Thus, our findings demonstrate that MALT1 suppression dramatically reduces FOLFOX-induced inflammatory and fibrotic conditions by modulating the NF-κB activation, paving the way for innovative HSOS therapy approaches.

P2, N=364, Recruiting, Kyungpook National University Hospital | Trial primary completion date: Dec 2024 --> Jun 2025

P3, N=507, Completed, Federation Francophone de Cancerologie Digestive | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Feb 2025 | Trial primary completion date: Dec 2025 --> Feb 2025

P3, N=708, Active, not recruiting, Kyungpook National University Hospital | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Dec 2026 --> Dec 2024 | Recruiting --> Active, not recruiting

A high-salt diet reduces the anti-CRC efficacy of FOLFOX through gut bacterial tryptophan metabolism mediated macrophage immunomodulation.

Carbohydrate antigen 19-9 after induction therapy, carbohydrate antigen 19-9 decrease, and performance status are independent prognostic factors for overall survival after surgical exploration for locally advanced pancreatic cancer. Three-year overall survival is best in patients with a performance status of zero, a greater than 80% decrease in carbohydrate antigen 19-9, and a post-induction carbohydrate antigen 19-9 level less than 50 U/ml.

P=N/A, N=264, Recruiting, University Hospital Tuebingen

FOLFIRI, a combination of folinic acid, 5-Fluorouracil, and Irinotecan, is one of the recommended first-line chemotherapeutic treatments for metastatic colorectal cancer (mCRC). Our analyses revealed a five-gene FOLFIRI resistance signature associated with RFS that may help to predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance.

Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment.

Mechanistic studies reveal that the HMB combination exerts its synergistic anticancer effects and enhances anti-PD-1 immunotherapy by inducing GSDME-dependent pyroptosis. Our study will hopefully provide a potential therapeutic strategy for mCRC patients in the future.

KRAS wild-type tumors are a distinct PDAC subgroup with a better prognosis. Consequently, KRAS status assessment before transcriptome-based subtyping can stratify patients into three prognostic molecular subgroups (KRAS wild type, KRAS mutant classical, and KRAS mutant basal like). This integrative way of classification should be validated prior to incorporation in diagnostic practice.

P2, N=56, Completed, John Hays | Unknown status --> Completed

FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance.

P2, N=17, Recruiting, Sixth Affiliated Hospital, Sun Yat-sen University | Trial completion date: Sep 2026 --> Dec 2028 | Trial primary completion date: Sep 2024 --> Sep 2027

Pathological examination confirmed negative surgical margins, but remained tumor cells were confirmed. The patient continued mFOLFOX6 treatment for 12 months postoperatively, with no disease progression observed.

P=N/A, N=108, Recruiting, West China School of Public Health and West China Fourth Hospital, Sichuan University; West China School of Public Health and West China Fourth Hospit

MCPs present significant sensitivity not only to immune checkpoint inhibitors, but also to systemic chemotherapy and that the latter treatment modality should not be overlooked. They also present different pathological and molecular features compared with conventional PDAC, meaning they should be considered a separate pathological entity.

Drug repurposing analysis identified four potential SHMT1-targeting compounds (Mimosine, Pemetrexed, Leucovorin, and Irinotecan), supported by molecular docking studies. SHMT1, in particular, represents a promising candidate for future therapeutic development. These findings provide new opportunities for developing causative treatments for PA, though further clinical validation is warranted.

The patient underwent six cycles of chemotherapy with FOLFOX (oxaliplatin in combination with 5-fluorouracil and leucovorin), and radiofrequency ablation (RFA) was applied to the lesion in segment VI, resulting in a favorable response in imaging control. In addition to the dissection and section of the middle and left hepatic vein included in the surgical specimen. The patient experienced a rapid postoperative recovery with good liver function, an early hospital discharge, and a quick return to work, highlighting the clear advantages of laparoscopic surgery.

