bluuebunny/crossref_metadata_2025 huggingface dataset:
Commonly prescribed medications and risk of pneumonia and all-cause mortality in people with idiopathic pulmonary fibrosis: a UK population-based cohort study
Authors: Morgan Ann D. , Massen Georgie M. , Whittaker Hannah R. , Stewart Iain , Jenkins Gisli , George Peter M. , Quint Jennifer K.
Published: January 2025

Background

A growing body of evidence suggests that prolonged use of inhaled corticosteroids (ICS) and proton pump inhibitors (PPIs) is associated with increased risks of pneumonia. A substantial proportion of people with idiopathic pulmonary fibrosis (IPF) are prescribed PPIs or ICS to treat common comorbidities, giving rise to concerns that use of these medications may be associated with potential harms in this patient population.

Methods

We used UK Clinical Practice Research Datalink (CPRD) Aurum primary care data linked to national mortality and hospital admissions data to create a cohort of people diagnosed with IPF on or after 1 January 2010. Patients were assigned to one of three exposure categories according to their prescribing history in the 12 months prior to IPF diagnosis as follows: “regular” users (≥ 4 prescriptions), “irregular” users (1–3 prescriptions) and “non-users” (no prescriptions). We explored the association between PPI/ICS prescription and pneumonia hospitalisation and all-cause mortality using multinomial Cox regression models.

Results

A total of 17,105 people met our study inclusion criteria; 62.6% were male and 15.9% were current smokers. Median age at IPF diagnosis was 76.7 years (IQR: 69.6–82.7). 19.9% were regularly prescribed PPIs, and 16.0% ICS, prior to IPF diagnosis. Regular prescribing of PPIs and ICS was positively associated with hospitalisation for pneumonia; the adjusted HR for pneumonia hospitalisation comparing regular PPI users with non-users was 1.14 (95%CI: 1.04–1.24); for regular ICS users the corresponding HR was 1.40 (95%CI: 1.25–1.55). We also observed a small increased risk for all-cause mortality in the “regular ICS user” group compared with the “non-user” control group (HRadj = 1.19, 1.06–1.33). We found no evidence of an association between PPI prescribing and all-cause mortality.

Conclusion

Prolonged prescription of medications used to treat common comorbidities in IPF may be associated with increased risks for severe respiratory infections. These findings point to a need to adopt an adequate risk–benefit balance approach to the prescribing of ICS-containing inhalers and PPIs in people with IPF without evidence of comorbidities, especially older patients and/or those with more advanced disease in whom respiratory infections are more likely to result in poorer outcomes.
Angus: efficient active learning strategies for provenance based intrusion detection
Authors: Wu Lin , Xie Yulai , Li Jin , Feng Dan , Liang Jinyuan , Wu Yafeng
Published: January 2025

As modern attack methods become more concealed and complex, obtaining many labeled samples in big data streams is difficult. Active learning has long been used to achieve better intrusion detection performance by using only a small number of training samples. Intrusion behaviors can be described by provenance graphs that record the dependency relationships between intrusion processes and the infected files. It is a challenge to develop active learning strategies that consider defining and selecting the most valuable provenance and ensure that the strategy for querying provenance is efficient. We present Angus, an active learning framework for provenance-based intrusion detection. We propose two novel active learning strategies: the most similar graph query strategy and the maximum difference query strategy. They either select samples to update the training set according to similarities of provenance graphs or preferentially select samples with low redundancy and large differences from the current training set. Besides, we also improve the above query strategies by using the parallel query to reduce detection time overheads. The experiments on various real-world applications demonstrate their performance and efficiency.
Pyrogallol acts as a novel anticancer factor to enhance the sensitivity to cisplatin in ovarian cancer cells through inducing miR-15a upregulation
Authors: Shirani Azin , Mirabbasi Razieh , Shabani Leila , Reiisi Somayeh
Published: January 2025

Introduction

Pyrogallol is a catechin compound, as an active ingredient extracted from Emblica officinalis, has antiproliferative and antiapoptotic effects on some of the human cancer cells. Cisplatin is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and apoptosis. However, the effect of pyrogallol alone and in combination with cisplatin on proliferation and apoptosis of ovarian cancer has not yet been reported.

Methods

In the present study, ovarian carcinoma cell line A2780 was cultivated, and the anticancer properties of pyrogallol and cisplatin determined by cell treatment of the two drugs separately and combination. Cell viability and apoptosis rate was investigated by MTT assay and flow cytometry. The effects of the compounds in inhibiting colony formation and migration were measured by colony formation and scratch methods.

Results

The results of the present study revealed that pyrogallol significantly inhibited the proliferation of A2780 cells in a dose-dependent manner. The combination treatment of pyrogallol and cisplatin exhibited a prominent inhibitory effect on the growth, colony formation and migration, and increased the induction of apoptosis up to 2.5 times compared to single treatments. Also, the qPCR results showed a significant increase in the expression of miR-15a and a decrease in the expression of miRNA target genes under treatment with the drugs both separately and in their combination.

