bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial and regional disparities in the management of locally advanced rectal cancer.
Authors: Luo William Yu , Agala Chris B , Shetty Pragna , Kapadia Muneera Rehana , Stem Jonathan Michael , Guillem Jose G. 
Published: January 2023

14 Background: Surgical margins following rectal cancer resection impact oncologic outcomes and may reflect adequacy of care. We examined the relationship between race, ethnicity, or region of care with margin positivity following rectal cancer resection. Methods: We queried the National Cancer Database (NCDB) for patients diagnosed with stage II-IV rectal cancer between 2004-2018 who underwent surgical resection and excluded patients with missing data for race/ethnicity and radiation therapy/surgery status, and/or who had local excision only. We performed a propensity-score analysis via inverse probability of treatment weighting (IPTW) of margin positivity rate as outcome and race/ethnicity and region as predictors of interest. We controlled for age, sex, Charlson-Deyo Score, pathologic stage, pathologic grade, time from diagnosis to surgical resection, surgery type, sequence of radiation and surgery, facility type, insurance type, level of education, distance between patient and facility, and region of the United States. Results: Our query yielded 73,269 patients. Median patient age was 63 (IQR: 54-72) years and 40% were female. 81%,8%, 6%, and 5% were non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Other, respectively. After IPTW adjustment, non-Hispanic Black patients had 19% higher odds of margin positivity relative to non-Hispanic White patients (OR: 1.185, 95% CI: 1.094-1.284; p<.0001) Patients in the Northeast United States had a 10% lower odds of margin positivity compared to those in the South (OR: 0.900, 95% CI: 0.842-0.962; p=0.0019). Conclusions: Being non-Hispanic Black was significantly associated with a higher likelihood of positive margin following rectal cancer resection when compared to their non-Hispanic White counterparts. Patients in the South also experienced significantly higher rates of positive margin when compared to Northeast patients. Further investigation into potential interactions between racial and regional disparities and other contributors is warranted.[Table: see text]
A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.
Authors: Raghav Kanwal Pratap Singh , Guthrie Katherine A , Kopetz Scott , Tan Benjamin R. , Denlinger Crystal S. , Fakih Marwan , Overman Michael J. , Dasari Arvind , Corum Larry R. , Hicks Lee G. , Patel Mital , Esparaz Benjamin T , Kazmi Syed Mohammad Ali , Alluri Nitya , Colby Sarah , Gholami Sepideh , Gold Philip Jordan , Chiorean E. Gabriela , Hochster Howard S. , Philip Philip Agop 
Published: January 2023

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]
Identification and external validation of clinical-molecular features to predict benefit from oxaliplatin reintroduction/rechallenge in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Salva Francesc , Paes Rafael , Costa e Silva Matheus , Cruz Heloisa , Saoudi Gonzalez Nadia , Baraibar Iosune , Ros Montañá Javier , Comas Raquel , Ruiz-Pace Fiorella , Garcia Ariadna , Dalpino Renata , Jácome Alexandre A. , Tabernero Josep , Elez Elena , Dienstmann Rodrigo 
Published: January 2023

153 Background: Oxaliplatin is a backbone cytotoxic treatment for mCRC patients, particularly in the front-line setting. In the refractory disease, current treatment options are scarce and with limited efficacy. Several retrospective studies have explored the efficacy of oxaliplatin reintroduction/rechallenge (OxRe) in this scenario. However, more evidence is still needed to determine which patients do benefit from this treatment strategy. Methods: The discovery cohort includes all patients treated with oxaliplatin in a third- or fourth-line setting at VHIO between 2015 and 2021 (N = 102). Results were externally validated in a real-world cohort of patients treated at community oncology practices from Oncoclínicas Group in Brazil (N = 157). We analyzed the impact of clinical-molecular features in uni- and multivariable prognostic models in terms of median progression free survival (mPFS) (discovery cohort) and median time to treatment discontinuation (mTTD) (validation cohort). For both cohorts separately, data was extracted from EHRs in structured formats (demographics, tumor characteristics, pharmacy records) and combined with elements from unstructured sources (physician