bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sub 2-h Official Marathon is Possible: Developing a Drafting Strategy for a Historic Breakthrough in Sports
Authors: Fernandes G. D. , Laureano Gandur Nazir , Santos Dioser , Maldonado Victor
Published: January 2025

Background

Drafting for drag reduction is a tactic commonly employed by elite athletes of various sports. The strategy has been adopted by Kenyan runner Eliud Kipchoge on numerous marathon events in the past, including the 2018 and 2022 editions of the Berlin marathon (where Kipchoge set two official world records), as well as in two special attempts to break the 2 h mark for the distance, the Nike Breaking2 (2017) and the INEOS 1:59 Challenge (2019), where Kipchoge used an improved drafting formation to finish in 1:59:40, although that is not recognized as an official record.

Results

In this study, the drag of a realistic model of a male runner is calculated by computational fluid dynamics for a range of velocities. The formations employed in the past by Kipchoge, as well as alternative formations, are analyzed and systematically compared with respect to mechanical power. In a quest to show that running an official marathon in under 2 h is possible, the power analysis is extended to the pacers. We developed a simple drafting and pacing strategy that Kipchoge could have used to run the 2022 Berlin marathon in a surprising 1 h, 59 min and 48 s.

Conclusions

Elite marathon runners can make better use of the pacers to experience reduced drag in races. The associated energy reduction makes it possible to run faster, finishing the race in less time. Using a better drafting strategy and a positive splitting pacing strategy, Kenyan runner Eliud Kipchoge could have broken the sub 2 h barrier in both the 2018 and 2022 editions of Berlin Marathon.
Acute decompensated right heart failure potentially triggered by multiple factors including pulmonary vasodilator removal during plasma exchange: a case report
Authors: Toki Takayuki , Mizunoya Kazuyuki , Itabashi Misa , Nishikawa Naoki , Hoshino Koji , Saito Hitoshi , Morimoto Yuji
Published: January 2025

Background

Plasma exchange (PE) removes high-molecular-weight substances and is sometimes used for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with alveolar hemorrhage. Hypotension during PE is rare, except in allergic cases. We report a case of shock likely caused by increased pulmonary vascular resistance (PVR) during PE.

Case presentation

A 66-year-old man with pulmonary hypertension (PH) and glomerulonephritis was admitted with dyspnea. He had discontinued sildenafil prior to admission. Alveolar hemorrhage associated with AAV was suspected, and PE was performed. Soon after, he developed circulatory failure and hyperlactatemia. Echocardiography revealed right ventricular dilation, suggesting increased PVR. Inhaled nitric oxide (iNO) was administered, rapidly improving hyperlactatemia and oxygenation. The shock observed during PE was attributed to multiple factors, including the potential removal of sildenafil, which may have led to an increase in PVR.

Conclusions

The shock was attributable to acute right heart failure caused by an exacerbation of PH, possibly due to sildenafil removal via PE, although other contributing factors could not be excluded.
Hepatoprotective potential of Chrysin in a rat model of isoniazid- and rifampicin-induced hepatic injury: suppression of matrix metalloproteinase and transforming growth factor β
Authors: Mandlik Deepa , Tokey Akhilesh , Lokhande Rohit , Dagadu Yash , Choudhary Heena , Mandlik Satish
Published: January 2025

Background

The ability of Chrysin (CHY) to scavenge free radicals has been widely explored. The scope of the research was to show that CHY protects the rat liver against damage caused by the drugs isoniazid (INH) and rifampicin (RFM).

Results

Rats were divided into 6 groups, each of which had six rats. Isoniazid (100 mg/kg, p.o.) and rifampicin (100 mg/kg, p.o.) were administered to Group II to VI rats for 21 days; this caused hepatocellular damage. CHY was administered in the dose of 50, 75, and 100 mg/kg, p.o. body weight to Group III to V rats before administration of INH + RFM. In this study, Group VI Silymarin (100 mg/kg, p.o.) functioned as the standard drug. The blood was drawn as the study was done, and tests for oxidative stress indicators, haematological parameters, biochemical parameters, and pro-inflammatory cytokines were performed. The liver samples were subjected to histopathology. The administration of CHY (50, 75, and 100 mg/kg) restored serum biochemical, haematological, proteins, and lipid parameters. Due to the administration of CHY, the levels of superoxide dismutase (SOD), glutathione oxidase (GSH), myeloperoxidase (MPO) and catalase (CAT) were also restored. The inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), transforming growth factor-β (TGF-β), malondialdehyde (MDA), myeloperoxidase (MPO) and nitric oxide (NO) levels were found to be decreased. The alterations in the biochemical parameters were reinforced by histological analysis of liver tissue.

Conclusions

It is concluded that the CHY protects against INH + RFM-induced oxidative liver injury in rats.