Conclusion

This study suggests that the combination treatment of pyrogallol and cisplatin significantly increases the death of ovarian cancer cells by inducing apoptosis. Therefore, it can boost the efficacy of chemotherapy and reduce its side effects. It is hoped that the findings of the present study can provide a new perspective for pyrogallol as a therapeutic agent in the treatment of ovarian cancer.
Sustainable digital leap: a bibliometric study on its impact on human learning and organizational development in the MENA region
Authors: Singh Ajay
Published: January 2025

The study aims to explore how sustainable digital transformation affects human learning and organizational development in MENA region using bibliometric analysis. The researchers used Scopus and WOS databases for data extraction. The researcher analyzed the cumulative data using performance analysis, and scientific mapping with VOS Viewer software. The findings indicated that Blau, I from Israel is the leading author, King Faisal University from Saudi Arabia is the most productive institution, “International Journal of Emerging Technologies in Learning” is the most productive journal, and “Investigating users’ perspectives on e-learning: An integration of TAM and IS success” is the highly cited article in target domain. Furthermore, the scientific mapping indicated that Saudi Arabia has highest co-author country collaboration. Finally, E-learning is the high co-occurred keyword because of collaborative research from MENA region for the subject. The study provides most productive author, institutions, journal, articles, country, and keyword in order to understand the literature for the impact of sustainable digital transformation on human learning and organizational development from MENA region.
How to improve psychiatric nosography in the XXI century: a phenomenologist”s viewpoint
Authors: Stanghellini Giovanni
Published: January 2025

Classifications of mental disorders reflect much more the minds of psychiatrists than the patients’ minds since these classifications are more focused on the interests of stakeholders (including governmental agencies, advocacy groups, medical insurance, and pharmaceutical companies) than on the experiences of patients. We live in times of rapid socio-cultural changes, and respective changes in the forms of mental suffering are increasingly characterized by fragmentariness and episodicity. These new forms of suffering may escape nosographic framing based on the identification of symptoms and syndromes. A paradigm shift in the psychiatric nosography is necessary. The way forward could be to enhance the ability of clinicians to grasp the “fragments” provided by patients rather than aggregations of symptoms. “Existential knots” can manifest themselves in these fragments to be used as “floating buoys” for clinical navigation, in the absence of exhaustive and detailed “maps” of the symptoms and syndromes that afflict patients. A tentative collection of these existential knots is provided, building on and extending the legacy of existential philosophy and phenomenological psychopathology.
The TAB-EOAO study: Trends in use and benefit of adjuvant chemotherapy between early onset and average onset locally advanced colon cancer.
Authors: Bernabe Carolina , Orkoulas Razis Dennis , Moon Jee-Young , Zhang Chenxin , Choi Jihoon John , Laderian Bahar , Bteich Fernand , Kuang Chaoyuan , Saenger Yvonne M. , Kaubisch Andreas , Anampa Jesus Del Santo
Published: January 2025

105

Background:
Despite the declining incidence rates (IR) in average onset colon cancer (AO-CC), IR for early onset colon cancer (EO-CC), defined as patients (pts) younger than 50-years-old at diagnosis, has been increasing. Treatment for high risk locally advanced colon cancer (CC) is surgical resection followed by adjuvant chemotherapy (AC). Data indicates a more permissive chemotherapy use in EO-CC. There is limited data about treatment and survival trends in EO-CC. Thus, we aimed to assess the use and benefit of AC between in EO vs AO CC in locally advanced disease.
Methods:
CC diagnosed between 2000-2020 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. Eligible pts were adults (≥18), Stage II or III at diagnosis. Stage II disease was further stratified as low risk (pT1-3) and high risk (pT4). Logistic regression methods were used to assess Odds Ratio (OR) of AC between EO-CC and AO-CC; Cox models were used to compare overall survival (OS) and Cancer-specific survival (CSS) between both groups during 2000-2010 and 2011-2020.
Results:
Our study included 136,676 pts (AO-CC= 121,606; EO-CC =15,070). The median age for EO-CC was 44 years versus 71 years for AO-CC population. The use of AC increased over time for both the EO-CC (63% vs 66%) and AO-CC (33% vs 40%). Moreover, pts with AO-CC received less AC than EO-CC in the entire study time (see table). In pts with AO-CC, AC improved CSS (HR=0.69 for 2000-2010, HR=0.50 2011-2020). However, among those with EO-CC, AC improved CSS in 2011-2020 (HR=0.76) but did not improve CSS in 2000-2010 (HR=1.02).
Conclusions:
Over the past 20 years EO-CC has been managed aggressively, especially for stage II low risk patients where current guidelines do not support the use of AC. In this real world data set we show that for EO-CC AC did not improve CSS in the decade 2000- 2010 but did improve CSS in the 2011- 2020 period. Further analysis may clarify stage specific benefits of AC. There clearly remains a need for better risk stratification, including the use of ctDNA, to identify the subpopulations of EO-CC patients that will best benefit from AC.

Multivariable logistic regression model of chemotherapy by timeframe with interaction term: Age* stage.

