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Journal of Gastrointestinal Oncology Dec 2023There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair...
Significant response from fruquintinib plus anti-PD-1 immunotherapy for microsatellite stable metastatic colorectal cancer with liver and lung metastasis in the third line: case report.
BACKGROUND
There are limited treatment options available for patients with metastatic colorectal cancer (mCRC). About 95% of CRC patients have mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors are virtually unresponsive to programmed cell death protein 1 (PD-1) antibody treatment. This report shows that a patient with pMMR/MSS mCRC achieved significant response and the longest progression-free survival (PFS) of 28 months currently reported from tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) family (VEGFR-1,2,3) (fruquintinib) plus anti-PD-1 immunotherapy in the third line, providing a new and promising treatment option for some MSS mCRC patients.
CASE DESCRIPTION
This case details a 65-year-old male with CRC who was diagnosed with pT4aN2bM0, IIIC, and pMMR/MSS after curative surgery in August 2018. Subsequently, he received adjuvant chemotherapy [FOLFOX (folinic acid, fluorouracil, and oxaliplatin) for 5 cycles], first-line treatment (pelvic radiation plus capecitabine), and second-line treatment [TOMIRI (raltitrexed and irinotecan) plus cetuximab for 2 cycles]. Lung, liver, and pelvic cavity metastases worsened in October 2019. He began receiving the fruquintinib plus PD-1 inhibitor (FP) regimen as third-line treatment and after 3 cycles, the size of the lung lesions was significantly reduced and evaluated as partial response (PR), whereas the liver and pelvic cavity lesions remained stable. As of December 2021, he had received a total of 33 courses of FP regimen. In February 2022, liver metastases progressed. In brief, he achieved a long PFS of 28 months and an overall survival (OS) of 40 months from the third-line treatment. Additionally, the patient only experienced mild proteinuria after the combined treatment and tolerated well.
CONCLUSIONS
Fruquintinib combined with immunotherapy could exert good therapeutic effects with safety in MSS mCRC patients. And patients with lung metastasis may be the principal beneficiaries.
PubMed: 38196522
DOI: 10.21037/jgo-23-862 -
Repurposing of Raltitrexed as an Effective G9a/EHMT2 Inhibitor and Promising Anti-Alzheimer's Agent.ACS Medicinal Chemistry Letters Nov 2023Herein, we report for the first time the G9a/EHMT2 inhibition and anti-Alzheimer's activities of the drug raltitrexed. G9a is a lysine methyltransferase that mainly...
Herein, we report for the first time the G9a/EHMT2 inhibition and anti-Alzheimer's activities of the drug raltitrexed. G9a is a lysine methyltransferase that mainly dimethylates the H3K9 of chromatin, which triggers the repression of genes epigenetically, leading to various diseased conditions, including Alzheimer's disease (AD). First, we demonstrate that raltitrexed inhibits G9a at 120 nM. Moreover, raltitrexed lowers the total H3K9me2/H3K9 levels in AD transgenic CL2006 worms, indicating that raltitrexed targets G9a directly. As toxicity is the bottleneck in G9a drug discovery, we conducted detailed toxicity (TOPKAT) analyses of raltitrexed and measured the food consumption by , demonstrating that raltitrexed's toxicity/function range is safe for the worm's growth. Moreover, we demonstrate that raltitrexed enhances the locomotive function of worms dose-dependently. Finally, we show that raltitrexed reduced the Aβ aggregates in worms up to 47%, highlighting the potential of raltitrexed in AD treatment.
PubMed: 37974951
DOI: 10.1021/acsmedchemlett.3c00344 -
ACS Omega Oct 2023Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the...
Stearoyl chitosan (SC), derived from the acylation of chitosan, contributes to the efficiency of drug delivery systems because of its structure, which accommodates the drug in a particle. Nonetheless, its role in chemotherapy has been largely unexplored. The present study involves the synthesis of stearoyl chitosan through the reaction of depolymerized chitosan with stearoyl chloride under mild reaction conditions. The resulting compound was subjected to structural analysis utilizing Fourier-transform infrared (FTIR) spectroscopy, H NMR, and X-ray diffraction (XRD) spectroscopy. The dispersion of SC molecules in phosphate-buffered saline (PBS) forms SC nanoparticles. The best dispersion of SC in the solution was achieved at a 1:60 chitosan-to-stearoyl chloride weight ratio. Three antimetabolite drugs, methotrexate, pemetrexed, and raltitrexed, were selected to examine the loading efficacy of SC. Pemetrexed had the highest drug-loading value of 36.8% among the three antimetabolites incorporated into SC, along with an encapsulation efficiency of 85.1%. The size of SC loaded with antimetabolites ranged from 225 to 369 nm, and their spherical form was verified via a transmission electron microscope. The in vitro release study showed that SC demonstrated controlled drug release, suggesting that SC nanoparticles have significant promise as a delivery strategy for chemotherapy.
