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Therapeutic Advances in Gastroenterology 2022Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the...
BACKGROUND
Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the effectiveness and safety of two different regimens in patients with refractory mCRC.
METHODS
This retrospective cohort study included mCRC patients who were treated with RS or regorafenib from February 2017 to June 2021. A propensity score matching (PSM) analysis was conducted to balance the baseline characteristics of all patients. Progression-free survival (PFS), overall survival (OS), tumor response, and safety of two regimens were evaluated.
RESULTS
A total of 187 patients were included in our study, with 107 patients in the RS group and 80 patients in the regorafenib group. After PSM, 78 pairs were recognized. Patients treated with RS had a semblable PFS compared to those treated with regorafenib before PSM (4.8 months 5.5 months, = 0.400) and after PSM (4.7 months 5.4 months, = 0.430). Patients in the RS group were associated with a longer OS than those in the regorafenib group (13.4 months 10.1 months, = 0.010). A similar trend of OS was also obtained in the matched cohort (13.3 months 10.0 months, = 0.024). Both objective response rate (12.8% 5.1%, = 0.093) and disease control rate (53.8% 46.2%, = 0.337) in the RS cohort were higher than those in the regorafenib group, without significant differences. Adverse events (AEs) of each group were well tolerated.
CONCLUSION
Patients treated with RS demonstrated a longer OS than those treated with regorafenib and had manageable AEs, which could be recognized as a primary choice for refractory mCRC.
PLAIN LANGUAGE SUMMARY
-Both raltitrexed plus S-1 (RS) and regorafenib showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. No study has compared the two regimens yet. Therefore, we compare the efficacy and safety between RS and regorafenib to provide an optimal treatment option. We retrospectively included patients with mCRC who failed at least two standard treatments. All enrolled patients received RS or regorafenib treatments. We conducted a propensity score matching to eliminate differences in the enrolled patients. After the analysis, we found no significant differences in progression-free survival in patients between the two groups. However, patients treated with RS had a longer OS than those treated with regorafenib, whether before matching (13.4 months 10.1 months, = 0.010) or after matching (13.3 months 10.0 months, = 0.024). In addition, the adverse effects caused by cancer-related therapy were tolerable for the patient. Certainly, this is a non-randomized retrospective study with a small sample size, so we conducted a propensity score matching to minimize potential bias. Importantly, this is the first research comparing the two treatments, and we believe that the results of this article could present a primary choice for clinical doctors dealing with patients with standard treatments that failed mCRC.
PubMed: 35601804
DOI: 10.1177/17562848221098246 -
Gastroenterology Report 2022Unresectable hepatocellular carcinoma (HCC) has a poor prognosis. According to the HCC management guidelines in China, the standard treatment of Barcelona Clinic Liver...
BACKGROUND
Unresectable hepatocellular carcinoma (HCC) has a poor prognosis. According to the HCC management guidelines in China, the standard treatment of Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC with portal vein tumour thrombosis (PVTT) is chemoembolization. However, some patients with BCLC stage B or C HCC with PVTT respond poorly to chemoembolization. We aimed to compare tumour responses and survival benefits between patients with unresectable HCC with or without PVTT.
METHODS
We reviewed 119 consecutive patients with unresectable HCC with PVTT (=67) and without PVTT ( = 52) who underwent hepatic arterial infusion of oxaliplatin plus raltitrexed between January 2018 and April 2021. Overall survival, progression-free survival, tumour responses, and adverse events were compared between the groups.
RESULTS
There were no significant between-group differences in the objective response rates and median progression-free survival. The median overall survival was significantly longer in the group without PVTT than in that with PVTT (17.0 vs 10.4 months, respectively; = 0.024).
CONCLUSION
Hepatic arterial infusion of oxaliplatin plus raltitrexed may be efficacious in patients with unresectable HCC with or without PVTT.
PubMed: 35582475
DOI: 10.1093/gastro/goac016 -
Lung Cancer (Amsterdam, Netherlands) May 2022A minimally important difference (MID) is the smallest difference in quality of life (QoL) perceived as relevant by patients or clinicians. MIDs aid interpretation of...