notes on progression and survival status) using technology-based abstraction techniques. Results: In the discovery cohort, 102 out of 735 mCRC patients (13,9%) were eligible. Median oxaliplatin-free interval (from Oxl stop to OxRe) was 17 months (CI95% 13.0-23.2). In OxRe setting, mPFS was 4.0 months (CI95% 3.29-5.03). In PFS multivariate analysis, determinants of favorable outcome were left tumor location (p = 0.01), oxaliplatin-free interval (p = 0.03), administration of Bev in refractory setting (p = 0.001), and not receiving Bev in first-line treatment (p = 0.008). Overall, 27% of all patients had a mPFS > 6 months with OxRe. In the validation cohort, out of 4,317 patients with mCRC, 157 (4%) were treated with OxRe. Median oxaliplatin-free interval was 15 months. Median time to treatment discontinuation (mTTD) of the OxRe was 3.4 months (CI95% 2.8-4.2). In multivariable model, the only independent prognostic factor was addition of Bev to OxRe (p = 0.036). Interestingly, 31% of all patients had mTTD > 6 months, largely enriched (65%) in patients with first Bev exposure at the time of OxRe. Conclusions: This study suggests that in refractory mCRC patients re-exposed to oxaliplatin-based chemotherapy, the addition of Bev is associated with improved outcomes. One-third of the patients are long-term responders (PFS/TTD > 6 months), reinforcing the value of this strategy in selected populations and the relevance of anti-angiogenic agents in refractory mCRC.
Total neoadjuvant oxaliplatin-based therapy (TNT) before (induction) and after (consolidation) chemoradiation for advanced rectal cancer: MRI correlation on complete response and outcome.
Authors: Cen Putao , Chan Kok Hoe , Van Eps Jeffrey , Rowe Julie Haewon , Wray Curtis Jackson 
Published: January 2023

165 Background: Preoperative chemoradiation with fluoropyrimidine, followed by total mesorectal excision (TME) and adjuvant chemotherapy is the standard care for locally advanced rectal cancer (LARC). Studies have shown the potential benefit of oxaliplatin based TNT approach. The benefits of using of both induction and consolidation chemotherapy with chemoradiation prior of TME is not well studied. We investigate whether the use of oxaliplatin based before (induction) and after (consolidation) neoadjuvant chemoradiation will increase the pCR and clinical Complete response (cCR), improve survival and MRI correlation. Methods: Patients treated with curative intent surgery for LARC who received oxaliplatin based induction and consolidation chemotherapy with neoadjuvant capecitabine chemoradiation were identified. Demographics and clinicopathologic data were analyzed. Multiparametric MRI was used for initial staging and restaging before surgery. The primary endpoint will be the complete response (pathological and clinical), recurrent-free survival (RFS), and overall survival (OS). Results: A total of 21 patients have been identified, all patient has T3/T4 and positive nodes N1/N2 on initial MRI staging, 2 (10%) patients had Stage IV disease with abdominal para-aortic nodes. Median age was 63 (range: 26-76); 14 (67%) male. As for the induction regimen, 9 (43%) had CAPOX/FOLFOX, 7 (33%) had short-course capecitabine, 5 (24%) had FOLFIRINOX. All patient received neoadjuvant chemoradiation with capecitabine. As for consolidation, 19 (90%) had CAPOX/FOLFOX, 1 (5%) had capecitabine and 1 (5%) had FOLFIRINOX. Median time for induction and consolidation chemotherapy was 8.5 weeks (range: 1-24) and 8 weeks (range: 2-16) respectively. Median time from starting induction chemotherapy to surgery was 6.8 months (range: 3.2-11). Eight (38%) patients had cCR and pCR. Post-treatment restaging MRI prior of resection has 100% concordant rate with pCR. All (100%) pateints had tumor downstaged after treated with TNT and chemoradiation. The sensitivity of MRI in detecting the residual lymph node post TNT/neoadjuvant chemoradiation was 55% (95% CI: 26-81%), and the negative predictive value was 75% (51-90%); the specificity was 100% (76-100%) and the positive predictive value was 100% (57-100%). There is no death and one patient had recurrence after recurrence free for 2 years. Median RFS and OS are not meet. Median follow up time is 25.7 months (range: 9.1-76.8). Conclusions: Neoadjuvant oxaliplatin based therapy before and after chemoradiation for rectal cancer potentially improves CR rate, and accurately predicted by post-treatment MRI. The use of MRI can potentially help to select candidates who desire organ preservation.
