bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meaningful score changes for SF-36v2, FACIT-fatigue, and RASIQ in rheumatoid arthritis
Authors: Rendas-Baum Regina , Lin Xiaochen , Kosinski Mark , Bjorner Jakob Bue , Bracher Marguerite G. , Chen Wen-Hung 
Published: January 2024

Abstract
Background
Interpretation thresholds for patient-reported outcome (PRO) scores are of crucial importance, particularly when interpreting treatment benefit. This study was designed to determine the within-patient meaningful improvement (WPMI) thresholds for the Short-Form 36 Health Survey version 2 (SF-36v2), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and the novel Rheumatoid Arthritis Symptoms and Impact Questionnaire (RASIQ) among patients with rheumatoid arthritis (RA).

Methods
In this post-hoc analysis, anchor-based and supportive distribution-based methods were used to derive WPMI based on blinded data from all treatment arms in two Phase 2 RA trials with otilimab. Patient’s Global Assessment of Disease Activity (PtGA) was the general anchor for all SF-36v2 scales. SF-36 Patient’s Global Impression of Status (PGIS), PtGA, and VT03 (an SF-36v2 item) were used as anchors for FACIT-Fatigue. SF-36 PGIS, PtGA, and Patient’s Assessment of Arthritis Pain (PAIN) were anchors for RASIQ. Mean change was calculated for the anchor category associated with minimal meaningful improvement from baseline to Week 24 for SF-36v2 and FACIT-Fatigue, and to Week 12 for RASIQ. Sensitivity and specificity were used to evaluate the accuracy of estimated WPMI values.

Results
For the SF-36v2 physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health domains, anchor-based estimates of WPMI based on 0–100 scores were 24.5, 24.5, 25.4, 13.6, 21.5, 20.5, 16.9, and 14.3, respectively. Anchor-based WPMI estimates were 9.7 for the Physical Component Summary score and 7.6 for the Mental Component Summary score (using norm-based T-score metric). For FACIT-Fatigue (range 0–52), WPMI estimates ranged from 9.7 to 11.3 points. For RASIQ (range 0–100), anchor-based WPMI was determined as a change between -32.7 and -21.7 points for the Joint Pain scale, -26.7 to -23.7 for the Joint Stiffness scale, and -21.1 to -17.4 for the Impact scale.

Conclusions
This study derived WPMI thresholds for SF-36v2, FACIT-Fatigue, and RASIQ among patients with RA, using multiple anchors. Derivation of WPMI thresholds for these PRO instruments will enable their broader use in evaluating and interpreting treatment benefit in future RA studies.
Characterization of the hoof bacterial communities in feedlot cattle affected with digital dermatitis, foot rot or both using a surface swab technique
Authors: Wong Nicholas S. T. , Malmuthge Nilusha , Gellatly Désirée , Nordi Wiolene M. , Alexander Trevor W. , Ortega Polo Rodrigo , Janzen Eugene , Schwartzkopf-Genswein Karen , Jelinski Murray 
Published: January 2024