Graphical abstract
Bayesian Fourier coefficient inversion for gravity-induced stress parameters in tilted transversely isotropic gas-bearing reservoirs
Authors: Li Lin , Zhang Guangzhi , Wang Yaojun , Hu Guangmin
Published: January 2025

Field observations and core data reveal that natural fractures may not be perfectly vertical but are commonly inclined, yielding an effective tilted transversely isotropic (TTI) medium. Neglecting TTI symmetry can lead to erroneous stress prediction results, which are important for hydrocarbon exploration and development. We have developed a Bayesian Fourier coefficient (FC) inversion approach to estimate gravity-induced stress parameters in TTI media, specifically horizontal stress and the differential horizontal stress ratio (DHSR). The gas-bearing reservoir with dipping fractures is modeled as a linearly elastic, homogeneous TTI material. Under the assumption of no lateral strain, we combine fracture-effective medium models with the generalized Hooks law to establish the relationship between gravity-induced stress parameters and TTI elastic and fracture parameters. Based on seismic scatter theory, we derive a linearized PP-wave reflection coefficient and corresponding FC expressions parameterized by P- and S-wave moduli, density, fracture density, and fracture dip in TTI media. Furthermore, we present a Bayesian FC inversion constrained by a joint multivariable Cauchy prior model to estimate these model parameters, which are then used to calculate gravity-induced stress parameters. A synthetic example demonstrates that Bayesian FC inversion under the TTI model assumption produces more reliable estimates of gravity-induced stress parameters compared to those obtained under the horizontal transversely isotropic (HTI) model assumption. Additionally, a real data set from a gas-bearing reservoir is employed to demonstrate the feasibility of our method. Results indicate that our method yields reasonable estimates of gravity-induced stress parameters with good lateral continuity. The proposed method could aid in identifying optimal zones for hydraulic fracturing of a subterranean formation with TTI symmetry.
Prevalence of extracolonic malignancies in patients with familial adenomatous polyposis.
Authors: Rami Avina , Garcia-Gonzalez Araceli , Moskowitz Julie , Mork Maureen E , Ricciardiello Luigi , Thirumurthi Selvi , Grubbs Elizabeth G. , You Y. Nancy , Vilar Sanchez Eduardo
Published: January 2025

103

Background:
Familial adenomatous polyposis (FAP) is an autosomal-dominant inherited colorectal cancer syndrome resulting from mutations in the adenomatous polyposis coli (
APC
) gene. Patients with FAP have nearly 100% lifetime risk of colorectal cancer, typically managed with prophylactic colectomies. As patient survival has improved, the incidence of extracolonic tumors, including thyroid malignancies and desmoid tumors, has increased. However, limited research exists on the prevalence of extracolonic malignancies in FAP patients.
Methods:
We prospectively enrolled 219 patients with FAP in the Hereditary Gastrointestinal Cancers Cohort at the MD Anderson Cancer Center between December 2015 and July 2024. Inclusion criteria included either a clinical or molecular diagnosis of FAP. Data on demographics, cancer history (including cancers diagnosed both prior to and during the study period), BMI, tobacco use, medications, endoscopy results, thyroid ultrasound findings, and abdominal/pelvic CT results were collected. Screening for thyroid and desmoid tumors was provider-dependent, with additional screenings as deemed appropriate. Descriptive and inferential statistics were used to identify associations between demographic and clinical factors and the prevalence of extracolonic malignancies.
Results:
Among 219 patients, 20.5% developed desmoid tumors, 18.7% developed colorectal cancer, and 6.8% developed well-differentiated thyroid cancer (6.4% papillary thyroid cancer, 0.4% follicular thyroid cancer). Prophylactic colorectal surgery was performed in 151 patients (68.9%). Per chart review, benign thyroid disease and hypothyroidism were present in 21% and 11.4% of patients, respectively. Female sex was significantly associated with hypothyroidism (p=0.007) and thyroid cancer (p=0.009). BMI > 30 was also linked to increased thyroid cancer risk (p=0.046). Desmoid tumors were found in 20.5% of patients, most commonly in the abdominal wall. Female sex, BMI > 30, and history of colorectal surgery were significantly associated with desmoid tumor development (p=0.004, 0.0064, 0.0038).
Conclusions:
FAP patients exhibit a higher prevalence of benign thyroid disease, thyroid cancer, and desmoid tumors compared to the general population. Given these findings, adherence to existing surveillance guidelines, such as those outlined by the National Comprehensive Cancer Network (NCCN), is essential. Our findings further support the importance of these established surveillance strategies in the management of FAP patients.
Disparities in prophylactic tetracycline use among patients with metastatic colorectal cancer undergoing treatment with EGFR inhibitors.
Authors: Rubnitz Zach , Braun Emma , Jridi Amani , Florou Vaia , Garrido-Laguna Ignacio , Nevala-Plagemann Christopher Duane
Published: January 2025

