bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of alternating mXELOX/mXELIRI plus bevacizumab (BEV) as first-line treatment for metastatic colorectal cancer (mCRC).
Authors: Li Sheng , Zhu Liangjun , Li Xiaoyou , Huang Jiayuan , Xu Hanfeng 
Published: June 2024

3574 Background: First-line fluoropyrimidine (FL), oxaliplatin (OX), irinotecan (IRI) plus BEV had better efficacy but worse safety vs FL, IRI plus BEV for mCRC. Preliminary data showed promising anti-tumor activity and acceptable toxicity of alternating FL plus OX and FL plus IRI. This study aimed to assess the alternating schedule of modified capecitabine (XEL), OX (i.e., mXELOX) plus BEV and modified XEL, IRI (i.e., mXELIRI) plus BEV for mCRC. Methods: This single-arm phase II trial was conducted in China. Patients aged 18–75 years, with histologically confirmed unresectable mCRC, ≥one measurable lesion via RECIST v1.1, ECOG PS of 0 to 2, and life expectancy of ≥3 months were eligible. Prior systemic therapies were not allowed except adjuvant chemotherapy. Induction treatment consisted of XEL 1000 mg/m2 bid D2–8 and D16–22, OX 85 mg/m2 D1, IRI 150 mg/m2 D15, and BEV 5 mg/kg D1 and 15 for 28-day cycles (up to six cycles). XEL 1000 mg/m2 bid D2–15 and BEV 7.5 mg/kg D1 for 21-day cycles were used as maintenance treatment. The primary endpoint was progression-free survival (PFS). Results: Between Apr 2020 and May 2023, 52 patients were included. As of Dec 30, 2023, median follow-up was 25.0 months. Mean age was 58.5±9.1 years old. 28 (54%) were male. 45 (87%) patients had either right-sided diseases, RAS or BRAF mutations. Median PFS was 11.0 months (95% CI 9.0–12.4). Subgroup analyses showed prior treatments, tumor locations and metastases, and BRAF mutations did not affect efficacy. RAS wild-type patients had longer PFS vs mutant patients (median 12.3 months vs 9.8 months; P=0.024). Objective response rate and disease control rate were 73% (59%–84%) and 94% (84%–99%), respectively. Overall survival (OS) reached 28.1 months (18.4–34.0). Efficacy data were detailed in the Table. Grade 3–4 treatment-related adverse events (TRAE) occurred in 17 (33%) of 52 patients. No treatment-related death was reported. The most common grade 3–4 TRAE were hypertension (13 [25%]), neutrophil count decreased (three [6%]), and hand-foot syndrome (two [4%]). Additionally, grade 3–4 TRAE of diarrhoea occurred in one [2%] patient and no grade 3–4 peripheral neuropathy was reported. Conclusions: Alternating mXELOX/mXELIRI plus BEV demonstrated promising anti-tumor activity against mCRC, with acceptable tolerability and no new safety signal. Further studies were warranted to confirm the efficacy of the regimen. Clinical trial information: NCT04324476 . [Table: see text]
Evaluating the potential of micronuclei DNA from erythrocytes for early detection or recurrence risk prediction of colorectal cancer.
Authors: Yao Xingyun , Sun Haobo , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Pan Jie , Zhu Fangchao , Meng Fei , Liang Honghao , Cao Yanfei , Li Jun , Ding Kefeng , Gao Xiaofei 
Published: June 2024