2000-2010
2011-2020

AO-CC vs EO-CC

OR

95% CI

OR

95% CI

Stage II low risk
0.23
(0.21, 0.26)
0.28
(0.24, 0.32)

Stage II high risk
0.28
(0.22, 0.36)
0.28
(0.21, 0.36)

Stage III
0.36
(0.32, 0.4)
0.30
(0.26, 0.34)
Sex differences in toxicities and survival outcomes among patients with stage III colorectal cancer receiving adjuvant fluoropyrimidine monotherapy: A pooled analysis of four randomized controlled trials (JCOG2310A).
Authors: Hirano Hidekazu , Kataoka Kozo , Yamaguchi Toshifumi , Wagner Anna Dorothea , Shimada Yasuhiro , Inomata Masafumi , Hamaguchi Tetsuya , Takii Yasumasa , Mizusawa Junki , Sano Yusuke , Shiomi Akio , Shiozawa Manabu , Ohue Masayuki , Adachi Tomohiro , Ueno Hideki , Ikeda Satoshi , Komori Koji , Tsukamoto Shunsuke , Takashima Atsuo , Kanemitsu Yukihide
Published: January 2025

116

Background:
Fluoropyrimidine agents are the key component of adjuvant chemotherapy for pathological stage III colorectal cancer (CRC). Western studies have shown that female sex is associated with favorable survival outcomes after surgery, yet a risk factor for fluoropyrimidine-related adverse events (AEs) during adjuvant chemotherapy. However, it remains unclear whether there are sex differences in the treatment outcomes in this setting among the Japanese population.
Methods:
Patients enrolled in four randomized controlled trials (JCOG0205, JCOG0404, JCOG0910, and JCOG1006) who received adjuvant fluoropyrimidine monotherapy for pathological stage III CRC were analyzed. Incidences of AEs and survival outcomes (relapse-free survival [RFS], and overall survival [OS]) were compared between males and females. Multivariable logistic regression analyses were performed to evaluate associations between sex and the development of AEs. Multivariable Cox regression analyses were performed using Cox proportional hazard models to evaluate associations between sex and survival outcomes.
Results:
A total of 3170 patients (male, n = 1654; female, n = 1516) were included in the analysis. Compared with male patients, female patients were more likely to require dose reduction (male, 20.4%; female: 28.8%, p < 0.0001) and had low completion proportions of adjuvant chemotherapy (male, 81.7%; female, 77.0%, p = 0.0011). Female patients experienced higher incidences of any-grade hematological and non-hematological AEs (Table). Female sex was associated with higher incidences of grade 3/4 hematological AEs (odds ratio [OR]: 1.702 [95% CI 1.272–2.278], p = 0.0003) and non-hematological AEs (OR: 1.666 [95% CI 1.373–2.020], p < 0.0001). Female sex was identified as a favorable prognostic factor for RFS (hazard ratio [HR]: 0.729 [0.627–0.848], p < 0.0001) and OS (HR: 0.796 [0.653–0.970], p = 0.0238).
Conclusions:
Sex differences had implications for the development of AEs and survival outcomes of Japanese patients with pathological stage III CRC who received adjuvant fluoropyrimidine monotherapy.

Incidences of adverse events.

Adverse event
Any grade

Grade 3/4

Male% (95% CI)
Female% (95% CI)
p-value

Male% (95% CI)
Female% (95% CI)
p-value

Any hematological toxicity
63.7 (61.3–66.0)
83.9 (82.0–85.8)
<0.0001

5.0 (4.0–6.1)
8.9 (7.5–10.4)
<0.0001

Any non-hematological toxicity
93.3 (92.0–94.5)
96.1 (95.0–97.0)
0.0006

13.3 (11.7–15.1)
20.8 (18.8–22.9)
<0.0001
The crossover of the bevacizumab and panitumumab survival curves in the PARADIGM study: A clue to time-related effects of bevacizumab on the risk of tumor progression.
Authors: Aderka Dan , Muro Kei , Yoshino Takayuki
Published: January 2025