109

Background:
Epidermal growth factor receptor (EGFR) inhibitors have been shown to improve survival in metastatic colorectal cancer and are considered a standard of care option for patients with RAS/RAF wild-type disease. However, anti-EGFR agents are associated with an acneiform rash that can lead to decreased quality of life and early discontinuation of treatment. Prophylactic doxycycline has been shown in a randomized clinical trial to decrease any skin toxicity ≥ grade 2 by 50%. In this study we sought to determine the rate of prophylactic tetracycline use in metastatic colorectal cancer patients receiving anti-EGFR therapy in the United States.
Methods:
The Flatiron Health Electronic Health Record-derived, de-identified database was used to analyze the records of patients who were at least 18 years old, diagnosed with metastatic colorectal cancer, and received treatment with an anti-EGFR agent (cetuximab or panitumumab). Patients were stratified by receipt of prophylactic tetracycline versus not. This was defined by an order for a tetracycline 28 days before to 1 day after initiation of an anti-EGFR agent. Demographic and clinical characteristics were compared via multivariable logistic regression. The change in percentage of patients who received a prophylactic tetracycline over time was assessed and was compared to the rate of anti-emetic prescription which served as a control to ensure drug administration data was accurately captured.
Results:
The records of 6,713 patients who met inclusion criteria and received an anti-EGFR agent between 2013 and 2023 were included in our analysis. A logistic regression model assessing the association between patient characteristics and the receipt of a prophylactic tetracycline suggested that older age, race (black/African American or Other), presence of RAS mutation, and higher line of therapy were all significantly associated with not receiving prophylactic tetracyclines. Other patient characteristics including gender, ECOG status, mismatch repair status, and RAF mutation status did not appear to impact the likelihood of receiving a prophylactic tetracycline. The rate of prophylactic tetracycline use increased from 10.9% in 2013 to 22.3% in 2023 while the rate of prophylactic anti-emetic remained stable at around 82%.
Conclusions:
This real-world analysis suggests the use of preemptive treatment for skin toxicity in patients with metastatic colorectal cancer who are treated with an anti-EGFR in US is suboptimal. Disparities in cancer care are also evidenced by lower use of tetracyclines in elderly and African Americans. Randomized controlled trials support the use of prophylactic tetracycline in these patients; thus, further research into the reason for this practice gap is necessary. Educational efforts should be undertaken to improve tetracycline prescribing rates in this population.
Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.
Authors: Jones Daniel Thomas , Aboaid Hazem , Nanda Rishi Kumar , Srinivasmurthy Ramaditya , Nguyen Kevin , Ta Jason , Thein Kyaw Zin
Published: January 2025

118

Background:
Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib.
Methods:
A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied.
Results:
A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96).
Conclusions:
This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.
The role of sequential PET/CT imaging to predict complete response after definitive chemoradiotherapy for locally advanced squamous cell carcinoma of the anal canal.
Authors: Valzano Marianna , Aquilano Michele , Loi Mauro , Morelli Ilaria , Frosini Giulio , Bonomo Pierluigi , Galardi Alessandra , Francolini Giulio , Di Cataldo Vanessa , Mangoni Monica , Meattini Icro , Livi Lorenzo
Published: January 2025

12

Background:
The standard treatment for locally advanced squamous cell carcinoma of the anal canal (SCCAC) is definitive radiotherapy (RT) with concurrent chemotherapy (CRT), with excellent outcomes. Nevertheless, rates of locoregional failure of 10% to 30% have been reported. Due to the narrow therapeutic window between time-dependent response to RT and prompt salvage surgery, the definition of a surveillance strategy after radical CRT is challenging. In particular the contribution of 18-FDG PET/CT is not clearly established. The purpose of this study was to evaluate the effectiveness of follow-up MR and 18-FDG PET/CT to predict response to CRT in patients with SCCAC.
Methods:
We analyzed a cohort of consecutive patients who received definitive RT/CRT from January 2019 to February 2024. After completion of therapy, radiologic (rCR) and metabolic complete response (mCR) was assessed with pelvic MR (RECIST v.1.0) and 18-FDG PET/CT at 3 ad 6 months respectively. Local Control (LC) was defined as time from the end of CRT to local failure or last follow-up. Univariate analysis (UVA) was performed to identify variables associated with outcome using the log rank test. Sensitivity and Specificity analysis was performed to assess the correlation between rCR/mCR and LC.
Results:
A total of 67 patients (median age 67 years, range 44-83) were included. All patients completed RT, and 52 received concurrent CRT. Baseline and surveillance MR and 18-FDG PET/CT were available for 49 patients. After a median follow-up of 28 months, 12 patients experienced disease progression (PD) (10 local; 2 distant), resulting to salvage surgery in 10 cases after biopsy. At 3 years, LC rate was 78%. At UVA, only mCR was correlated with LC (3-year LC 90% versus 59%, p=0,0137; HR 0,01660, IC 95% 0,03-0,84). For prediction of LC, accuracy of mCR at 6 months was 83.7% versus 62.5% for rCR. Specificity/Sensitivity analysis is summarized in the table.
Conclusions:
18FDG PET/CT at 6 months may identify patients with a higher likelihood of developing complete tumor regression following CRT. Further data is needed to confirm the appropriate surveillance strategy for patient undergoing CRT in clinical practice.