3577 Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Also, better predicting the recurrence risk following initial treatment serves as an important factor influencing survival of CRC patients. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and CRC patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we explored the potential of MN-DNA for early detection or recurrence risk prediction of CRC patients. Methods: Peripheral blood (1-2ml) was obtained from a training cohort of 1165 individuals, a validation cohort of 290 individuals, and a test cohort of 363 individuals. MN-DNA was isolated and sequenced from erythrocytes. Predictive models were developed using distinctive taMN-DNA features identified by genome-wide analysis to differentiate between HD and AA or CRC. A clinical trial comparing MN-DNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). In addition, we conducted a retrospective study on CRC patients after postoperative treatment for evaluating the potential of MN-DNA in predicting CRC recurrence risk, with 28 non-recurrent after initial surgery and treatment and 6 relapsed patients enrolled. Results: The predictive CRC model built on taMN-DNA features achieved an AUC of 97.93%, with 88.61% sensitivity at 95.05% specificity, especially 89.58% sensitivity for early-stage (stage I-II) CRC in the test cohort. The detection of AA achieved an AUC of 93.01%, with 68.29% sensitivity at 92.48% specificity in the test cohort. Comparing MN-DNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Finally, 92.86% patients who had no recurrence were detected with negative prediction results, whereas 83.33% patients who had relapsed were detected positive prediction result. Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enable accurate detection of AA and early-stage CRC as well as recurrence risk prediction. A larger clinical study (NCT05875584) is ongoing and will further validate the application of MN-DNA in CRC detection.
Sintilimab plus axitinib for advanced fumarate hydratase-deficient renal cell carcinoma: A multi-center, open-label, single-arm, phase II study (SAFH).
Authors: Zeng Hao , Zhang Xingming , Liang Jiayu , Zhao Junjie , Liu Haoyang , Zhang Yaowen , Chen Yuntian , Sun Guangxi , Sheng Xinan , Wang Yongquan , Liu Xiaodong , Huang Rui , Wei Qiang , Li Xiang , Liu Jiyan , Shen Pengfei , Shen Pengfei , Chen Ni , Yao Jin , Liu Zhenhua 
Published: June 2024

4523 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) is a rare and highly invasive subtype of renal cell carcinoma. Previous studies have shown that immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) can be considered for first-line systemic treatment of FH-dRCC. We aimed to provide high-quality prospective clinical trial evidence regarding the efficacy and safety of Sintilimab plus Axitinib in FH-dRCC. Methods: This study was an investigator-initiated, open-label, single-arm, multiple institutional, phase II trial in patients (pts) aged 18 years or older with treatment naive, advanced FH-dRCC. Patients received Sintilimab (intravenous injection, every 3 week) in combination with Axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary endpoint was objective response rate (ORR; RECIST v1.1) and progression-free survival (PFS). This study is registered with ClinicalTrials.gov, NCT04387500. Results: From June 2021 to August 2023, 52 patients were screened, and 41 patients were enrolled. The median follow up was 16.0 months. Thirty-eight patients were available for efficacy assessment. Confirmed complete response rate was 10.5% (4/38), ORR was 60.5% (23/38). Disease-controlled rate (DCR) was 86.8%. The median PFS was 19.83 months (95% CI: 7.68-31.99). All grade and ≥3 treatment-emergent adverse events occurred in 87.8% (36/41) and 22.0% (9/41), respectively. Details about FH mutation status were available in 40 patients, and different FH mutation patterns were found to be associated with different therapeutic efficacy. Conclusions: The combination of Sintilimab and Axitinib showed manageable safety profile and durable anti-tumor efficacy in FH-dRCC. Evaluating mutation status of FH gene could help to predict potential survival benefit from ICI plus TKI therapy. Clinical trial information: NCT04387500 .
CA-62: A new biomarker for the detection of early-stage renal cell carcinoma.
Authors: Tcherkassova Janneta , Tsurkan Sergei , Prostyakova Anna , Klinski Evgueni , Sekacheva Marina , Boroda Alexander , Moro Ricardo 
Published: June 2024