AbstractBackgroundLameness is defined as altered or abnormal gait due to dysfunction of the locomotor system, and is a health issue of feedlot cattle, having major economic, labour, and welfare implications. Digital dermatitis (DD—a lesion of the plantar surface of the foot) and foot rot (FR—affects the interdigital cleft) are common infectious causes of lameness in feedlots. These hoof lesions can occur alone or in combination (DD + FR) in the same hoof. A total of 208 hoof swabs were collected from three commercial feedlots located in southern Alberta. Every lesion sample was matched with a corresponding control skin sample taken from a healthy contralateral foot. Control skin samples were also collected from cattle with no lesion on any feet. Bacterial communities of three types of hoof lesions (DD, DD + FR, FR) and healthy skin were profiled using 16S amplicon sequencing.ResultsAlpha diversity analysis revealed a lower bacterial diversity on DD and FR lesions compared to control skin. Beta diversity analysis showed that bacterial communities of DD, FR, and DD + FR lesions were distinct from those of the control skin. While the impact of feedlot was minimal, lesion type contributed to 22% of the variation observed among bacterial communities (PERMANOVA-R = 0.22,P < 0.01). Compared to the corresponding control skin, there were 11, 12, and 3 differentially abundant (DA) bacterial genera in DD, DD + FR, and FR lesions, respectively.ConclusionsThe bacterial community description of a DD + FR lesion is a novel finding. Not only did lesions lead to altered bacterial communities when compared to healthy skin, but the composition of those communities also differed depending on the hoof lesion. The 16S amplicon sequencing of surface swabs has significant value as a research tool in separating different hoof lesions and can provide additional insights to the polybacterial etiology of DD and FR in feedlot cattle.
Health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) treated with sotorasib and panitumumab (pmab) versus trifluridine/tipiracil (T/T) or regorafenib (rego) in CodeBreaK 300.
Authors: Modest Dominik Paul , Fakih Marwan , Salvatore Lisa , Esaki Taito , Paez Lopez-Bravo David , Taieb Julien , Karamouzis Michalis , Ruiz-Garcia Erika , Kim Tae Won , Kuboki Yasutoshi , Meriggi Fausto , Cunningham David , Yeh Kun-Huei , Cremolini Chiara , Tran Qui , Chan Emily , Chao Joseph , Majer Istvan Matyas , Pietrantonio Filippo 
Published: January 2024

10 Background: CodeBreaK 300 (NCT05198934) is a phase 3, multicenter, randomized, open-label study, evaluating sotorasib 960 mg (soto960) + pmab, sotorasib 240 mg (soto240) + pmab against investigator’s choice T/T or rego in patients with chemorefractory KRAS G12C-mutated mCRC. The study met its primary endpoint and demonstrated statistically significant improvement in progression-free survival with both doses of sotorasib. This analysis evaluated patient-reported outcomes (PROs) as secondary and exploratory endpoints in CodeBreaK 300. Methods: Change in PRO scores from study baseline through week 8 was compared for soto960+pmab and soto240+pmab vs the control group using a mixed effect model for repeated measures. PRO instruments included the Brief Fatigue Inventory, the Brief Pain Inventory, and the European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life questionnaire. Time to deterioration (TTD) were assessed using Kaplan-Meier plots and Cox proportional hazard models. All analyses were conducted on patients with baseline and at least one post-baseline PRO score. Results: 160 pts were randomized 1:1:1 to soto960+pmab (n=53), soto240+pmab (n=53), or T/T or rego (n=54). Compliance rates for PRO assessments were high (>83%) and similar across the three treatment groups. Least square (LS) mean changes from baseline in fatigue at its worst, pain at its worst, physical functioning (PF), and global health status (GHS)/QoL favored the two sotorasib dose groups (Table). The 95% confidence intervals (CI) suggested improvement in pain at its worst and PF for both sotorasib dose groups, and improvement in GHS/QoL for the soto960+pmab group versus the control group. TTD hazard ratios < 1 indicated a trend in delayed deterioration for patients treated in both sotorasib dose groups. The 95% CIsuggested delays with respect to fatigue at its worst and PF for the soto240+pmab group. Conclusions: In CodeBreaK 300, both doses of sotorasib resulted in better HRQoL and a trend to decreased risk of deterioration vs the control group. In addition to improved clinical outcomes, these findings provide further evidence on the benefit of soto+pmab in patients with chemorefractory mCRC. Clinical trial information: NCT05198934 . [Table: see text]
A retrospective analysis of the prognostic impact of KRAS G12D mutation in patients with RAS-mutated metastatic colorectal cancer.
Authors: Hirose Toshiharu , Matsuguma Kunihito , Hirano Hidekazu , Okita Natsuko Tsuda , Shoji Hirokazu , Takashima Atsuo , Kato Ken 
Published: January 2024