Specificity and sensitivity analysis.

Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value

mCR
83.3%
84.0%
92.6%
68.7%

rCR
25.0%
70.0%
14.0%
82%
Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.
Authors: Ishibashi Naoya , Kamatani Takashi , Kinugasa Yusuke , Ikeda Sadakatsu
Published: January 2025

130

Background:
Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies.
Methods:
This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers.
Results:
In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p<0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p<0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites.
Conclusions:
This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.
Adverse events (AEs) –derived biomarker in predicting clinical outcomes in patients with colorectal cancer (CRC) treated with immunotherapy (IC).
Authors: Chen Dung-Tsa , Mehta Rutika , Kim Richard D. , Permuth Jennifer B , Shaw Timothy I , Kim Dae Won
Published: January 2025

132

Background:
There are insufficient studies evaluating the role of AEs in CRC patients treated with IC. This study aims to transform AEs from traditional toxicity evaluation tools to informative biomarkers for assessing treatment efficacy by utilizing modern analytical strategies.
Methods:
We analyzed a single arm study of 51 mismatch repair proficient, refractory CRC patients (NCT03712943) treated with regorafenib and nivolumab. Data for analysis included CTCAE version 5 AE data, RECIST treatment response, progression-free survival (PFS), and overall survival (OS). Analytic approach leveraged multiple AE parameters to develop a set of innovative AE biomarkers. One AE biomarker of interest was treatment related low-grade early AEs (TR-LG-AE) which was defined as frequency of all TR-LG-AEs occurring between the 1st day and day 30 after the 1st treatment.
Results:
TR-LG-AE was associated with treatment response (p<0.001 by ANOVA trend test). Patients with higher AE events tended to be a responder, compared to PD patients with a lower frequency of AE events. The TR-LG-AE also correlated with improved PFS and OS with hazard ratio of 0.83 (p=0.01) and 0.89 (p=0.03), respectively. Accordingly, patients were grouped into high versus low TR-LG-AE based on optimal cutoff of 6 events for further analysis. The dichotomized TR-LG-AE (high vs low) showed significant association with survival outcomes (median PFS: 15.3 vs 3.7 months; p<0.001; median OS: 21.9 vs 9 months; p=0.02). Further interaction analysis showed patients with high TR-LG-AE had improved PFS regardless of occurrence of high-grade AE (HG-AE) (p=0.01), suggesting its independence of HG-AE. Individual AE analysis identified patients experienced with early low-grade rash maculo-papular, lipase increased, or hypertension had improved PFS (p<0.001). In biomarker analysis, one key mutation biomarker, RAS, did not show significant association with survival outcomes (PFS: p=0.66; OS: p=0.81). In contrast, integration with TR-LG-AE led to remarkable improvement. Specifically, the TR-LG-AE was able to help improve RAS classification by identifying patients with better treatment benefit. Specifically, patients with RAS mutation and high TR-LG-AE experiences had a median PFS of 15.3 months compared to others (median PFS of 3.7 months; p=0.007), and a median OS of 21.9 months compared to others (median OS of 9.4 months; p=0.04).
Conclusions:
The study demonstrated utility of AE in predicting clinical outcomes in CRC, similar to our previous findings in lung cancer. Moreover, it discovered that integration of AE-derived biomarkers with molecular biomarkers could produce a more robust classifier than when considered individually. This analysis is the first of its kind to identify subgroups of CRC patients that benefit from IC treatment.
Total neoadjuvant therapy with FOLFOX plus bevacizumab and short-course radiotherapy for Ras mutant, high-risk, locally advanced rectal cancer: The TRAINER trial.
Authors: Feng Bo , Liu Jingyi , Ma Tao , Cai Zhenghao , Zhang Sen , Yang Xiao , Song Haiqin , Cai Gang , Xu Ximo , Zhong Hao , Yu Mengqin , Abuduaini Naijipu , Jiang Lixuan , Wang Xiaohan , Wang Wanyu
Published: January 2025