4526 Background: The American Cancer Society classifies Renal Cell Carcinoma (RCC) to be among the ten most common cancers. However, in spite of this need, effective biomarkers for early-stage detection of RCC are not yet available. The purpose of this study was to assess the diagnostic characteristics of a carcinoma-specific transmembrane N-glycoprotein biomarker, CA-62, for the detection of early-stage kidney cancer. Blinded serum samples from 204 patients were included in the clinical study, of which 68 had TNM-classified stages IA, IB, IIA or IIB renal cell carcinomas, while 136 were drawn from healthy volunteers. Methods: Quantitative measurement of serum CA-62 levels was performed using a chemiluminescent immunoassay ("JVS Diagnostics" LLC). Statistical analysis (MedCalc; version 19.7.4, MedCalc Software Ltd, Belgium, EU) was used to assess the diagnostic characteristics of the CA-62 biomarker for detection of RCC, including sensitivity and specificity, and test accuracy. Results: Significantly higher median concentrations of CA-62 were found in sera of RCC patients compared to those found in healthy controls as follows; stage I A, B (8,935 U/mL), stage II A (6,291 U/mL), stage II B (8,808 U/mL), and healthy controls (2,815 U/mL). It was expected that serum CA-62 levels would be elevated at these early stages of RCC (Stages I-IIB), demonstrating significant overexpression of this epithelial carcinoma marker during the initial stages of cancerogenesis. The results of the study are presented in the table. Area under the ROC curve (AUC) for RCC patients vs. healthy controls was 0.98 with a 95% CI (0.950-0.994), z-statistics (67.3), and a significance of p<0.0001. Conclusions: CA-62 demonstrated a 94.3% sensitivity for RCC at 96% specificity during the early stages of kidney cancer. Given that CA-62 is not specific for kidney cancer, it is reasonable to suggest that use of a combination of CA-62 with some other biomarkers that may lack the sensitivity of CA-62 but are often elevated in renal cell carcinoma patients, such as tumor-infiltrating lymphocytes and/or possibly some inflammation biomarkers. In particular, the combination of transmembrane glycoproteins CA-62 and CD105, combined with biomarkers such as Endothelial Vascular Growth Factor (EVGF) and/or a growth factor derived from platelets (PDGF) could be successfully used for kidney cancer screening in order to achieve both high sensitivity and specificity for RCC detection.[Table: see text]
Changes in treatment (Rx) patterns and attrition rates in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Galarza Fortuna Gliceida , Jo Yeonjung , Hage Chehade Chadi , Narang Arshit , Gebrael Georges , Mathew Thomas Vinay , Chigarira Beverly , Anderson Ethan , Mazumder Archisman , Ozay Zeynep Irem , Agarwal Neeraj , Maughan Benjamin L. , Swami Umang 
Published: June 2024

4527 Background: Rx landscape of mccRCC has evolved rapidly with the approval of antibodies directed against programmed cell death protein-1 (PD-1) in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor receptor tyrosine kinase (TKI) inhibitors. However, real-world data on Rx trends and attrition before and after PD-1 inhibitor approval are lacking. Herein, we analyze them in a large real-world cohort in the United States. Methods: This IRB-approved retrospective study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Inclusion: Metastatic RCC with clear cell histology diagnosed between 1/1/2011 to 1/31/2022 receiving Rx with opportunity of at least 1 year follow up. Exclusion: Pts needing Rx for ≥2 malignancies. Based on the approval date of PD-1+CTLA4 of 4/16/18, pts were separated into 2 groups: b2018 (1L Rx before 4/16/2018) and a2018 (1L Rx after 4/16/18). Landmark analysis was performed at 1 year after Rx discontinuation to identify pts who died, were alive but did not need Rx, or starting next-line Rx. All analysis was done using R version 4.2.3. Results: Of 12707 pts, 7923 met the eligibility criteria (b2018: 4561 pts and a2018: 3362 pts). Rx trends are summarized in the table. 1L Rx for the majority of pts changed from TKI monotherapy (mono; 79%) b2018 to PD-1 combination therapies a2018 (58%). TKI mono remained the most common Rx in both groups after 1L (Table). In the b2018 cohort, 58% of patients received 2L Rx, and 32% received 3L. In the a2018 cohort, 42% and 16% received 2L and 3L, respectively. At 1-year landmark analysis after 1L discontinuation: in the b2018 group, 58% pts received next Rx, 30% died without further Rx, and 12% were alive without Rx while in the a2018 group, 42% pts received next Rx, 26% died without further Rx and 32% were alive without Rx. Conclusions: Despite the increase in the utilization of PD-1+CTLA-4 and PD-1+TKI regimens since 2018, a significant number of patients still did not receive novel combination regimens in the 1L mccRCC setting in this real-world population in the United States. Furthermore, with the uptake of PD-1 based combinations in 1L, a higher proportion of pts experience treatment free interval or were alive without further therapy at 1 year landmark analysis after 1L Rx discontinuation. These findings need validation in other datasets and can help patient counseling in clinics.[Table: see text]
Applying genomic analysis to refine unclassified renal cell carcinoma.
Authors: Yekeduz Emre , Braun David A. , El Hajj Chehade Razane , Eid Marc , Labaki Chris , Machaalani Marc , Nassar Amin , Nawfal Rashad , Saad Eddy , Saliby Renee Maria , Semaan Karl , Sun Maxine , Hirsch Michelle S. , Ürün Yüksel , El Zarif Talal , CHOUEIRI Toni K. 
Published: June 2024