Clinical development and evaluation of plasma angiogenesis factors from phase II study of FOLFIRI plus ramucirumab with recurrent colorectal cancer refractory to adjuvant chemotherapy with oxaliplatin/fluoropyrimidine (RAINCLOUD): RAINCLOUD-TR.
Authors: Hata Tsuyoshi , Sugimoto Naotoshi , Ohara Nobuyoshi , Miyo Masaaki , Yoshioka Shinichi , Kagawa Yoshinori , Naito Atsushi , Tei Mitsuyoshi , Tamagawa Hiroshi , Konishi Ken , Sawada Genta , Danno Katsuki , Shimokawa Toshio , Satoh Taroh , Miyoshi Norikatsu , Takahashi Hidekazu , Uemura Mamoru , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi 
Published: January 2023

173 Background: Higher levels of vascular endothelial growth factor-D (VEGF-D) is a potential predictive biomarker for ramucirumab (Ram) efficacy on overall survival and progression-free survival (PFS) in Ram+FOLFIRI vs Placebo+FOLFIRI for bevacizumab (Bev) refractory metastatic colorectal cancer (mCRC). However, it is not clear whether VEGF-D acts as a predictive biomarker in pts who pretreated without Bev. RAINCLOUD showed the clinical benefit of FOLFIRI+ plus Ram for pts with recurrent CRC refractory to adjuvant chemotherapy (median PFS was 6.2 months (M); ESMO-GI 2022). RAINCLOUD-TR was designed as a prospective biomarker study estimating the association of biomarkers with Ram efficacy. Methods: Plasma sample collections were done at time points of pre-/ post-treatments in pts receiving FOLFIRI+Ram. Measurements of 17 factors (including VEGF-A, VEGF-D and PlGF) were performed by multiplex assay with Luminex technology. The high/ low groups were defined bases on the median plasma level at the baseline. Results: From September 2017 to September 2021, 81 plasma samples were collected from 48 pts and 32 pts in both pre/ and post treatment. Level of VEGF-A, VEGF-D, PlGF and TSP-2 were all significantly higher in post vs pre-treatment [Table]. The ORR analyses were as follows; VEGF-A, VEGF-D and PlGF in low vs high were 50.0%/33.3% (p=0.35, HR 1.97), 55.0% /33.3% (p=0.22, HR 2.39), and 60.0%/28.6% (p=0.35, HR 1.95). The PFS analyses were as follows; VEGF-A, VEGF-D, and PlGF in low vs high were 6.1M/6.0M (p=0.815, HR 0.92), 7.6M /5.6M (p=0.095, HR 0.56), and 8.0M/4.2M (p=0.014, HR 0.40). In other factors, low TSP-2 were better ORR (low vs high: 66.7%/20.0% (p=0.004, HR 7.54) and PFS 7.5M/4.3M (p=0.022, HR 0.45). Conclusions: In this exploratory study, PFS was numerically greater for pts with low vs high VEGF-D for Ram in pts with mCRC pretreated without Bev. VEGF-D may not be predictive biomarker, but TSP-2 may be a potential prognostic biomarker, further studies in larger cohorts are needed to confirm our results. Clinical trial information: UMIN000028678 . [Table: see text]
Circulating tumor cells (CTCs) as liquid biopsies in patients with metastatic colorectal cancer versus other GI malignancies.