159

Background:
The PARADIGM study in CRC patients demonstrated a cross over of the bevacizumab survival curve below the panitumumab survival curve at 28 months, followed by a steady decrease of the bevacizumab survival curve below the panitumumab survival curve up to 11% by 5 years. Similar differences were seen in the FIRE3, CALGB-80405 and PEAK trials starting at 20 months, suggesting an unsuspected time-related effect of bevacizumab on patient’s survival starting at about 2 years after its 1st administration.
Methods:
Review of time related effects of bevacizumab in 1st and 2nd line trials conducted in CRC, breast, ovary and renal cancer showed a significant PFS but no OS survival benefit, with a detrimental effect on survival in the adjuvant setting (AVANT, NSABP-08 studies). Preclinical data on tumor biology, intratumor-heterogeneity, clonal evolution and the cross talk between bevacizumab and the diverse tumor microenvironments, was correlated to the clinical data, in an attempt to explain the time-related effects of the biological.
Results:
In the NSABP-08 trial, bevacizumab reduced relapse for 6 months, effect diminished and lost at 12 months. At 24 months after bevacizumab's 1st administration, the relapse of the bevacizumab treated population increased steadily over the control. Identical kinetics were shown in AVANT study and metastatic ovarian patients suggesting that these time-related effects of bevacizumab are universal. The biologic explanation of the clinical data is that short-term treatment with bevacizumab (plus chemotherapy) induces initial tumor stasis and shrinkage, followed by selection and emergence of more aggressive and resistant tumor clones, characterized by an accelerated growth, invasiveness and metastasis shifting the overall tumor growth kinetics to a steeper angle. Bevacizumab appears to be effective for the time of its administration, followed by a slow rebound after its discontinuation. The initial survival benefit will be lost at about 20-24 months after its first administration, as clearly demonstrated in the PARADIGM, FIRE-3, CALGB 80405 and the PEAK studies.
Conclusions:
As bevacizumab benefit persist for about 2 years after its 1
st
administration, it explains the "survival benefit" obtained in studies with with median survival of 20 months but not in studies with survivals >30 mo. (PARADIGM, FIRE-3, CALGB 80405 and the PEAK). This phenomenon also explains the crossover of the survival curves in PARADIGM study and the benefits of bevacizumab obtained preferentially in patients with short survival (rt. sided tumors), high tumor burden, and 2
nd
and 3
rd
line CRC.
Dual versus single immune checkpoint blockade for patients with metastatic colorectal cancer harboring microsatellite instability: The Saint-Antoine immunoMSI score.
Authors: Jehanno Léa , Cohen Romain , Loisel Camille , Samaille Thomas , Cervantes Baptiste , Colle Raphael , Henriques Julie , Vernerey Dewi , Andre Thierry
Published: January 2025

168

Background:
Anti-PD1 monotherapy (mono) and anti-PD1 plus anti-CTLA4 therapies (combo) are validated for metastatic colorectal cancer (mCRC) harboring microsatellite instability and/or mismatch repair deficiency (MSI/dMMR). We aimed at assessing the efficacy of combined anti-CTLA4 and anti-PD1 blockade versus anti-PD1 monotherapy and identifying which subgroups benefit more from the combo.
Methods:
All patients (pts) with MSI/dMMR mCRC treated by anti-PD1 ± anti-CTLA4 included in the prospective monocenter immunoMSI cohort were analyzed. The choice between monotherapy or combination therapy varied according to open studies and regulatory approvals, without taking pt characteristics into account. Datalock date was April 23, 2024. Main endpoints were progression-free survival (PFS) per iRECIST and overall survival (OS) estimated with the Kaplan-Meier method. Univariate Cox proportional hazards models were used to estimate hazard ratios with CI. The interactions between studied subgroups and the treatment group were modelized by adding in a single Cox model the studied subgroups, the treatment group parameters, and their interaction term.
Results:
Among 210 pts, 97 were treated combo and 113 with mono. Baseline characteristics were similar in both groups. 25% and 17% were in first line, respectively. Median follow-up was 4.4 years: 4.1 years for combo and 5.4 years for mono. Combo was associated with better PFS (HR=0.48; 95%CI 0.31-0.76) and OS (HR=0.49; 0.29-0.84). Best observed response rates were: 78% of objective responses, 17% of stable diseases and 5% disease progressions with combo versus 60%, 25% and 15% with mono. Subgroup analyses showed significant differential effect of the treatment group for gender (PFS HR=0.21 vs 0.87 for females and males, P-interaction: 0.0067), liver metastases (PFS HR=0.30 vs 0.79 for pts without liver mets and those with liver mets, P-interaction: 0.0479) and sidedness (PFS HR=0.27 vs 0.64 for left-sided and right-sided mCRC, P-interaction=0.0922), but not
RAS
/
RAF
mutations. We computed a predictive score based on gender (female: 2 points), no liver met (1 point) and left side (1 point). PFS HR was 0.1 (0.03-0.33) for the group ≥3 points (N=67), 0.66 (0.36-1.23) for the group with 1-2 points (N=113) and 1.54 (0.50-4.70) for the group with 0 point (N=30).
Conclusions:
Combined CTLA4 and PD1 blockade is associated with improved PFS and OS compared to anti-PD1 alone in MSI/dMMR mCRC. The subgroup deriving the highest benefit of the combo seems to be female pts with left sided tumor and no liver met. Data from the randomization between nivolumab versus nivolumab + ipilumumab in the CheckMate-8HW phase III study are expected.
Liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab as second-line therapy in metastatic colorectal cancer (IRIS): A multi-center, single-arm, prospective, phase II study.
Authors: Hu Xuhua , Jiang Bo , Hongxia Lu , Yu Bin , Yi Bo , Wang Yudong , Zhu Lingjun , Li Shengmian , Li Baokun , Kong Dalu , Wang Zhiwu , Niu Wenbo , Ma Hongqing , Wang Shanchuan , Chen Yanglin , Lin Chao , Yang Rong , Zhu Weiyou , Liu Jia , Wang Guiying
Published: January 2025