4551 Background: Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate. Results: Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P>0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q<0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2(15.8%), TP53 (13.9%), TERT(13.4%), and VHL(11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q<0.001), chRCC (0.7%, Q<0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2(n=29) than in those with unaltered NF2(n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q<0.001), followed by VHL and BAP1 (Q<0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%). Conclusions: uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2alterations were frequent and correlated with a poorer prognosis. [Table: see text]
Response and outcomes with immune checkpoint inhibitor (ICI) in patients (pts) with urothelial carcinoma (UC) and subtype histology (SH).
Authors: Bakaloudi Dimitra Rafailia , Makrakis Dimitrios , Talukder Rafee , Diamantopoulos Leonidas Nikolaos , Jindal Tanya , Nguyen Charles B , Hobeika Charbel , Mathew Thomas Vinay , Johnson Jeffrey , Marmolejo Castañeda David Humberto , Korolewicz James , Zakopoulou Roubini , Hui Gavin , Barata Pedro C. , Alonso Buznego Lucia Andrea , Brown Jason R , Stewart Tyler F. , Epstein Ilana B. , Khaki Ali Raza , Grivas Petros 
Published: June 2024

4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1st line [1L] upfront, maintenance avelumab [mAV], ≥2nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]
Tumor fraction and copy number burden from urinary cell-free tumor DNA (utDNA) to predict minimal residual disease prior to repeat-transurethral resection in high-risk non-muscle invasive bladder cancer (HR-NMIBC).
Authors: Linscott Joshua , Miyagi Hiroko , Gould Billie , Murthy Prithvi , Rose Kyle M , Camperlengo Lucia P , Bonora Giancarlo , Zemp Logan , Gilbert Scott Michael , Spiess Philippe E. , Sexton Wade J. , Meeks Joshua J , Du Pan , Jia Shidong , Li Roger 
Published: June 2024

4600 Background: Genomic alterations detected in urinary cell-free tumor DNA (utDNA) are concordant with those from tissue samples in patients with urothelial carcinoma. In this prospective study, we demonstrate that utDNA alterations and copy number variation can be used to detect minimal residual disease (MRD) prior to standard-of-care repeat transurethral resection of bladder tumors (rTURBT) in patients with high risk non-muscle invasive bladder cancer (HR-NMIBC). Methods: A total of 53 patients with high-risk NMIBC were enrolled prior to rTURBT. PredicineWES+ whole exome sequencing with boosted 600+ oncogene coverage was performed on the index TURBT (iTURBT) tissue. Urine samples were collected immediately prior to rTURBT (preUR). Low Pass Whole Genome Sequencing (LP-WGS) was used to detect utDNA and estimate copy number burden (CNB). Tumor fraction (tf) detected in utDNA was measured using PredicineBEACON personalized ultra-deep sequencing MRD probes designed from somatic variants detected in iTURBT tissue. MRD probes leverage up to 60 patient-specific alterations and a fixed 500 gene hotspot panel. Analysis included receiver operator curves (ROC) to establish CNB and tf efficacy in detecting residual cancer, based on the pathological findings from rTURBT. Specific thresholds for test positivity were set from ROC analysis and used to evaluate performance characteristics of CNB and tf separately and then in step-wise model. Results: In this HR-NMIBC cohort, residual disease was detected in 36/53 pts (68%) on pathologic evaluation. Using the CNB score from preUR samples, residual disease was detected with an overall AUC of 0.86. Setting the CNB threshold >6.1 yielded a positive likelihood ratio of 11.7 and negative likelihood ratio of 0.37 for detecting MRD. For patients with personalized urinary tf (n=34), a receiver operator curve demonstrated an area under the curve (AUC) of 0.89. Median urinary tf was 3.5% for patients with MRD vs. <0.05% (undetectable) for disease-free patients (p<0.001). Best thresholds for MRD detection per Youden’s index were tf >=6.8% and CNB >6.1. When combined into a step-wise model, the two assays together led to improved performance with 85.7% sensitivity, 100.0% specificity and an overall accuracy of 91.4%. Conclusions: Minimal residual disease can be detected using utDNA prior to rTURBT with high accuracy, making this a promising urinary biomarker. If validated, the combined approach using CNB and tf from utDNA for the detection of MRD can be used to predict patients in need of maximal resection prior to starting intravesical therapy.