Authors: Kasi Pashtoon Murtaza , Malkawi Walla I , Salem Aliasger K 
Published: January 2023

192 Background: Most of the focus on liquid biopsies for patients with colorectal cancers and other solid tumors has been on circulating tumor DNA (ctDNA). Circulating Tumor Cells (CTCs) are the other less talked about liquid biopsies. This is due to need for real-time processing and handling of CTCs, and is less conducive on previously banked samples. We took this prospective discovery endeavor to report in real-time CTC analyses using 2 very different platforms in patients with colorectal and other GI cancers. Methods: CTCs were evaluated using 2 platforms: RareCyte, which is simplistically based on density of CTCs and unbiased selection/identification for enumeration/biomarker analyses, and Parsortix, which is based on size/compressibility of CTCs. All patients signed written informed consent. Up to 4 serial draws were done for each patient (Total = 150 draws; 281 test results). CTCs were identified using standard definitions of nuclear/epithelial markers. À la carte we selected PD-L1, HER2, EGFR, Ki-67, and where adequate, confirmation with panel based single cell sequencing was also performed. Cell cultures were attempted for the Parsortix collections. Results: Patients with colorectal cancer (CRC) had the highest number of CTCs (Mean: 15.8; Median: 7.5). This was in sharp contrast to the number of CTCs in patients with pancreatic cancer (PC) (Mean: 4.2; Median: 3). At least a third of patients with CRC had at least 3 CTCs. Another 17.4% and 11.4% had at least 10, and at least 20 CTCs in CRC; while no patients with PC had more than 20 CTCs. CTCs in clusters were also common at baseline. In addition, we detected a significantly lower number of CTCs from patients receiving treatment versus those were not (Median 2.7 versus 0.7). Striking differences were also observed in CTCs for those with untreated/progressive disease versus those who had responding/stable disease (Median of 2.7 versus 0). Biomarker analyses on HER2/PD-L1/Ki-67/EGFR were feasible when CTCs were detected. There was overall agreement on CTCs detected on either platform. Where available, single cell sequencing data was concordant with clonal aberrations on sequencing. Conclusions: This is one of the largest prospective real-time endeavors in patients with colorectal and other GI cancers providing data on CTCs as liquid biopsies using 2 very different platforms. The descriptive insights gained from processing, enumeration, kinetics, timing of collection, biomarker analysis, costs, comparison across tumor types, attempts at cell culture, and single cell sequencing are of value for studies and investigators considering the use of CTCs in patients with colorectal and other GI cancers. While most of the focus is on ctDNA-based platforms, CTCs offer a different lens from a liquid biopsy standpoint that is complimentary and worth developing further.
A retrospective study of circulating tumor DNA for minimal residual disease detection in the management of colorectal cancer.
Authors: Storandt Michael H. , Emiloju Oluwadunni Eunice , Zemla Tyler J. , McWilliams Robert R. , Sinicrope Frank A. , Mitchell Jessica L. , Shi Qian , Jin Zhaohui 
Published: January 2023

227 Background: Circulating tumor DNA (ctDNA) consists of small fragments of DNA released into the plasma from cancer cells. Tumor informed ctDNA testing by whole exome sequencing of the primary tumor coupled with multiplex polymerase chain reaction (PCR)-based next generation sequencing of cell free DNA in serum, can detect and quantify ctDNA, allowing for detection of minimal residual disease (MRD). Methods: We conducted a retrospective analysis of 120 patients with colorectal cancer who had at least one tumor-informed ctDNA MRD assay completed between May 6, 2019, and July 1, 2022, at Mayo Clinic, Rochester. Disease recurrence was defined as radiographic evidence consistent with recurrence with or without biopsy confirmation. Data are presented descriptively, including number of ctDNA assays completed, ctDNA positivity prior to disease recurrence, and ctDNA concordance with carcinoembryonic antigen (CEA). The study protocol was exempt after review