195

Background:
In patients with advanced colorectal cancer (CRC), the recommended second-line treatment following first-line therapy with oxaliplatin-based regimens is irinotecan-based therapy. Liposomal irinotecan, a novel formulation of traditional irinotecan, has demonstrated potential to enhance efficacy while minimizing toxicity. This study aims to investigate the efficacy and safety of liposomal irinotecan in combination with 5-FU/LV and bevacizumab as a second-line treatment option for metastatic CRC.
Methods:
This is a multi-center, single-arm, prospective, phase II study. Patients with metastatic CRC who received oxaliplatin-based chemotherapy as first-line treatment were enrolled to receive liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab regimen until disease progression and/or unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Results:
A total of 50 patients were enrolled from Jan 2024 to Jul 2024 across 6 sites in China. The median age was 56.5 years (range: 30.0-76.0), with 58.0% male and 36.0% ECOG 0. Among the patients, 38.0% had left-sided colon cancer, 24.0% had right-sided colon cancer, and 38.0% had rectal cancer. As of Sept 14, 2024, 39 patients had at least one tumor assessment and 19 patients were still on treatment. ORR and DCR were 20.5% (8/39, 95% CI: 9.3%-36.5%) and 84.6% (33/39, 95% CI: 69.5%-94.1%), respectively. Eleven patients had disease progression and 5 patients died, and the median PFS and OS were not reached. The relative dose intensity of liposomal irinotecan and 5-fluorouracil were 92.8% (range: 23.6%-109.6%) and 89.5% (range: 13.3%-116.8%), respectively. During treatment, 43 (86.0%) patients had at least one adverse event (AE) and 24 (48.0%) had grade 3-4 AE. Most common (≥ 10%) grade 3-4 AEs were neutropenia (20.0%), leukocytopenia (16.0%) and diarrhea (10.0%). No unexpected toxicities observed in this study.
Conclusions:
These preliminary results reveled that liposomal irinotecan + 5-fluorouracil + leucovorin + bevacizumab after oxaliplatin-based treatment for metastatic CRC was well tolerated with encouraging clinical activity, which warrants further follow up.
Clinical trial information: NCT06184698
.
Real-world outcomes of targeted therapies and local interventions in BRAF V600E–mutated metastatic colorectal cancer: A single-center retrospective study.
Authors: Lin Ziqin , Xie Xiaoyu , Zhang Jianwei , Hu Huabin , Ling Jiayu , Cai Yue , Wu Zehua , Deng Yanhong
Published: January 2025

203

Background:
Metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations, especially those with microsatellite stable (MSS) tumors, have poor prognoses. Chemotherapy has limited efficacy in this subgroup, especially for second-line or subsequent-line treatments. Current research is increasingly focusing on the integration of targeted therapies and local interventions, but real-world evidence remains scarce, particularly from Asian cohorts. This study leverages real-world data to evaluate the impact of novel therapeutic combinations, including triplet and doublet targeted therapies, alongside local treatments in this high-risk patient population.
Methods:
This retrospective study includes MSS-type mCRC patients with BRAF V600E mutations treated at the Sixth Affiliated Hospital of Sun Yat-sen University between April 2014 and May 2024. Patients receiving targeted therapies were stratified into three groups: Triplet group (BRAF, EGFR, and MEK inhibitors, including Dabrafenib, Cetuximab and Trametinib), Doublet group (BRAF and EGFR inhibitors, including Dabrafenib and Cetuximab or Encorafenib and Cetuximab), and Doublet target-chemotherapy group (BRAF and EGFR inhibitors combined with chemotherapy, including Vemurafenib, Irinotecan, and Cetuximab). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and objective response rate (ORR).
Results:
Among 239 enrolled patients, 58 received targeted therapy and 68 underwent conventional chemotherapy as second-line treatment. 63.5% (80/126) of these patients underwent local interventions, including primary tumor resection, metastasectomy, CRS±HIPEC, and liver ablation. Targeted therapy demonstrated significantly improved mPFS compared to conventional chemotherapy (5.5 vs. 4.2 months, HR = 0.44; 95% CI: 0.29-0.68, p < 0.001). OS did not differ significantly between the two treatment arms (12.7 vs. 12.1 months, HR = 0.80; 95% CI: 0.50-1.25, p = 0.330). In the triplet group, ORR, mPFS, and mOS were 21%, 5.8 months and 18.0 months, respectively, showing a trend towards enhanced efficacy compared to the other targeted therapy groups, albeit without statistical significance. Patients who received targeted therapy (n=35) or chemotherapy (n=45) in combination with local interventions demonstrated significantly prolonged OS compared to those without local therapy (mOS: 22.3 vs. 9.6 months; HR = 0.19; 95% CI: 0.09-0.42; p < 0.001 and 14.3 vs. 10.9 months; HR = 0.53; 95% CI: 0.29-0.98; p = 0.042, respectively).
Conclusions:
Optimal treatment for BRAF V600E mCRC remains under investigation. This study suggests that combining targeted therapies with selective local interventions may significantly improve patient survival in this challenging subgroup, warranting further prospective evaluation.
The importance of treatment handling and compliance on overall response rate in a phase III study of metastatic colorectal cancer: Post-hoc per protocol analyses of the AGENT trial.
Authors: Pivodic Aldina , Carlsson Göran , Hjalmarson Åke
Published: January 2025