133

Background:
Total neoadjuvant therapy (TNT) intensified by the combination of targeted therapy or immunotherapy is warranted to achieve satisfying local and systemic control for high-risk locally advanced rectal cancer (LARC). Our study aimed to explore the efficacy and safety of a FOLFOX-based TNT regimen plus bevacizumab and short-course radiotherapy (SCRT) in Ras-mutant high-risk LARC patients.
Methods:
In this single-arm, single-center, phase II trial, LARC patients with at least one risk factor (cT3c-4, mesorectal fascia positive, cN2, lateral lymph node involvement, and extramural venous invasion positive) were recruited and only Ras-mutant patients were included. Four cycles of FOLFOX plus bevacizumab were arranged as induction chemotherapy followed by SCRT (25Gy/5Fx) and two cycles of FOLFOX as consolidation chemotherapy. Surgery was performed 8 weeks after completion of radiotherapy. After surgery, high-risk stage III patients (T4 or N2) were recommended to receive an extra 6 cycles of FOLFOX as adjuvant chemotherapy, while low-risk stage III patients were scheduled for regular follow-up. Patients with clinical complete response(cCR) were allowed to choose the “Watch & Wait” (W&W) strategy instead of surgery. The primary endpoint was the complete response (CR) rate, defined as the total rate of cCR plus pathological complete response (pCR). Secondary endpoints included adverse events of TNT, postoperative complications, 2-year disease-free survival, and overall survival.
Results:
Between April 2, 2021, and March 12, 2024, 47 of 51 enrolled patients were eligible for treatment. All patients completed the prescribed TNT cycles, and six (12.8%) of them had dose reduction. The CR was achieved in 18 (38.3%) patients, including 14 (29.8%) pCR. No grade IV-V toxicity was observed and the incidence of grade III toxicities was 34.0%. Four patients (8.5%) achieved cCR and chose the W&W strategy. The other 43 patients underwent curative surgery and anal preservation was achieved in 39 (90.7%) patients. Seven patients (16.3%) experienced postoperative complications, including four (9.3%) cases of anastomotic leakage.
Conclusions:
The intensified TNT regimen combined with bevacizumab achieved a satisfying CR rate with acceptable toxicities and complications for Ras-mutant high-risk LARC patients. Long-term survival data of this cohort are needed to validate the efficacy of this regimen further.
Clinical trial information: NCT04923620
.
What is the optimal treatment strategy of salvage line treatment after progression on anti-epidermal growth factor receptor monoclonal antibody in patients with tissue
RAS/BRAF
wild-type metastatic colorectal cancer?
Authors: Tange Emiko , Osumi Hiroki , Shimozaki Keitaro , Yoshino Koichiro , Tamba Mikako , Udagawa Shohei , Fukuoka Shota , Ogura Mariko , Wakatsuki Takeru , Ooki Akira , Chin Keisho , Yamaguchi Kensei , Shinozaki Eiji
Published: January 2025

138

Background:
Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) and anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) re-challenge are treatment options for tissue
RAS/BRAF
wild-type (WT) metastatic colorectal cancer (mCRC) in salvage line, although the optimal treatment sequence of salvage line remains unclear.
Methods:
RAS/BRAF
WT mCRC patients refractory to anti-EGFR mAb were retrospectively enrolled at a single cancer institute from November 2017 to April 2024. We compared responses, progression-free survival (PFS), and overall survival (OS) between Group A (anti-EGFR mAb re-challenge given first) and B (FTD/TPI plus BEV given first). We compared responses between Group C (treated with anti-EGFR mAb re-challenge at any line) and D (treated with FTD/TPI plus BEV at any line). We explored the clinical factors related to the treatment efficacy using multivariate analysis.
Results:
A total of 89 patients (median age, 63 years) were included. The cohort included 74 patients with a primary lesion in the left-sided colon, while 15 patients had a primary lesion in the right-sided colon. The response rate (RR) was 3.4%. The disease control rate (DCR) was 52.8%. The median PFS (mPFS) and OS (mOS) were 3.5 months (95% confidence interval [CI], 2.8-4.2) and 12.8 months (95% CI, 8.8-15.7) respectively. Two of 18 patients (11.1%) in Group A and 1 of 71 patients (1.4%) in Group B achieved partial response (PR). The RR of Group C was significantly higher than Group D (9.6% vs 1.2%; p = 0.031). Both PFS and OS showed no significant difference between Group A and B (mPFS: 3.3 vs 3.9 months; hazard ratio [HR], 1.08; 95% CI, 0.63-1.84; p = 0.79) (mOS: 12.8 vs 15.0 months; HR, 0.90; 95% CI, 0.49-1.65; p = 0.72). Multivariate analysis identified that primary tumor resection was associated with PFS (HR, 0.44; 95% CI, 0.25–0.80; p = 0.0068) and primary tumor resection (HR, 0.34; 95% CI, 0.18–0.65; p = 0.0010) and serum CA19-9 level (HR, 1.75; 95% CI, 1.02-3.00; p = 0.043) were associated with OS.
Conclusions:
No significant survival difference was observed between patients administered anti-EGFR mAb re-challenge first and those administered FTD/TPI plus BEV first, whereas the RR of anti-EGFR mAb re-challenge is significantly higher than that of FTD/TPI plus BEV.
Short-course radiotherapy-based total neoadjuvant therapy combined with tislelizumab in the treatment of locally advanced rectal cancer (Neo-STAR): Early outcomes of a prospective, randomized phase II trial.
Authors: Wu Fengpeng , Xiao Linlin , Zhou Chaoxi , Niu Wenbo , Fan Haiyan , Ma Hongqing , Wang Guanglin , Zhang Jianfeng , Hu Xuhua , Hu Jitao , Wang Guiying
Published: January 2025