Minimally important differences of EORTC QLQ-C30 scales in patients with lung cancer or malignant pleural mesothelioma - Interpretation guidance derived from two randomized EORTC trials.
OBJECTIVES
A minimally important difference (MID) is the smallest difference in quality of life (QoL) perceived as relevant by patients or clinicians. MIDs aid interpretation of QOL data in research and clinical practice. We aimed to determine MIDs for the EORTC QLQ-C30 for patients with lung cancer or malignant pleural mesothelioma.
MATERIALS AND METHODS
Data were drawn from two EORTC-sponsored randomized clinical trials (RCTs): a three-arm RCT of two cisplatin-based treatments and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer, and an RCT comparing cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma. MIDs for interpreting within-group change and between-group differences in change over time were computed using anchor-based approaches, for improvements and deteriorations separately. Distribution-based approaches provided corroborative evidence.
RESULTS
The combined data from the trials comprised 730 patients. Available data allowed us to determine 8/14 anchor-based MIDs for EORTC scales for improvements, and 9/14 MIDs for deterioration. Furthermore, we provided distribution-based estimates for all 14 QLQ-C30 scales. Most MIDs for improvements ranged between 5 and 10, for both within-group and between-group differences. Outliers were appetite loss and constipation, with MIDs up to 15 score points. MIDs were slightly larger for within-group deterioration, ranging from -5 to - 15, with the largest for Nausea/vomiting (-1 to 4) and Appetite loss (-1 to 5). MIDs for between-group differences in deterioration ranged from - 4 (Physical, Role, and Social functioning, and Global quality of life) to -9 (Nausea/vomiting, Appetite loss and Constipation).
CONCLUSIONS
MIDs vary over scales and for between- versus within-group comparisons; this must be taken into account when interpreting changes. Nevertheless, the majority of MIDs range between 5 and 10 score points, in line with previously used thresholds for QLQ-C30. These findings and those from other tumor-specific MID analyses will inform a planned consensus process identifying commonalities and differences across tumor sites.
Topics: Cisplatin; Constipation; Humans; Lung Neoplasms; Mesothelioma, Malignant; Nausea; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Vomiting
PubMed: 35413526
DOI: 10.1016/j.lungcan.2022.03.018 -
Cancer Control : Journal of the Moffitt... 2022Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this... (Clinical Trial)
Clinical Trial
OBJECTIVE
Irinotecan-based doublet chemotherapy strategy was standard second-line backbone for patients with oxaliplatin-refractory metastatic colorectal cancer. The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.
METHODS
The study was a prospective, single-center, non-randomized, open-label phase II clinical trial. Patients with mCRC after failure with oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m) and raltitrexed (2.5 mg/m) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AEs).
RESULTS
Between December 2012 and October 2016, 33 and 35 patients enrolled were assessed for response and safety, respectively. The ORR was 8.6%, and the DCR was 71.4%. The median PFS was 4.5 months (95% CI 3.8-5.2). The median OS was 12.0 months (95% CI 8.5-15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 AEs were anorexia (14.3%), vomiting (14.3%), nausea (11.4%), fatigue (8.6%), and leukopenia (8.6%). No one died from treatment-related events. The incidence and severity of toxicity were irrelevant to UGT1A1 status.
CONCLUSIONS
The combination of irinotecan with raltitrexed is an efficient, convenient, and acceptable toxic regimen for second-line treatment for mCRC patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Irinotecan; Prospective Studies; Quinazolines; Thiophenes
PubMed: 35343258
DOI: 10.1177/10732748221080332 -
Malawi Medical Journal : the Journal of... Sep 2021Metastasis from extramammary primary tumor to breast is extremely rare. (Review)
Review
BACKGROUND
Metastasis from extramammary primary tumor to breast is extremely rare.