205

Background:
To study the compliance in handling the investigational medicinal product (IMP) and its impact on outcomes in patients with metastatic colorectal cancer participating in the AGENT trial (NCT03750786).
Methods:
In a randomized, multicenter, multinational, phase III study, patients were randomized to receive either arfolitixorin (n=245) or leucovorin (n=245) with 5-fluorouracil (5-FU), oxaliplatin and bevacizumab as a first-line treatment. Logistic regression was applied for overall response rate (ORR) and Cox regression for all-cause death, and all-cause death or progression, adjusted for randomization strata.
Results:
Missing or incorrect IMP handling was reported for 28 (11%) patients in the arfolitixorin and 23 (9%) in the leucovorin arm, <80% compliance for duration of bolus 5-FU 2-4min for 101 (42%) and 97 (41%), respectively. Considering the time between the bolus 5-FU and arfolitixorin, non-compliance, defined by <80% doses given within 25-35min PP window, was reported for 92 (38%) in arfolitixorin patients. Adherence to the timing between the first and second arfolitixorin dose (30-60min) was high. In total, 91 (37%) patients in the arfolitixorin and 134 (55%) in the leucovorin arm fulfilled PP definitions (cPP population). The bolus 5-FU dose was equally likely to be reduced in both the arfolitixorin and leucovorin arms across regions (ranging from 22% to 39%), except for Japan where 55% of patients in the arfolitixorin arm had their bolus 5-FU dose reduced, compared to 28% in the leucovorin arm. In the cPP population, the ORR was achieved by 54 (59%) in the arfolitixorin and 69 (51%) in the leucovorin arm, adjusted odds ratio (aOR) 1.40 (95% CI 0.81-2.45), p=0.23. Excluding Japan, the ORR was 41 (62%) in the arfolitixorin and 49 (46%) in the leucovorin arm, aOR 2.11 (95% CI 1.09-4.06), p=0.026. Corresponding aOR for Europe was 1.50 (95% CI 0.71-3.15), p=0.29, and for North America aOR 7.95 (95% CI 1.45-43.62), p=0.017. In Japan, the ORR had better outcome in the leucovorin arm (71.4%) compared to the arfolitixorin arm (52.0%), aOR 0.42 (95% CI 0.13-1.31), p=0.14. However, the relationship was numerically opposite for patients without bolus 5-FU dose reduced. All-cause death during the complete follow-up was reported for 37 (41%) in the arfolitixorin and 61 (46%) in the leucovorin arm.
Conclusions:
In the AGENT trial, 46% of the included patients met per protocol compliance for treatment handling. In this cPP population, there was a non-significant, but clinically relevant, increase in the overall response rate in the arfolitixorin compared to the leucovorin arm. Notably, in all regions excluding Japan, the overall response rate was higher for arfolitixorin, with statistical significance. Adherence to the treatment protocol is crucial for the outcomes of patients with metastatic colorectal cancer.
Clinical trial information: NCT03750786
.
Outcomes in management of locally advanced rectal cancer with total neoadjuvant therapy in an underserved population.
Authors: Ganguly Arup , Paladiya Ruchir , Ingawale Sushrut , Giri Suprabhat , Abbagoni Vaidarshi , Thumar Jaykumar Ranchodbhai
Published: January 2025

208

Background:
The use of total neoadjuvant therapy is now standard of care and is favored when treating locally advanced rectal cancer but its treatment is seldom studied in an underserved population.
Methods:
A retrospective study was conducted on patients with Stage II and III locally advanced colorectal cancer treated with either total neoadjuvant therapy (TNT) followed by resection or conventional therapy (CT) with chemoradiation followed by surgery, with or without adjuvant treatment afterwards. Patients completed treatment between 2015 and 2023 at the Hartford Hospital Helen and Harry Gray Cancer Center at Hartford, Connecticut. Data collected included demographics, type of treatment, tumor location (high vs mid vs low) and pathological response to treatment spread out among the two groups. Propensity score matching was used to minimize baseline differences between the two groups, adjusted for age, gender, ethnicity and tumor location and Fisher’s exact test was performed to then check for significance.
Results:
Out of the 133 patients analyzed, 90 underwent TNT, and 43 received CT. The average age at diagnosis was 57.5 years (SD: 11.15). In the TNT group, 79 patients (87.7%) achieved either a partial or complete response (PCR), while 11 patients (12.3%) had No response (NR). Tumor locations in the TNT group were distributed as follows: 13.4% (n=12) had high tumors, 34.4% (n=31) had mid tumors, and 52.2% (n=47) had low tumors. In the CT group, 31 patients (72.9%) achieved PCR, while 12 patients (27.9%) had NR. Tumor locations in the CT group were distributed as follows: 9.3% (n=4) had high tumors, 51.2% (n=22) had mid tumors, and 39.5% (n=17) had low tumors. After propensity score matching and adjusting for demographic covariates, the TNT group demonstrated a higher proportion of responders compared to the CT group (p=0.048). Furthermore, 40% (n=36) of patients in the TNT group achieved a complete response, compared to 32% (n=14) in the CT group. Partial response rates were 39.5% (n=17) in the TNT group and 47.8% (n=43) in the CT group.
Conclusions:
TNT demonstrated superior pathological response rates compared to CT, which supports its growing role in the management of locally advanced rectal cancer even in this underserved population.
Efficacy of plogosertib (CYC149462), a novel orally bioavailable PLK1 inhibitor, on patient-derived models of colorectal cancer.
Authors: Zokaasadi Mohammad , Watlington Wylie K , Dayanidhi Divya Lakshmi , Rupprecht Gabrielle , McCall Shannon J. , Schwartz Brian , Somarelli Jason A. , Hsu Shiaowen David
Published: January 2025