150

Background:
It has been found that radiotherapy possess synergistic anticancer effect with immune checkpoint inhibitors (ICIs). Therefore, this phase II randomized clinical trial (RCT) (ClinicalTrials.gov identifier: NCT05086627) aimed to evaluate the efficacy and safety of SCRT followed by CAPOX and tislelizumab in patients with LARC.
Methods:
Patients initially diagnosed rectal adenocarcinoma with cT1-2N+M0 or cT3-4NanyM0 were recruited, randomly assigned to receive SCRT (25Gy/5f), followed by four cycles of CAPOX combined with tislelizumab or CAPOX alone, respectively. After total mesorectal excision (TME), two cycles of postoperative adjuvant chemotherapy were given according to the patient's preferences. The pCR rate was set as the primary endpoint, and the major pathological response (MPR) (tumor regression grade (TRG) 0+1), 3-year progression free survival (PFS), 3-year overall survival (OS) and treatment safety were set as the secondary endpoints.
R
esults:
Between September 2021 and March 2024, 118 patients were randomly assigned and 111 patients started allocated treatment, with 53 in the trial group and 58 in the control group. Ninety-six patients (86.5%) completed SCRT and 4 cycles of CAPOX chemotherapy with/without tislelizumab, including 49 patients (92.5%, 49/53) in the trial group and 47 patients (81.0%, 47/58) in the control group. Eighty-two patients (85.4%) had surgical resection, including 42 patients (85.7%, 42/49) in the trial group and 40 patients (85.1%, 40/47) in the control group. Among 82 patients who underwent surgery, 54.8% (23/42) patients in the trial group achieved pCR compared with 37.5% (15/40) in the control group. During the neoadjuvant treatment period, the incidence of grade 3-4 AEs were 9.4% in the trial group and 10.3% in the control group.
Conclusions:
SCRT-based TNT combined with tislelizumab followed by TME exhibited a favorable pCR rate in LARC.
Clinical trial information: NCT05086627
.

Surgical and postoperative pathological outcomes.

Characteristic

Experimental group (n=
42
)

Control group (n=4
0
)

R0 resection

Yes
42 (100%)
40 (100%)

No
0 (0%)
0 (0%)

pCR

Yes
23 (54.8%)
15 (37.5%)

No
19 (45.2%)
25 (62.5%)

TRG score

0
23 (54.8%)
15 (37.5%)

1
3 (7.1%)
2 (5%)

2
14 (33.3%)
15 (37.5%)

3
2 (4.8%)
8 (20%)

Pathological T stage

T0
24 (57.1%)
15 (37.5%)

Tis
1 (2.4%)
0 (0%)

T1
0 (0%)
1 (2.5%)

T2
9 (21.4%)
6 (15%)

T3
6 (14.3%)
10 (25%)

T4
2 (4.8%)
8 (20%)

Pathological N stage

N0
39 (92.9%)
36 (90%)

N1
3 (7.5%)
3 (7.5%)

N2
0 (0%)
1 (2.5%)

Type of surgery

Anterior resection
36 (85.7%)
24 (60%)

Abdominoperineal resection
6 (14.3%)
13 (32.5%)

Hartmann procedure
0 (0%)
3 (7.5%)

Anus preservation

Yes
36 (85.7%)
27 (67.5%)

No
6 (14.3%)
13 (32.5%)
Cetuximab every second week in combination with daily encorafenib in patients with BRAF V600E mutated metastatic colorectal cancer: Interim analysis from NEW BEACON.
Authors: Eriksen Martina , Pfeiffer Per , Rohrberg Kristoffer Staal , Yde Christina Westmose , Petersen Lone Nørgård , Poulsen Laurids , Qvortrup Camilla
Published: January 2025

153

Background:
Weekly administered cetuximab in combination with the BRAF inhibitor encorafenib has improved survival in pre-treated patients (pts) with BRAF V600E mutated (BRAFmut) metastatic colorectal cancer (mCRC), with a median progression free survival (PFS) of 4.3 months in the BEACON study. It is now standard-of-care in the second line treatment. However, a regimen with cetuximab administered every second week may demonstrate comparable efficacy and is more convenient for the pts. Thus, we initiated the NEW BEACON study investigating cetuximab given every second week together with daily encorafenib. Details on the rationale and aims of the study have previously been published (doi: 10.1186/s12885-022-10420-x.).
Methods:
NEW BEACON is an open-label, single-arm, multicenter, phase II study including pts with pre-treated BRAFmut mCRC. The primary end point is 2 months PFS rate. We report here the result of a pre-specified interim analysis after treatment of the first 19 included pts. We collected fresh tumor tissues for comprehensive molecular profiling in order to explore features associated with response and resistance. Baseline genomic variants will be reported.
Results:
From February 2021 to February 2024 20 pts were included in the study. 1 patient never started study treatment due to rapid disease progression. At the data cut-off date 19 pts had initiated study treatment. The 2 months PFS rate was 89% (17/19 pts). We had tumor tissue for molecular profiling available from 12 pts. Pathogenic variants in TP53 were the most frequently detected co-mutations at baseline in 83% of pts (10/12 pts). Available preliminary safety, efficacy, and survival data and more extensive genomic data will be presented at the meeting.
Conclusions:
The preliminary PFS data from pts with BRAFmut mCRC treated with cetuximab every second week together with daily encorafenib is promising demonstrating a 2 months PFS rate of 89%. This is similar to what was reported from the BEACON study (2 months PFS rate of 84%). Loss-of-function mutations in tumor suppressor genes were frequently detected as co-mutations at baseline.
Clinical trial information: EudraCT: 2020-003283-10
.
Nelmastobart (hSTC810) combined with capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A phase 1b clinical trial.
Authors: Lee Soohyeon , Lee Jiwon , Kim Jwa Hoon , Sim Jong Min , Kim Boyeon , Hong Bong-Ki , Jung Hyunjin , Yoo Stephen S.
Published: January 2025