105 Background: KRAS is an oncogene that is mutated in about half of all metastatic colorectal cancers (mCRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising efficacy for advanced solid tumors, including mCRC. A therapy targeting KRAS G12D mutation is also under development and promising efficacy is expected. However, the prognostic impact of the KRAS G12D mutation in patients with mCRC is still unclear. Methods: We retrospectively reviewed the medical records of patients with mCRC harboring RAS mutation who received first-line chemotherapy between January 2013 and December 2022 at our hospital in Japan. We compared the survival outcomes between patients with KRAS G12D mutation (G12D group) and those with non- KRAS G12D mutations (non-G12D group) in terms of progression-free survival (PFS) and overall survival (OS), using the Kaplan–Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 340 patients were included in this study. The main RAS mutations were KRAS G12D in 80 patients (23.4%), KRAS G12V in 72 (21.2%), KRAS G13D in 43 (12.6%) and KRAS G12C in 16 (4.7%). There were 80 patients in the G12D group and 260 in the non-G12D group. Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%). Median PFS was 9.2 months (95%CI: 7.8-12.2) in the G12D group vs. 11.5 months (95%CI: 9.2-13.1) in the non-G12D group (HR 0.97 [95%CI: 0.73-1.28]; p=0.81). Median OS was 25.8 months (95%CI: 18.8-39.8) vs 32.9 months (95%CI: 28.5-36.1) (HR 0.84 [95%CI: 0.60-1.19]; p=0.33). Second-line treatment was administered in 55 (69%) vs 192 (74%) patients in the G12D and non-G12D group, respectively. Conversion surgery was performed in 4 (5%) vs 18 (7%) patients in the G12D and non-G12D group, respectively. Multivariate analysis adjusted for PS, sex, age, site of primary tumor, number of metastatic sites and treatment regimen showed no significant differences in PFS and OS between the G12D and non-G12D groups. Conclusions: The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.
Refining first-line treatment decision in RAS wildtype (RAS-WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).
Authors: Holch Julian Walter , Ohnmacht Alexander , Stintzing Sebastian , Heinrich Kathrin , Westphalen Benedikt , Weiss Lena , von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Kaiser Florian , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Link Hartmut , Hoeffkes Heinz-Gert , Moehler Markus H. , Modest Dominik Paul , Menden Michael , Heinemann Volker 
Published: January 2024

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .
The interaction of radiotherapy and dual inhibition of BET and HAT/p300 in colorectal cancer.
Authors: Pennock Michael Matthew , Pandey Sanjay , Wahlestedt Claes , Guha Chandan , Kuang Chaoyuan 
Published: January 2024

