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Journal of Cancer Research and Clinical... Jul 2024In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy.
PATIENTS AND METHODS
The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11.
RESULTS
The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed.
CONCLUSION
The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Male; Fluorouracil; Female; Middle Aged; Leucovorin; Aged; Oxaliplatin; Irinotecan; Adult; Camptothecin; Progression-Free Survival; Cross-Over Studies
PubMed: 38951245
DOI: 10.1007/s00432-024-05827-x -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024
Topics: Humans; Piperidines; Pyrimidines; Leukemia, Prolymphocytic, T-Cell; Pyrroles; Male; Middle Aged
PubMed: 38951074
DOI: 10.3760/cma.j.cn121090-20231024-00227 -
Journal of Managed Care & Specialty... Jul 2024Neurotrophic tyrosine receptor kinase () gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%),...
BACKGROUND
Neurotrophic tyrosine receptor kinase () gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for -positive solid tumors in academic cancer centers remains largely unknown.
OBJECTIVE
To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with -positive solid tumors treated at US academic cancer centers.
METHODS
This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an fusion-positive (1, 2, 3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate.
RESULTS
In total, 6 centers contributed data for 55 patients with -positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to testing was 85 days (IQR = 44-978). At the time of testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). 1 fusions were most common (45%), followed by 3 (40%) and 2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies.
CONCLUSIONS
This study reports on contemporary real-world testing patterns and use of TRKis in solid tumors, including time between testing and initiation of TRKi therapy and duration of TRKi therapy.
Topics: Humans; Female; Male; Retrospective Studies; Middle Aged; United States; Neoplasms; Receptor, trkC; Aged; Receptor, trkA; Adult; Protein Kinase Inhibitors; Receptor, trkB; Academic Medical Centers; Membrane Glycoproteins; Oncogene Proteins, Fusion; Cohort Studies; Pyrimidines; Pyrazoles; Benzamides; Young Adult; Indazoles
PubMed: 38950155
DOI: 10.18553/jmcp.2024.30.7.672 -
Oncology Research 2024Despite the availability of chemotherapy drugs such as 5-fluorouracil (5-FU), the treatment of some cancers such as gastric cancer remains challenging due to drug...
BACKGROUND
Despite the availability of chemotherapy drugs such as 5-fluorouracil (5-FU), the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects. This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines (AGS and EPG85-257).
MATERIALS AND METHODS
In this study, AGS and EPG85-257 cells were treated with different concentrations of celastrol, 5-FU, and their combination. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The synergistic effect of 5-FU and celastrol was studied using Compusyn software. The DNA content at different phases of the cell cycle and apoptosis rate was measured using flow cytometry.
RESULTS
Co-treatment with low concentrations (10% inhibitory concentration (IC10)) of celastrol and 5-FU significantly reduced IC50 ( < 0.05) so that 48 h after treatment, IC50 was calculated at 3.77 and 6.9 μM for celastrol, 20.7 and 11.6 μM for 5-FU, and 5.03 and 4.57 μM for their combination for AGS and EPG85-257 cells, respectively. The mean percentage of apoptosis for AGS cells treated with celastrol, 5-FU, and their combination was obtained 23.9, 41.2, and 61.9, and for EPG85-257 cells 5.65, 46.9, and 55.7, respectively. In addition, the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase.
CONCLUSIONS
Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells, additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol.
Topics: Humans; Pentacyclic Triterpenes; Fluorouracil; Stomach Neoplasms; Apoptosis; Cell Proliferation; Cell Line, Tumor; Triterpenes; Drug Synergism; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle
PubMed: 38948023
DOI: 10.32604/or.2024.047187 -
Oncology Research 2024Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase...
Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both (MCF7 and MDA-MB-468 cells) and (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.
Topics: Humans; Animals; Autophagy; Breast Neoplasms; Pyridines; Pyridones; Female; Pyrimidinones; Mice; Xenograft Model Antitumor Assays; Piperazines; Cell Line, Tumor; Drug Resistance, Neoplasm; Cell Proliferation; Drug Synergism; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; MAP Kinase Signaling System; Protein Kinase Inhibitors; Cell Survival; MCF-7 Cells
PubMed: 38948022
DOI: 10.32604/or.2024.046139 -
Journal of Cancer 2024Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer...
Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.
PubMed: 38947375
DOI: 10.7150/jca.96320 -
Yakugaku Zasshi : Journal of the... 2024The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However,...