162

Background:
Treatment options for patients with metastatic colorectal cancer (mCRC) who experienced disease progression after receiving oxaliplatin and irinotecan-based chemotherapy are limited. Nelmastobart (hSTC810), a humanized anti-BTN1A1 (butyrophilin subfamily 1 member A1) monoclonal antibody of the IgG4 isotype, showed acceptable safety profile and the disease control rate was 39.3% in the first-in-human study, suggesting its potential efficacy. This phase Ib study was designed to evaluate the safety and explore synergistic anti-tumor activity of nelmastobart in combination capecitabine. The study aims to determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination therapy in patients with mCRC who are refractory to standard therapy.
Methods:
Dose escalation phases were conducted in patients with mCRC who were administered orally twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) and nelmastobart (400mg, 800mg intravenously every 3 weeks). Standard "3 + 3" dose escalation was used to define the MTD. In this phase 1b, 12 participants enrolled between February 5 2024 and June 11 2024 were 18 years of age or older with mCRC previously treated oxaliplatin and irinotecan in the metastatic setting.
Results:
The first 3 patients at the dose level 0 (nelmastobart 400mg, capecitabine 1,000 mg/m
2
twice daily) and level 1 (nelmastobart increased to 800 mg, capecitabine 1,000mg/m
2
twice daily) had no dose-limiting toxicities (DLTs). In dose level 2 (nelmastobart 400mg, capecitabine 1,250mg/m
2
twice daily), 2 of 3 had DLTs (grade 3 hand-foot syndrome), which were attributed to capecitabine. When dose level 2 was expanded to 3 additional patients, 2 more patients experienced DLTs (grade 3 mucositis and hand-foot syndrome). Consequently, the combination of nelmastobart 800 mg once every three weeks and capecitabine 1,000 mg/m² twice daily (2 weeks on 1 week off) was established as the MTD/RP2D in patients with mCRC. The most common AEs were hand-foot syndrome (n=4), nausea (n=3) and stomatitis (n=2) which were related with capecitabine. Four patients experienced grade 1 fatigue, which was considered to be related to nelmastobart. Two patients (16.7%) out of 12 showed partial response and 8 patients have maintained stable disease for more than 4 months among 9 patients who had a median follow-up of more than 4 months (as of August 30).
Conclusions:
The combination of hSTC810 and capecitabine is well tolerated at the MTD, without unexpected AEs and shows promising antitumor activity in patients with heavily treated mCRC. The phase 2 study is currently in progress.
Clinical trial information: NCT0599054
.
Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.
Authors: Liao Wangjun , Shi Min , Rong Xiaoxiang , Zheng Siting , Li Shaowei , Peng Weiwei , Wang Xiangcai , Yuan Xia , Zeng Wei , Wang Chunlin , Deng Qiong , Zhang Futing
Published: January 2025

166

Background:
Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290).
Methods:
Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m
2
, orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety.
Results:
At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance.
Conclusions:
Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC.
Clinical trial information: NCT05659290
.
Seven-year efficacy and safety in a randomized phase III trial investigating duration of adjuvant oxaliplatin-based therapy (3 vs. 6 months) for patients with high-risk stage II colon cancer: ACHIEVE-2 trial.
Authors: Sunami Eiji , Yamazaki Kentaro , Shiozawa Manabu , Manaka Dai , Kotaka Masahito , Sakamoto Yasuhiro , Shiomi Akio , Shinohara Yudai , Munemoto Yoshinori , Rikiyama Toshiki , Fukunaga Mutsumi , Ueki Takashi , Shitara Kohei , Yamada Jun , Tanida Nobuyuki , Misumi Toshihiro , Ohtsu Atsushi , Maehara Yoshihiko , Yoshino Takayuki
Published: January 2025