146 Background: Colorectal cancer (CRC) is characterized by extensive DNA methylation at the promoters of tumor suppressor genes and enhanced activity of histone modifying proteins such as histone acetyltransferases (HATs) or histone readers such as bromodomain and extra-terminal domain (BET) proteins. BET inhibition has been associated with the reduced expression of DNA repair proteins and therefore can be used in combination with radiotherapy (RT) and chemotherapy. In the current study, we have evaluated the therapeutic potential of a clinical stage (phase 1) dual BET and CBP/p300 inhibitor, EP31670 (EP), in combination with RT. Methods: HCT116 CRC 2-D cultures were treated with EP 4 hours before RT. After pretreatment with EP (0, 0.1, 0.5, 1, 2, 5, and 10µM), cells were irradiated with various doses (0, 2, 4, 6, and 8Gy) of RT (300-kv x-rays). Crystal violet (CV) assay at 48 hours post RT was used to determine growth inhibition and viability between the various drug, RT, and combination groups. Synergy between treatments was evaluated by estimating the combination index (CI) values via mass-action law CompuSyn calculations using CV data. CI values of <1 from the growth inhibition assay suggested that EP synergized with RT for enhanced cytotoxicity in HCT116 CRC cells. Flow cytometry was used to assess DNA damage (γH2Ax), apoptosis and total death (Annexin V-PI assay), cell cycle analysis, and proliferation (EdU). Results: There was a significant dose-dependent increase in the residual DNA damage at 6 hours (8Gy + EP 0.5µM vs. 8Gy, p<0.0001) and 24 hours (8Gy + EP 0.5µM vs. 8Gy, p=0.002) for combination therapy over RT alone. Four-hour treatment with EP promoted G2 cell-cycle arrest (8Gy + EP 0.5µM vs. 8Gy, p<0.001) and significantly reduced the number of HCT cells in S-phase (8Gy + EP 0.5µM vs. 8Gy, p<0.001) and proliferation (EdU) of the HCT cells (8Gy + EP 0.5µM vs. 8Gy, p=0.0003) compared to RT alone. There was a significant increase in apoptotic cells the combination group (8Gy + EP 0.5µM vs. EP 0.5µM, p=0.008) when compared to the unirradiated cells. The combination group also showed significant increase in the total death compared to RT alone (8Gy + EP 0.5µM vs. 8Gy, p=0.03) at the G1-S checkpoint. Conclusions: EP31670 enhanced RT-induced growth arrest, reduced proliferation, and enhanced cell death in HCT116 CRC cells in synergy with the RT. Additional preclinical studies, in vivo studies, and eventual clinical studies can be conducted to further exploit this synergistic interaction.
Genome-wide DNA methylation status to predict the efficacy of modified (m)-FOLFOXIRI plus cetuximab as initial treatment for RAS wild-type metastatic colorectal cancer: A biomarker study of the DEEPER trial (JACCRO CC-13AR).
Authors: Ouchi Kota , Tsuji Akihito , Shiozawa Manabu , Kawai Takashi , Yasui Hisateru , Ota Hirofumi , Kochi Mitsugu , Manaka Dai , Ohori Hisatsugu , Miyake Toru , Yamaguchi Tatsuro , Matsuura Masato , Sagawa Tamotsu , Makiyama Akitaka , Wakamura Kunihiko , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Ishioka Chikashi , Sunakawa Yu 
Published: January 2024

152 Background: Genome-wide DNA methylation status (GWMS) has been shown to be a predictor of therapeutic response to anti-EGFR antibody therapies. This study investigated the association between GWMS and clinical outcomes of first-line chemotherapy with anti-EGFR or anti-VEGF antibody agents for metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the JACCRO CC-13AR (clinical trial number: UMIN000018412) were analyzed for GWMS and were classified into low-methylated colorectal cancer (LMCC) and high-methylated colorectal cancer (HMCC). Clinical data were obtained from the randomized phase II trial, DEEPER trial (JACCRO CC-13) [NCT02515734], in which patients were randomly assigned to m-FOLFOXIRI plus cetuximab (CET) arm and m-FOLFOXIRI plus bevacizumab (BEV) arm for treatment. Progression-free survival (PFS), overall survival (OS), depth of response (DpR), and response rate (RR) were analyzed according to GWMS for each treatment arm. Results: One hundred thirty-seven out of 227 patients enrolled in the JACCRO CC-13AR were analyzed. Of these, 122 (89.1%) and 15 (10.9%) were classified in the LMCC and HMCC, respectively; 66 were assigned to the CET arm including 7 HMCCs, and 54 were assigned to the BEV arm including 8 HMCCs. In the CET arm, PFS and OS of the LMCC were significantly longer than those of the HMCC (median PFS 14.3 vs. 4.0 months, hazard ratio [HR] 0.11, 95% CI: 0.05–0.29, P<0.01; median OS 42.7 vs. 13.6 months, HR 0.04, 95% CI: 0.01–0.13, P<0.01). There were no differences in DpR and RR between the LMCC and the HMCC (median DpR 58.1% vs. 46.7%, P=0.45), although RR of the LMCC was numerically higher than that of the HMCC (71.2% vs. 42.9%, P=0.13). In contrast, in the BEV arm, there were no differences in PFS, DpR, and RR between the two groups (median PFS 16.1 vs. 12.2 months, P=0.08; median DpR 48.3% vs. 53.9%, P=0.99; RR 73.0% vs. 75.0%, P=0.91). However, OS of the LMCC was significantly longer than that of the HMCC (median OS 48.9 vs. 24.2 months, HR 0.39, 95% CI: 0.16–0.95, P=0.03). Conclusions: This study showed that GWMS may be a prognostic marker for initial treatment in RAS wild-type mCRC. Also, GWMS correlates to the survival outcomes of m-FOLFOXIRI plus CET as initial treatment for RAS wild-type mCRC. Clinical trial information: 000018412 .
Clinical utility of serial circulating tumor DNA (ctDNA) to identify acquired resistance to anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Loree Jonathan M. , Bubie Adrian , Eluri Madhulika , Parseghian Christine Megerdichian , Overman Michael J. , Zhang Nicole , Drusbosky Leylah , Kopetz Scott , Raghav Kanwal Pratap Singh 
Published: January 2024