209

Background:
Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC.
Methods:
Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining.
Results:
CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC
50
values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings
in vivo
using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05).
Conclusions:
Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.
Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.
Authors: Ando Koji , Ebata Yuho , Oki Eiji , Yoshizumi Tomoharu , Bharti Ajit
Published: January 2025

217

Background:
Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance.
Methods:
We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment.
Results:
Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice.
Conclusions:
Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.
Diverse stromal phenotypes at spatial resolution in colorectal cancer peritoneal metastasis.
Authors: Zhao Joseph J , Ong Johnny Chin-Ann , Liu Ying , Srivastava Supriya , Teo Melissa Ching Ching , Lee Joey Jia-Ying , Walsh Robert John , Loo Lit-Hsin , Tan Qiu Xuan , Ng Gillian , Tan Joey Wee-Shan , Ma Haoran , Ong Xuewen , Tay Su Ting , Sheng Taotao , Lum Jeffrey H Y , Yong Wei-Peng , Pietrantonio Filippo , Tan Patrick , Sundar Raghav
Published: January 2025

218

Background:
Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate spatially resolved molecular features facilitating transcoelomic dissemination and progression.
Methods:
50 PT, 116 PM and 37 primary normal samples from 96 patients were retrieved and profiled with digital spatial profiling (GeoMx DSP, Nanostring Technologies). Through unsupervised clustering, we characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. These findings were orthogonally validated through spatial proteomics (multiplex IHC [mIHC] - COMET, Lunaphore Technologies) of 10 paired PT-PM samples retrieved from 6 patients.
Results:
A median of 37 region of interests (ROIs) (IQR: 32-38) were selected from a total of 9 tissue microarray (TMA) slides. A total of 269 ROIs (181 tumor, 88 stroma) from PM samples, 45 ROIs (34 tumor, 11 stroma) from PT samples and 28 (all stroma) ROIs from primary normal samples were retrieved and profiled. Through consensus clustering of stroma ROIs, we identify a fibro-collagenous and immune infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer associated fibroblasts (CAFs), memory B cells, M2 macrophages and T-cell exhaustion. Patients with SC2 stroma had poorer survival (p=0.036). SC2 stroma was also observed to support adjacent tumor compartments with enriched oncogenic pathways such as TGF-beta, TNF-alpha, hypoxia and JAK-STAT. Through discriminatory gene expression profiles, we developed a 20-gene composite bidirectional signature of SC2. The prognostic significance of the SC2-signature was externally validated through several cohorts including TCGA and MSI-H only cohorts. Next, by inspecting mIHC retrieved immune cell type densities across ROIs, we confirmed a similar phenomenon in which two distinct stromal clusters were found – one being fibroblast infiltrated but T-cell depleted (SC2-like, n=67 ROI) and another which is T-cell infiltrated but fibroblast depleted (SC1-like, n=104 ROI). Diverging spatial distributions of T-cells and fibroblasts between SC1 and SC2-like stroma was appreciated as well. Between both PT and PM, we find close clustering of T cells in SC1-like stromal compartments and fibroblasts in SC2-like stromal compartments.
Conclusions:
We describe SC2, a pro-tumorigenic stromal phenotype characterized by increased CAFs, T cell exhaustion and is associated with poor prognosis in CRC PM.
A comprehensive molecular and clinical study of patients with young-onset CRC.
Authors: Nasrollahi Elham , Wang Shuaichao , Yanes Rami , Gonzalez Cyndi , Magge Tara , Overacre-Delgoffe Abigail E. , Hsieh Ronan Wenhan , Mcfarquhar Ashley , Singhi Aatur D. , Saeed Anwaar , Tatsuoka Curtis , Sahin Ibrahim Halil
Published: January 2025