PubMed: 37929136
DOI: 10.1021/acsomega.3c05108 -
Bioinformation 2023Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is...
Myeloid leukemia 1 (MCL-1), a BCL-2 protein family member, acts as an anti-apoptotic protein by interacting with pro-apoptotic BCL-2 proteins. Its overexpression is frequently observed in numerous cancer types including breast cancer, and is closely linked to the initiation and progression of tumors as well as poor prognosis and resistance to therapeutic interventions. Here, a database of 3402 chemicals with established therapeutic activity against various diseases was chosen and systematically screened against the MCL-1 protein. Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. Notably, their binding affinity was higher than that of the control compounds. These compounds exhibited strong interactions with critical amino acid residues of the MCL-1 protein. Furthermore, these compounds shared several common amino acid residue interactions with the control compounds. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings.
PubMed: 37885779
DOI: 10.6026/97320630019707 -
International Immunopharmacology Dec 2023Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used...
Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study.
BACKGROUND
Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC.
METHODS
This retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil bolus 400 mg/m administered on day 1, and 5-fluorouracil 2400 mg/m infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m and raltitrexed 3 mg/m on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile.
RESULTS
ORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia.
CONCLUSION
The effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Fluorouracil; Oxaliplatin; Leucovorin; Retrospective Studies; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Liver Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37879230
DOI: 10.1016/j.intimp.2023.111019 -
BMJ Open Oct 2023Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant...
INTRODUCTION
Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant chemoradiation (CRT). But the cCR rate is low and about one-third of tumour will regrow, which requires more effective local treatment. CRT combined with intra-arterial chemotherapy (IAC) might be a promising approach. Additionally, total neoadjuvant therapy using FOLFIRINOX induction chemotherapy improved survival while consolidation chemotherapy improved organ preservation. We assess whether IAC plus CRT and FOLFIRINOX consolidation chemotherapy can improve the chance of organ preservation and survival in distal rectal cancer.
METHODS AND ANALYSIS
This prospective, monocentric, open-label, single-arm phase II study will include 32 patients with cT3-4NanyM0 distal rectal adenocarcinoma. All patients will receive one cycle of IAC (irinotecan, raltitrexed and oxaliplatin), followed by CRT (50 Gy/25 fractions with concomitant capecitabine) and then with six cycles of FOLFIRINOX (leucovorin, 5-fluorouracil, oxaliplatin and irinotecan). After final evaluation, patients with cCR will receive non-operative management or surgery at their own discretion and others are mandatorily referred to surgery. Adjuvant chemotherapy with six cycles of mFOLFOX6 (leucovorin, 5-fluorouracil and oxaliplatin) will be used for patients with adverse pathological features. The primary endpoint is the rate of complete response (CR; pathological CR or sustained cCR≥2 years). The main secondary endpoints are toxicity, compliance, short-term and long-term oncological outcomes, surgical morbidity and quality of life. This protocol has been designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials 2013 guidelines.
ETHICS AND DISSEMINATION
This study was approved by the Academic and Ethics Committee of The Affiliated Hospital of Youjiang Medical University for Nationalities in March 2023. Trial results will be published in peer-reviewed international journals and on the ChiCTR website.
PROTOCOL VERSION
Registered on 18 April 2023; version #1.
TRIAL REGISTRATION NUMBER
ChiCTR2300070620.
Topics: Humans; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols; Irinotecan; Oxaliplatin; Leucovorin; Quality of Life; Prospective Studies; Pancreatic Neoplasms; Rectal Neoplasms; Fluorouracil; Chemoradiotherapy; Neoplasm Staging; Clinical Trials, Phase II as Topic
PubMed: 37798027
DOI: 10.1136/bmjopen-2023-075023 -
Journal of Gastrointestinal Surgery :... Nov 2023To investigate the efficacy of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (AGC).
PURPOSE
To investigate the efficacy of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (AGC).
METHODS
We included 198 patients treated from December 2016 to January 2019; of these patients, the 132 who had clinical T4 gastric cancer were divided into a hyperthermic intraperitoneal chemotherapy group (HIPEC group) and a radical gastrectomy and D2 lymph node dissection group (control group). Because this study was retrospective, we used propensity score matching (PSM) to reduce selectivity bias; we then assessed risk factors for recurrence and compared prognosis in terms of survival in the gastrectomy and prophylactic HIPEC groups.
RESULTS
Prophylactic HIPEC reduced the risk of postoperative peritoneal metastasis (PM: 27.5% vs. 10.5%, P = 0.015) and did not increase the risk of postoperative complications, but there was no significant difference in the effect on hepatic metastases or other distant metastases. Risk factors for recurrence included pT4 staging and positive lymph node metastases. Both disease-free survival (DFS: HR 0.592; 95% CI 0.354-0.990; P = 0.042) and peritoneal recurrence-free survival (PFS: HR 0.314; 95% CI 0.127-0.774; P = 0.008) were better in the prophylactic HIPEC group than in the gastrectomy-only group. In addition, there was no difference in the prognosis of patients between the two groups of raltitrexed (RT) and paclitaxel (PTX) for perfusion dosing.