The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However, discrepancies in the information on drug interaction are reported between J-PI and foreign databases. This study aimed to evaluate various information sources on N/r drug interactions. We categorized and compared information on N/r drug interactions from the J-PI, prescribing information from foreign regulatory agencies, guidance from the National Institutes of Health and University Health Network, the Ontario coronavirus disease 2019 (COVID-19) Science Advisory Table, University of Liverpool, Lexicomp, and the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS). We assessed information quantity, missing data in J-PI, predicted change of the area under the blood concentration-time curve (AUC) for nirmatrelvir or co-administered drugs, and the information source consistency. From these information sources, we compiled a dataset with 115 contraindications and 203 precautions for N/r co-administration, and 51 contraindications are missing in J-PI. Among them, at least 12 drugs have large predicted AUC changes with N/r (AUC ≥5-fold or <1/5 of the baseline value). Nine of these 12 drugs are included as contraindications in Lexicomp and the JSPHCS. The consistency among the information sources is low. Information in the J-PI alone may be insufficient and Lexicomp or the JSPHCS guidelines should be useful because of their large amounts of information and wide coverage of drugs with large AUC changes. Due to low source consistency, multiple sources are needed for clinical management.
Topics: Ritonavir; Humans; Drug Interactions; Drug Combinations; COVID-19 Drug Treatment; Lopinavir; Area Under Curve; Japan; Indazoles
PubMed: 38945847
DOI: 10.1248/yakushi.23-00204 -
Nature Communications Jun 2024One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and... (Randomized Controlled Trial)
Randomized Controlled Trial
One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV.
Topics: Humans; HIV Infections; Biomarkers; Africa South of the Sahara; Male; Female; Adult; Adolescent; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load; Young Adult; Anti-HIV Agents; Child
PubMed: 38944653
DOI: 10.1038/s41467-024-49317-7 -
Molekuliarnaia Biologiia 2024Photochemical reactions in cell DNA are induced in various organisms by solar UV radiation and may lead to a series of biological responses to DNA damage, including... (Review)
Review
Photochemical reactions in cell DNA are induced in various organisms by solar UV radiation and may lead to a series of biological responses to DNA damage, including apoptosis, mutagenesis, and carcinogenesis. The chemical nature and the amount of DNA lesions depend on the wavelength of UV radiation. UV type B (UVB, 290-320 nm) causes two main lesions, cyclobutane pyrimidine dimers (CPDs) and, with a lower yield, pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). Their formation is a result of direct UVB photon absorption by DNA bases. UV type A (UVA, 320-400 nm) induces only cyclobutane dimers, which most likely arise via triplet-triplet energy transfer (TTET) from cell chromophores to DNA thymine bases. UVA is much more effective than UVB in inducing sensitized oxidative DNA lesions, such as single-strand breaks and oxidized bases. Of the latter, 8-oxo-dihydroguanine (8-oxodG) is the most frequent, being produced in several oxidation processes. Many recent studies reported novel, more detailed information about the molecular mechanisms of the photochemical reactions that underlie the formation of various DNA lesions. The information is mostly summarized and analyzed in the review. Special attention is paid to the oxidation reactions that are initiated by reactive oxygen species (ROS) and radicals generated by potential endogenous photosensitizers, such as pterins, riboflavin, protoporphyrin IX, NADH, and melanin. The review discusses the role that specific DNA photoproducts play in genotoxic processes induced in living systems by UV radiation of various wavelengths, including human skin carcinogenesis.
Topics: Ultraviolet Rays; Humans; DNA Damage; Pyrimidine Dimers; Reactive Oxygen Species; DNA; Animals; Apoptosis; Oxidation-Reduction; 8-Hydroxy-2'-Deoxyguanosine
PubMed: 38943577
DOI: No ID Found -
Bratislavske Lekarske Listy 2024To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain...
OBJECTIVES
To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain tissueMETHODS: Citicoline, cytidine diphosphocholine, designated as CDP-choline, was purchased as a white powder with the molecular weight of 510.31 g/mol. The triblock copolymers of polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol (PEG-PPG-PEG), branded as Pluronic F127, was used.
RESULTS
When instilled into the nasal cavity, Pluronic F127 for intranasal administration is transformed into a gel that remains retained for 45-55 minutes, which promotes better penetration of drugs into the brain tissue.
CONCLUSION
The polymer's gelling and adhesive properties performed well, which is crucial for further research at the preclinical stage (Tab. 1, Fig. 5, Ref. 28).
Topics: Administration, Intranasal; Poloxamer; Brain; Drug Delivery Systems; Animals; Cytidine Diphosphate Choline; Gels; Polyethylene Glycols; Nasal Mucosa
PubMed: 38943505
DOI: 10.4149/BLL_2024_67