CASE SUMMARY
A 59-year-old woman with 1-year history of rectal cancer presented with asymptomatic breast mass. At 16 months after the diagnosis of rectal mucinous adenocarcinoma, a breast mass was confirmed by ultrasonography and identified by pathology and immunohistochemistry as a metastasis from the rectal cancer. Treatments included chemotherapy (6 cycles: 300 mg irinotecan on day 1, 4.5 mg raltitrexed on day 2, 450 mg bevacizumab on day 3), radiotherapy, and surgical resection. Two years of follow-up examinations (6-months intervals) showed no evidence of recurrence or novel distant metastasis.
CONCLUSION
Breast metastasis from rectal carcinoma is a rare secondary malignancy. Final diagnosis can be established by histopathology and immunohistochemistry.
Topics: Breast Neoplasms; Carcinoma; Female; Humans; Melanoma; Middle Aged; Rectal Neoplasms; Skin Neoplasms
PubMed: 35233281
DOI: 10.4314/mmj.v33i3.11 -
Journal of Pharmaceutical and... Apr 2022In this study, the values of ionization/protonation constants (pK) of pemetrexed and raltitrexed, which are folic acid antimetabolites, were determined by reversed-phase...
In this study, the values of ionization/protonation constants (pK) of pemetrexed and raltitrexed, which are folic acid antimetabolites, were determined by reversed-phase liquid chromatography (RPLC) and UV-visible spectrophotometric methods at 25 °C. The pKass values were evaluated by retention time (t) in binary acetonitrile-water mixtures with acetonitrile (ACN) contents of 13%, 15%, 17% and 20% (v/v) for the RPLC method and 13%, 15% and 17% (v/v) for the spectrophotometric method. The aqueous pK values (pKaww) of the studied compounds were calculated from the pKass value using the macroscopic parameters (mole fraction and dielectric constant), which play an important role in solvent properties. In addition, the degree of ionization of pemetrexed and raltitrexed was calculated using the pKaww values.
Topics: Antimetabolites; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Reverse-Phase; Folic Acid; Hydrogen-Ion Concentration; Spectrophotometry
PubMed: 35180566
DOI: 10.1016/j.jpba.2022.114647 -
FEBS Letters Feb 2022A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and...
A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. γ-Glutamyl hydrolase (GGH) catalyzes the removal of γ-polyglutamate tails of folylpoly-/antifolylpoly-γ-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH ) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH . Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition. Our findings clearly define the in vivo role of GGH in ALL cells and indicate a novel modulation of the GGH function, suggesting new avenues for ALL treatment in future.
Topics: CRISPR-Cas Systems; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Gene Editing; Glycosylation; HeLa Cells; Humans; Lymphocytes; Lysosomes; Methotrexate; Polyglutamic Acid; Protein Sorting Signals; Quinazolines; Thiophenes; gamma-Glutamyl Hydrolase
PubMed: 35040120
DOI: 10.1002/1873-3468.14285 -
ACS Chemical Biology Jan 2022Although thermal proteome profiling (TPP) acts as a popular modification-free approach for drug target deconvolution, some key problems are still limiting screening...
Although thermal proteome profiling (TPP) acts as a popular modification-free approach for drug target deconvolution, some key problems are still limiting screening sensitivity. In the prevailing TPP workflow, only the soluble fractions are analyzed after thermal treatment, while the precipitate fractions that also contain abundant information of drug-induced stability shifts are discarded; the sigmoid melting curve fitting strategy used for data processing suffers from discriminations for a part of human proteome with multiple transitions. In this study, a precipitate-supported TPP (PSTPP) assay was presented for unbiased and comprehensive analysis of protein-drug interactions at the proteome level. In PSTPP, only these temperatures where significant precipitation is observed were applied to induce protein denaturation and the complementary information contained in both supernatant fractions and precipitate fractions was used to improve the screening specificity and sensitivity. In addition, a novel image recognition algorithm based on deep learning was developed to recognize the target proteins, which circumvented the problems that exist in the sigmoid curve fitting strategy. PSTPP assay was validated by identifying the known targets of methotrexate, raltitrexed, and SNS-032 with good performance. Using a promiscuous kinase inhibitor, staurosporine, we delineated 99 kinase targets with a specificity up to 83% in K562 cell lysates, which represented a significant improvement over the existing thermal shift methods. Furthermore, the PSTPP strategy was successfully applied to analyze the binding targets of rapamycin, identifying the well-known targets, FKBP1A, as well as revealing a few other potential targets.
