This study investigated the clinical significance of ctEMVI and ctSpiculation as diagnosed via preoperative contrast-enhanced CT colonography (CTC) using three-dimensional multiplanar reconstruction (3D MPR) images. Methods: Patients with stage I–Ⅲ colon cancer (T2 or deeper) diagnosed via CTC at the National Cancer Center Hospital in Japan between 2013 and 2018 were retrospectively evaluated for ctEMVI and ctSpiculation, diagnosed by two observers using 3D MPR images of slices 0.5 mm thick. The interobserver reliability was assessed with Cohen’s kappa statistic, and recurrence-free survival (RFS) was analyzed using Kaplan–Meier curves. Preoperative clinical factors were subjected to Cox regression analysis in relation to RFS. Results: Of 922 patients, 544 eligible cases were analyzed. There were 50 (9.2%) ctEMVI-positive cases and 494 (90.8%) ctEMVI-negative cases, along with 186 (34.2%) ctSpiculation-positive cases and 358 (65.8%) with negative findings. Kappa coefficients for ctEMVI and ctSpiculation were 0.830 and 0.718, respectively. Kaplan–Meier analysis and log-rank tests demonstrated lower RFS in ctEMVI- and ctSpiculation-positive cases (p<0.001). In multivariable analysis, ctT4 (HR 2.95, 95% CI 1.73–5.02) and ctEMVI (2.97, 1.81–4.87) were independent factors associated with RFS. When stratifying TNM stages based on ctEMVI status, in N(+) (i.e., Stage III), ctEMVI-positive group had worse prognoses than negative group (5-year RFS rates; 52.0% vs. 78.5%, p=0.003). Similarly, in N(–) (i.e., Stage I and II), T3N0EMVI(+) cases had significantly worse prognoses than T3N0EMVI(–) and Stage I cases (50.6% vs. 89.3% and 90.1%) and were comparable to the T4N0 group (50.6% vs. 46.7%, p=0.844). Conclusions: Both ctEMVI and ctSpiculation are associated with RFS. ctEMVI is an independent predictor of recurrence and may be valuable in combination with preoperative TNM staging to identify patients at high risk for recurrence. [Table: see text]
Molecular and clinical characteristics of POLE/POLD1 alterations among patients with colorectal cancer.
Authors: Syed Masood Pasha , Ferrell Morgan , Cheng Svea , Gonzalez Cyndi , Giza Richard , Magge Tara , Bao Riyue , Singhi Aatur D. , Saeed Anwaar , Sahin Ibrahim Halil 
Published: January 2024

184 Background: POLE and POLD1 alterations (DNA polymerase ε and DNA polymerase δ) are key biomarkers of immune response for patients with MSS colorectal cancers (CRC). The clinical and molecular characteristics of POLE/POLD1 alterations are not yet well defined across CRCs. In this study, we investigated the clinical/molecular features of POLE and POLD1 alterations and its association with MSI-H CRC. Methods: All the patients and mutation data were selected from the cBioPortal database (https://www.cbioportal.org). All nonsynonymous mutations including missense, frameshift, nonsense, nonstop, splice site, and translation start site changes of POLE/POLD1 were considered. 21 studies were used in the analysis. 7179 data samples were obtained from 7179 patients. Tumors included were from all stages of CRCs. POLE/POLD1 mutations were from mutation tables, only protein-changing mutations were kept. MSI-H status was based on mutation data (presence of MLH1/PMS2/MSH2/MSH6 mutations). Results: Of 7179 patients with all stage CRCs, 6.1% (439) were found to harbor mutated POLE/POLD1 genes. Among those, 3446 patients had known MSI status and 14.9% (514/3446) had MSI-H disease. Notably, 3.3% patients with POLE/POLD1 mutations were found to have concurrent MSI-H disease (co-existence) and only 1.1% of patients with POLE/POLD1 mutations had MSS CRC. MSI status was unknown for 1.7% of patients with POLE/POLD mutant CRC. The mean age for patients with POLE/POLD1 + with or without MSI-H disease was 67. POLE/POLD mutations were exceedingly more common in colon than rectum regardless of MSI-H status (85% vs 15% overall and 88% vs 12% in MSI-H subgroup). No difference was seen among genders for the distribution of POLE/POLD1 mutations. Conclusions: POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.