158 Background: Real-world evidence informing on the value of incorporating serial ctDNA into clinical practice is lacking. We aimed to explore the utility of serial ctDNA for identifying mechanisms of resistance and new targets for patients (pts) receiving anti-EGFR therapy for mCRC. Methods: We retrospectively reviewed 2801 pts with mCRC who had ≥1 alteration detected on a Guardant360 assay (Guardant Health) and subsequently had serial ctDNA assessments with known intervening therapies. We compared detection of new MAPK pathway alterations ( RAS/EGFR/BRAFV600 SNV or indel, MET or ERBB2 amplification) among patients who initially lacked these alterations by whether patients received anti-EGFR antibody alone (panitumumab or cetuximab), in combination with chemotherapy, or if they had never received an anti-EGFR antibody between ctDNA assays. Patients with a subsequent ctDNA assay after therapy initiation were included for analysis of acquired alterations. Results: Of 2801 pts, 1308 (47%) harbored ≥1 MAPK alteration in their first ctDNA timepoint and were excluded from analysis. Of the remaining 1493 without a MAPK alteration prior to therapy, 588 (39.4%) had a MAPK alteration detected in a subsequent ctDNA timepoint. Among 447 of 1493 pts (31.8%) with subsequent exposure to anti-EGFR antibodies, acquisition of a MAPK alteration occurred in 229/447 (51.2%). This was more common (OR 2.01. 95% CI 1.61-2.51, P<0.0001) than in patients without exposure to anti-EGFR antibodies (359/1046 [34.3%]). Acquired MAPK alterations were more common among those receiving single agent antibodies (42/66, 63.6%) than anti-EGFR plus chemotherapy (187/381, 49.1%) (OR 1.82, 95% CI 1.05-3.08, P=0.030). Patients with anti-EGFR antibody exposure were found to have higher blood TMB scores in the first assay after treatment compared to patients treated with chemotherapy alone (11.5 vs. 8.8 mut/MB, respectively; P=0.001), with no significant blood TMB difference between those receiving single agent anti-EGFR versus anti-EGFR plus chemotherapy (median 12.4 vs. 11.5 mut/MB; P=0.52). Patients who acquired MAPK alterations after anti-EGFR therapy had higher blood TMB scores compared to patients who did not acquire MAPK alterations (median 14.3 vs 8.6 mut/MB, respectively; p<0.0001). Conclusions: In this large cohort of pts with mCRC and treatment information, we demonstrate serial ctDNA identified a large proportion of patients acquiring resistance alterations that may impact response to future therapies. These results suggest serial ctDNA analysis may provide additional molecular insights for patients receiving anti-EGFR therapy and inform future anti-EGFR rechallenge strategies.