169

Background:
ACHIEVE-2 was conducted as one of four phase III trials for patients with high-risk stage II colon cancer (CC) investigating the duration of adjuvant (adj) oxaliplatin-based therapy in a prospective pooled analysis, IDEA collaboration. The results of the 7-year follow-up are presented here.
Methods:
From Feb 2014 to Jan 2017, 525 Asian patients with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation, or vascular invasion) were randomly assigned to 3- or 6-month mFOLFOX6/CAPOX treatment after curative surgery. The cutoff date for the data was Jan 2024.
Results:
Of the 525 randomized patients, 11 were not treated. Among the 514 participants (255 in the 3-month arm; 259 in the 6-montharm), 432 (84%) received CAPOX and 184 (36%) presented with T4 as a high-risk factor for recurrence. The baseline characteristics of the patients in each arm were well balanced between the treatment arms and two therapy regimens. The 7-year disease-free survival (DFS) rates were 83.4% and 81.8% in the 3- and 6-month arms, respectively (hazard ratio [HR]= 1.00 [95% CI, 0.66-1.53]). The 7-year overall survival (OS) rates were 88.4% and 88.8% in the 3- and 6-month arms, respectively (HR= 1.16 [95% CI, 0.70-1.93]). With CAPOX, the HR for DFS and OS of the 3-month arm compared with the 6-month arm were 0.97 (95% CI, 0.61-1.52) and 1.09 (95% CI, 0.64-1.89), respectively. Multivariate analysis of the six high-risk factors for recurrence showed that T4 and inadequate nodal harvest were independent risk factors for both DFS and OS. The rates of any grade of peripheral sensory neuropathy (PSN) lasting up to 96 months in the 3- vs. 6-month arms were 7.9% vs. 25.0% (
P=
0.0189
). With CAPOX, the incidence of PSN lasting up to 96 months in the 3- vs. 6-month arms were 9.4% vs. 27.5%.
Conclusions:
The incidence of long-lasting PSN was significantly lower at 3 months than at 6 months of therapy. Three months of CAPOX therapy may be appropriate for high-risk stage II CC, as shorter treatment did not worsen the outcome, even after a long follow-up.
Clinical trial information: UMIN000013036
.
A phase 1 dose-escalation study of GCC19CART: A novel CAR T-cell therapy for metastatic colorectal cancer in the United States.
Authors: Keenan Bridget P. , Lieu Christopher Hanyoung , Fakih Marwan , Venook Alan P. , Chen Dongqi , Rowinsky Eric Keith , Lu Victor , Xiao Lei , Schlechter Benjamin L.
Published: January 2025

175

Background:
GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, pairs solid tumor CAR T-cells with CD19-targeting CAR T-cells to enhance proliferation, activation, and persistence against solid tumors. GCC19CART targets guanylate cyclase-C (GCC), a known mucosal marker. Building on the promising results from a clinical trial in China, a phase 1 study was initiated in the US for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy. As of August 14, 2024, a total of 9 subjects have been treated.
Methods:
Subjects were initially screened for GCC expression, however screening was discontinued after >95% of subjects with mCRC demonstrated GCC expression by immunohistochemistry (95/98). Eligible subjects underwent leukapheresis, lymphodepleting chemotherapy (fludarabine 30mg/m
2
and cyclophosphamide 300mg/m
2
on day-3), and then infusion of a single dose GCC19CART. Objective response was assessed by RECIST v1.1.
Results:
Four subjects have been enrolled at dose level 1 (1x10
6
cells/kg) and 5 subjects at dose level 2 (2x10
6
cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 9/9 subjects (Grade 1: 6/9 [66.7%] and Grade 2: 3/9 [33.3%]) and diarrhea in 8/9 subjects (Grade 1: 3/9 [33.3%], Grade 2: 3/9 [33.3%], Grade 3: 2/9 [22.2%]). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2/9 subjects (Grade 2: 1/9 [11.1%] or Grade 3: 1/9 [11.1%]) and resolved rapidly with corticosteroid and dasatinib treatment. Three out of 9 subjects had a mild tremor (Grade 1) that resolved with corticosteroids. One subject experienced a dose-limiting toxicity (DLT) at dose level 2, presenting with Grade 3 diarrhea, Grade 4 enterocolitis and Grade 5 sepsis, and died from fungal sepsis 48 days post-infusion. At dose level 1, the overall response rate (ORR) was 50.0% (2/4). Two subjects demonstrated a partial response (PR) with one confirmed PR, while 1 additional subject had partial metabolic response on PET/CT with stable disease (SD) and 1 patient had progressive disease. At dose level 2, the ORR was 80% (4/5), including 1 subject with a pathological complete response, and 3 with a confirmed partial response, of which 1 had a complete metabolic response on PETCT.
Conclusions:
Preliminary results indicate that GCC19CART exhibits significant clinical activity in patients with refractory mCRC. Adverse events were related to GCC19CART mechanism and in line with what has been observed with other CAR T-cell products. Strategies to further optimize the management of treatment-related diarrhea are currently being implemented. The trial is ongoing and updated data will be presented.
Clinical trial information: NCT05319314
.