Topics: Algorithms; Chemical Precipitation; Deep Learning; Drug Delivery Systems; Hot Temperature; Humans; K562 Cells; Proteins; Proteome; Proteomics
PubMed: 34989232
DOI: 10.1021/acschembio.1c00936 -
Cancer Biotherapy & Radiopharmaceuticals Nov 2023This study investigated the raltitrexed loading method, compatible stability with contrast agent, release profiles, and morphological properties of CalliSpheres, DC...
This study investigated the raltitrexed loading method, compatible stability with contrast agent, release profiles, and morphological properties of CalliSpheres, DC Bead, and HepaSphere. The amounts of raltitrexed added, loading medium, loading condition, and drug concentrations were investigated as factors influencing drug loading efficiency. Compatible stability with iopamidol was tested. Release profiles were accessed by a flowthrough apparatus system. Morphological properties were evaluated by a scanning electron microscope (SEM). Diameters were measured by a laser diffraction particle size analyzer. With the optimized method, the amount of raltitrexed loading to a marketed drug-eluting beads (DEBs) package was 2.67 mg for CalliSpheres, 2.34 mg for DC Bead, and 3.19 mg for HepaSphere. For all three DEBs, the drug leak rate was >50% within 2 h after mixing with iopamidol, and the time to reach 75% of the release plateau was within 10 min. Diameters increased after drug loading. Drug crystals were observed on the surface of DEBs in SEM. The amount of drug loading could meet clinical requirements by the optimized method. All three raltitrexed-loaded DEBs showed poor compatible stability with iopamidol, as well as rapid drug release performance, which should be noticed in clinical practice.
Topics: Humans; Iopamidol; Chemoembolization, Therapeutic; Quinazolines; Thiophenes; Microspheres
PubMed: 34767737
DOI: 10.1089/cbr.2021.0251 -
American Journal of Translational... 2021To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of...
OBJECTIVE
To investigate the short-term efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with epirubicin and raltitrexed in the treatment of intermediate and advanced primary hepatocellular carcinoma (PHC).
METHODS
One hundred patients with intermediate or advanced PHC were randomly divided into a control group (the CG, n=50) and an observation group (the OG, n=50). The CG was treated with conventional TACE (cTACE), and the OG was treated with DEB-TACE loaded with epirubicin and raltitrexed. The overall efficiency, the liver function indices, the tumor markers, the macrophage migration inhibitory factor (MIF) levels , the lesion diameters, the Child-Pugh scores, the adverse reactions, the median times to disease progression, the 1-year and 2-year recurrence rates, and the survival rates were compared between the two groups.
RESULTS
At 6 months after the surgery, the overall response rate in the OG (82.00%) was higher than it was in the CG (62.00%) (<0.05). The serum alanine aminotransferase, total bilirubin, and aspartate aminotransferase levels were elevated in both groups after the intervention, but they were lower in the OG than they were in the CG (<0.05). The serum alpha-fetoprotein, carcinoembryonic antigen, and MIF levels, and the lesion diameters were lower in both groups at one month after the intervention, and they were lower in the OG than they were in the CG (<0.05). The incidence of abnormal blood test results in the OG was lower than it was in the CG (<0.05). The OG also exhibited a longer median time to disease progression, lower 1-year and 2-year recurrence rates, and higher 1- and 2-year survival rates than the CG (<0.05).
CONCLUSION
DEB-TACE loaded with epirubicin and raltitrexed improves the short-term outcomes, reduces the tumor load, decreases the incidence of adverse events, and improves the survival rate in patients with intermediate and advanced PHC.
PubMed: 34540079
DOI: No ID Found