235

Background:
Young-onset colorectal cancer (YO-CRC), defined as colorectal cancer diagnosed in individuals under 50 years of age, has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS.
Methods:
We retrospectively reviewed 110 patients diagnosed with YO-CRCfrom our institution’s molecular database. All patients underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo Stage 4. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05.
Results:
Among 110 patients, N=44 (40%) presented with local disease (stage 1-3), while N=66 (60%) patients presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4% respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB >20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among the 66 Stage 4 patients, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7 - not reached). KRAS mutation was found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, P = 0.002 < 0.05), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients.
Conclusions:
KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic need to improve outcomes in this high-risk group.
Association between ctDNA levels, timing of blood collection, and overall survival in metastatic colorectal cancer.
Authors: Kobayashi Akinori , Nakamura Yoshiaki , Hashimoto Tadayoshi , Taniguchi Hiroya , Komatsu Yoshito , Esaki Taito , Sunakawa Yu , Yamaguchi Kensei , Kato Takeshi , Shiozawa Manabu , Takahashi Naoki , Ohta Takashi , Denda Tadamichi , Satake Hironaga , Nishina Tomohiro , Yasui Hisateru , Bando Hideaki , Yoshino Takayuki
Published: January 2025

245

Background:
While circulating tumor DNA (ctDNA) detection is influenced by various factors, the impact of blood collection timing remains understudied. This study investigated the relationship between ctDNA detection, and blood collection timing and prognosis in patients with metastatic colorectal cancer (mCRC) from the GOZILA study.
Methods:
GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. This study evaluated the association of ctDNA levels with blood collection timing and prognosis in patients with mCRC. ctDNA levels were determined by the maximum variant allele frequency. Blood collection timing was categorized into five groups: naive (before initiation of 1st line treatment), after treatment initiation (days 1-14 of treatment), during treatment (between “after treatment initiation” and “before progression disease [PD]”), before PD (from 28 days before PD to PD), and after PD (after disease progression but before the next line of treatment). Overall survival (OS) was compared across treatment lines using ctDNA level cutoff of 10.
Results:
We analyzed 2,398 blood samples from 1,994 patients with mCRC enrolled in the GOZILA between February 2018 and July 2023. ctDNA levels were significantly lower during treatment compared to the naive (median, 13.2 vs. 5.7, p < 0.001). No significant differences were observed between naive and other blood collection timing. Compared to blood collection before 1st line treatment, ctDNA levels significantly decreased before 2nd line (median, 13.5 vs. 8.3, p = 0.02) and 3rd line treatments (median, 13.5 vs. 7.6, p = 0.01). Patients with ctDNA levels<10 demonstrated significantly better OS across all treatment lines, including 1st line (median, NA vs. 23.9 months, HR 0.49, 95% CI, 0.34-0.72), 2nd line (median, 22.1 vs. 10.3 months, HR 0.42, 95% CI, 0.33-0.55), and later line treatments (FTD/TPI: median, 12.7 vs. 5.7 months, HR 0.51, 95% CI, 0.26-0.99; FTD/TPI+Bev: median, 9.3 vs. 6.5 months, HR 0.55, 95% CI, 0.37-0.82; Regorafenib: median, 13.5 vs. 7.4 months, HR 0.45, 95% CI, 0.26-0.80).
Conclusions:
In mCRC, blood collection during treatment is suboptimal due to decreased ctDNA levels. Patients with ctDNA levels <10 showed significantly better OS across all treatment lines. Optimal timing of blood collection can enhance ctDNA levels, enabling more accurate gene mutation assessment and stratifying outcomes.
VEGF-A as a prognostic indicator in advanced gastric and colorectal cancers and correlation with immune suppression involving myeloid-derived suppressor cells (MDSC).
Authors: Shibata Masahiko , Kono Koji , Takenoshita Seiichi
Published: January 2025

250

Background:
VEGF-A is important molecule should be controlled in cancer treatment since hypoxic and immunosuppressive conditions of tumor microenvironment are induced by VEGF-A. Myeloid-derived suppressor cells (MDSC), activated by chronic inflammation and VEGF-A, play critical roles in immunosuppression in patients with cancer.
Methods:
Serum levels of VEGF-A were measured by ELISA and circulating levels of MDSC were measured by Flow Cytometry (CD11b+, CD14-, CD33+). Patients with gastric and colorectal cancers were divided into two groups, high VEGF group (serum VEGF-A>330pg/ml) and lo group (≤330pg/ml).
Results:
Prognosis of stages III and IV gastric cancer with high VEGF-A was significantly worse than in low VEGF-A group, while difference was not significant in stages I and II. In colorectal cancer, the results were exactly same as found in gastric cancer. The levels of MDSC were significantly correlated with the levels of VEGF-A in patients with gastric and colorectal cancers. The levels of VEGF-A were also correlated with inflammatory markers including CRP and NLR (neutrophil to lymphocyte ratio), and inversely did to stimulation index of lymphocyte proliferation (SI: parameter of cellular immune reaction) and nutritional parameters such as albumin or rapid turnover protein.
Conclusions:
The observation in the present study suggest that VEGF-A is closely associated with inflammation-associated disease progression especially in advanced stages, and serve as useful marker of immunosuppression involving MDSC and prognosis in patients with gastric and colorectal cancers.