FOLFIRI (5-FU, leucovorin, irinotecan) is the first-line chemotherapy for metastatic colorectal cancer (mCRC), but response rates are under 50%...In conclusion, the REO-based signature effectively identifies mCRC patients likely to benefit from FOLFIRI. Furthermore, these signature genes may play a crucial role in the chemotherapy.

The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.

Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients' survival and, consequently, medical futility due to incorrect therapy application.

Progressive sarcopenic deterioration after four cycles of chemotherapy was associated with poor survival outcomes in patients with BR or LAPC after FOLFIRINOX. We also investigated the optimal clinical setting for the early application LRTs using the ΔSMI and post-chemotherapy CA 19-9.

This meta-analysis identified margin status, nodal disease, AJCC T-stage, and normalization of CA19-9 after NAT as prognostic factors for OS in patients with resected localized PDAC following NAT.

Here we examine the biochemical and cellular effects of a propargyl linked, non-classical antifolate that shows exceptional potency and resilience in the background of methotrexate resistance, UCP1162...Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate...Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.

Results suggest that aflibercept plus FOLFIRI, after failure of a prior oxaliplatin-based regimen, allows R0/R1 resection of CLM in almost 20 % of patients with a major pathological response in most cases and a median OS prolonged by more than 3-fold versus non-resected patients.

Immunohistochemical analysis of hypoxia-inducible factor HIF-2α detected tissue hypoxia as a consequence of inappropriate oxygen supply in the treated tumors. The obtained results show the prospects for monitoring of treatment efficacy using DRS and OCT-MA.

P2, N=312, Recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Sep 2024 --> Sep 2025

Adjuvant mFFX is effective and tolerable in resected PDAC in a non-trial setting, including for patients >70 years.

The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies...The results of our study suggest that a combination of pharmacological tools can be used in treating PDAC patients, targeting both TGFB2 and the components of the type-I interferon signaling pathway. The significant statistical interaction between TGFB2 and the nine marker genes suggests that TGFB2 is a negative prognostic indicator at low levels of the IFN-I activated genes and TAM marker expression, including the immune checkpoint LGALS9 (upregulated 16.5-fold in tumor tissue; p < 0.0001).

Studies on the clinical significance and treatment response to 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen in terms of the presence of these mutations remain inconclusive. PDAC patients with wild-type TP53 demonstrated longer OS than those with TP53 mutation, and this trend was intensified in patients with localized disease. This result may be due to an impaired response to FOLFIRINOX chemotherapy in patients with TP53 mutation.

Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

P2, N=322, Completed, Asan Medical Center | Unknown status --> Completed

Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen ((5-fluorouracil5-FU), oxaliplatin, Irinotecan) and platinum-based regimens for patients with BRCA mutations...In this study, we found that aberrantly overexpressed GALNT5 in PDAC took part in the activation of the NOTCH pathway by interacting with MYH9, thus inhibiting the DDR to achieve FOLFIRINOX resistance and causing poor prognosis. We identified GALNT5 as a potential therapeutic target for PDAC patients resistant to FOLFIRINOX chemotherapy.

Patients with low HMRS were sensitive to fluorouracil, oxaliplatin (FOLFOX), and anti-PD-1 immunotherapy, while those with high HMRS showed resistance. Additionally, HMRS was identified as an independent prognostic factor in other digestive tract tumors (hepatocellular carcinoma, pancreatic cancer, esophageal cancer, and gastric cancer), indicating potential extrapolation to other tumor types. In conclusion, GPNMB+ Macr promotes the malignant progression of CRC, and HMRS serves as a powerful predictive tool for prognosis, chemotherapy, and immunotherapy in CRC patients, aiding in improving the quality of survival.

Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.

FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

P2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A, N=30, Not yet recruiting, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University o

P2, N=40, Not yet recruiting, Shanghai General Hospital; Shanghai General Hospital

Using tissue-free MRD assessment in routine clinical practice can supplement standard-of-care procedures to determine prognosis and guide therapeutic decisions in patients with early stage CRC.

Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial. In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.