by the Mayo Clinic Institutional Review Board. Results: One-hundred twenty patients were included in the study with median age at initial disease diagnosis of 67.0 years. Sixty-four percent were male and 94% were white. At time of initial diagnosis, 10 had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. In 120 patients, 476 ctDNA assays were performed, and 110 recurrences were observed among 62 patients. There were 39 instances in which ctDNA was obtained prior to clinical detection of recurrence and of these, at least one ctDNA assay was positive in 28 cases (72%). CEA was obtained prior to recurrence in 88 instances and was elevated in only 39 cases (44%). Among 37 instances where both ctDNA and CEA testing were obtained prior to recurrence, ctDNA was positive in 27 cases (73%) while CEA was positive in 14 cases (38%). ctDNA was positive in 83% of recurrences involving liver and 62.5% of recurrences involving only the lungs. ctDNA and CEA positivity are shown by location of recurrence. ctDNA and CEA were discordant in 44% of instances in which the assays were completed within 2-weeks of each other. Results of a ctDNA assay impacted management decisions in 16% of cases. Conclusions: ctDNA detected 72% of recurrences with higher rates of detection in liver versus lung metastasis. ctDNA performed superiorly to serum CEA in detection of recurrence, suggesting a role in disease surveillance. However, ctDNA impacted disease management in only 16% of patients, suggesting need for better patient selection and further study for ctDNA-based disease management strategy (more details will be reported). [Table: see text]
The prediction of pathological complete response after total neoadjuvant therapy for locally advanced rectal cancer using versatile liquid biopsy.
Authors: Matsuda Akihisa , Yamada Takeshi , Sonoda Hiromichi , Shinji Seiichi , Iwai Takuma , Takeda Kohki , Yonaga Kazuhide , Ueda Kohji , Kuriyama Sho , Miyasaka Toshimitsu , Kanaka Shintaro , Yoshida Hiroshi 
Published: January 2023

230 Background: Total neoadjuvant therapy (TNT) has conferred a dramatic paradigm shift in the treatment for locally advanced rectal cancer (LARC), which can prolong the survival associated with high pathological complete response (pCR) rate and introduce non-operative management (NOM). However, useful biomarkers predicting the treatment efficacy of TNT and the prognosis has not been developed. Our previous study demonstrated that volume of blood long- and short-fragments DNA ( > 300 bp and < 180 bp) in LINE-1 gene are derived from tumor cell necrosis, and normal cell apoptosis, and the ratio (LSR) could reflect tumor growth or shrinkage, and minimal residual disease. Methods: A total of 17 LARC patients receiving consolidation TNT consisting of short-course radiation (5Gy x 5days) and 4 courses of CapOX, followed by total mesorectal excision were included. Blood concentrations of long-, short-fragment DNA and LSR in neoadjuvant phase were serially measured at pre-treatment, every treatment cycle, and pre-operation by real-time PCR. Results: Median age of patients were 64 years old and 65% were female. Clinical stage (IIa/IIc/IIIb/IIIc) were 2/1/8/6, respectively. Down staging was shown in 88% of patients. Tumor regression grade (0/1a/1b/2/3(pCR)) were 1/2/3/34/7(41%), respectively. Only 44% of patients had elevated CEA levels before TNT, which indicates less usefulness as the biomarker. The dynamics of the LSR in the entire cohort showed the gradual decrease until pre-operative phase (decrease to 77.8%). The LSR change from pre-treatment (or just after SCRT) to early preoperative treatment phase (1 or 2 course after CapOX) was significantly greater in the pCR(+)(n = 7) than the pCR(-)(n = 10) groups (66.8% vs. 101%, p = 0.03). The AUC of ROC analysis was 0.72 (cut off: 66.8%). Conclusions: NGS based liquid biopsy is the gold standard for the cancer prediction and monitoring, but limitations such as unsatisfied sensitivity and high cost are still involved. However, LSR measurement has great benefits on those points. Early phase LSR measurement could be a good predictive marker for the response of TNT and might be clinically useful for optimizing the preoperative therapy.