CONCLUSION
Our study showed that prophylactic HIPEC could prevent postoperative PM in patients with AGC and did not increase the incidence of postoperative complications. However, it was not found to be effective in the prevention of other metastases, such as hepatic metastases.
Topics: Humans; Stomach Neoplasms; Hyperthermic Intraperitoneal Chemotherapy; Retrospective Studies; Prognosis; Propensity Score; Hyperthermia, Induced; Antineoplastic Combined Chemotherapy Protocols; Postoperative Complications; Liver Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Survival Rate
PubMed: 37715013
DOI: 10.1007/s11605-023-05823-5 -
Cancer Biology & Medicine Aug 2023Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing effectiveness and safety of paclitaxel plus raltitrexed paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial.
OBJECTIVE
Paclitaxel (P) is a standard second-line chemotherapy in the treatment of advanced gastric cancer. This study compared the clinical outcome of a paclitaxel plus raltitrexed (RP) regimen as second-line treatment in metastatic gastric cancer (MGC) patients.
METHODS
An open, randomized, multi-center phase II clinical trial was conducted involving 148 patients who were randomly assigned and treated with RP [raltitrexed (3 mg/m on day 1) and paclitaxel (135 mg/m on day 1 every 3 weeks)] or P [paclitaxel (135 mg/m on day 1 every 3 weeks)] as 2-line chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), and safety.
RESULTS
PFS had a tendency to be prolonged with RP compared to P (2.7 months 1.7 months; = 0.148). OS was also prolonged with RP compared to P (10.2 months 6.1 months; = 0.140). The ORR was equal in the RP and P groups (6.8% and 4.0%; = 0.72). The disease control rate (DCR) in the RP and P groups was 56.2% and 36.0%, respectively. Grade 3-4 treatment-related adverse events occurred in 36.2% (RP) and 28.2% (P) of patients. Frequent grade 3-4 toxicities for RP and P were neutropenia (11.0% and 4.0%), anemia (1.4% and 4.0%), and thrombocytopenia (1.4% and 5.3%), and all grades of peripheral neurotoxicity (12.3% 17.3%). All grades of hepatic toxicity were demonstrated for the RP and P groups based on elevated aminotransferase levels (27.4% and 14.1%). Subgroup analysis shows if MGC was combined with ascites or peritoneal involvement, the OS of the RP regimen was longer ( = 0.05).
CONCLUSIONS
Second-line palliative chemotherapy with RP was shown to prolong the PFS and OS, especially among patients with ascites or peritoneal involvement, which warrants confirmation using larger sample studies.
Topics: Humans; Paclitaxel; Stomach Neoplasms; Ascites; Adenocarcinoma
PubMed: 37653589
DOI: 10.20892/j.issn.2095-3941.2023.0112 -
Frontiers in Oncology 2023Breast and vulvar metastases from rectal signet ring cell carcinoma (SRCC) represent a rare and obscure clinical entity associated with poor survival. Managing patients...
BACKGROUND
Breast and vulvar metastases from rectal signet ring cell carcinoma (SRCC) represent a rare and obscure clinical entity associated with poor survival. Managing patients with metastatic rectal SRCC is extremely challenging due to the absence of high-quality evidence.
CASE PRESENTATION
A 26-year-old woman presented with progressively worsening anal pain, constipation, and hematochezia for approximately two years. Following the diagnosis of locally advanced rectal cancer (TNM), she received neoadjuvant chemotherapy with modified FOLFOX6 regimen and underwent laparoscopic abdominoperineal resection. Metastases to the breast and vulva developed during postoperative chemotherapy. Genetic testing revealed RAS/BRAF wild-type and microsatellite instability (MSI)-low status. Though sequential administration of irinotecan plus tegafur and tegafur plus raltitrexed-based chemotherapy in combination with bevacizumab, the disease progressed rapidly. Sadly, the patient passed away 15 months after initial diagnosis due to rapidly progressive disease.
CONCLUSION
Rectal SRCC is associated with younger on-set, aggressive behaviors, and worse survival outcomes. Due to poor cohesiveness, SRCC tends to develop metastases. A patient's medical history and immunohistochemical staining (such as CK20, CK7, and CDX-2) can aid in identifying the tumor origin of breast and vulvar metastases. Mutations and signaling pathways predominant in the tumorigenesis of SRCC remains unveiled. There is poor effect of conventional chemotherapies, targeted and immunotherapies for colorectal adenocarcinoma on SRCC, so novel therapies are needed to treat this patient population.
PubMed: 37483522
DOI: 10.3389/fonc.2023.1213888 -
Journal of Gastrointestinal Surgery :... Nov 2023
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Doxorubicin; Drug Delivery Systems; Treatment Outcome
PubMed: 37407896
DOI: 10.1007/s11605-023-05738-1