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Cancer Immunology, Immunotherapy : CII May 2024Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This... (Observational Study)
Observational Study
The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.
BACKGROUND
Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC
plus cisplatin CCRT ) for LANPC patients. METHODS
From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors.
RESULTS
After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064).
CONCLUSION
Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.
Topics: Humans; Male; Female; Nasopharyngeal Carcinoma; Middle Aged; Chemoradiotherapy; Propensity Score; Adult; Nasopharyngeal Neoplasms; Induction Chemotherapy; Antineoplastic Combined Chemotherapy Protocols; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Aged; Cisplatin; Deoxycytidine; Retrospective Studies; Gemcitabine
PubMed: 38733402
DOI: 10.1007/s00262-024-03698-2 -
International Journal of Molecular... Apr 2024Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label...
Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.
Topics: Humans; Riboflavin; Urinary Bladder Neoplasms; Gemcitabine; Deoxycytidine; Cell Line, Tumor; Light; Photosensitizing Agents; Oxidative Stress; Cell Survival; Lipid Peroxidation; Adenosine Triphosphate; Mitochondria; Blue Light
PubMed: 38732087
DOI: 10.3390/ijms25094868 -
PLoS Medicine May 2024It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.
BACKGROUND
It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM.
METHODS AND FINDINGS
This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection.
CONCLUSIONS
The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03493048.
Topics: Humans; Cetuximab; Antineoplastic Combined Chemotherapy Protocols; Male; Middle Aged; Liver Neoplasms; Female; Colorectal Neoplasms; Leucovorin; Fluorouracil; Organoplatinum Compounds; Proto-Oncogene Proteins B-raf; Aged; Adult; Camptothecin; Treatment Outcome; ras Proteins
PubMed: 38728364
DOI: 10.1371/journal.pmed.1004389 -
Cells Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug.
METHODS
For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pH 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine.
RESULTS
We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments.
CONCLUSIONS
We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.
Topics: Deoxycytidine; Gemcitabine; Humans; Tumor Microenvironment; Pancreatic Neoplasms; Cell Line, Tumor; Carcinoma, Pancreatic Ductal; Podosomes; Drug Resistance, Neoplasm; Prodrugs
PubMed: 38727266
DOI: 10.3390/cells13090730 -
Antiviral Therapy Apr 2024Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen... (Randomized Controlled Trial)
Randomized Controlled Trial
Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.
BACKGROUND
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1.
METHODS
This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires.
RESULTS
Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers.
CONCLUSION
Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04006704.
Topics: Humans; Male; HIV Infections; Female; Cobicistat; Child; Emtricitabine; Tablets; HIV-1; Anti-HIV Agents; Tenofovir; Darunavir; Drug Combinations; Alanine; Cross-Over Studies; Deglutition; Adenine
PubMed: 38725258
DOI: 10.1177/13596535241248282 -
Saudi Journal of Kidney Diseases and... Nov 2023Patients with end-stage renal disease (ESRD) are at an increased risk of hepatitis C virus (HCV) infection. This study evaluated the prevalence of HCV infection in...
Prevalence of Hepatitis C Virus Infection and Efficacy of Sofosbuvir-Velpatasvir and Sofosbuvir-Daclatasvir Treatment Regimens in End-stage Renal Disease Patients on Maintenance Hemodialysis.
Patients with end-stage renal disease (ESRD) are at an increased risk of hepatitis C virus (HCV) infection. This study evaluated the prevalence of HCV infection in patients with ESRD on maintenance hemodialysis (MHD) and studied the effectiveness of sofosbuvir-velpatasvir and sofosbuvir-daclatasvir regimens in these patients. This study included patients with ESRD on MHD between January 2019 and December 2021 who were screened for HCV serology status. HCV-positive patients received sofosbuvir-velpatasvir or sofosbuvir-daclatasvir. Efficacy was assessed by the sustained virological response (SVR), and safety assessments included monitoring adverse events and laboratory parameters. Out of 1330 patients, 188 patients (14.1%) were positive for anti-HCV, with Genotype 1 being the most common genotype. Of these, 106 patients were included. The majority were males (61.3%), and the mean age was 48.4 years. Hypertension (45.3%) was the most common cause of renal failure, followed by diabetes (31.1%). Most patients (63.2%) were positive for HCV in the first 2 years of their dialysis treatment. Out of 106 patients, only 54 had received blood transfusions. Ninety-four (88.7%) patients received sofosbuvir-velpatasvir, whereas 12 (11.3%) received sofosbuvir-daclatasvir. SVR at 12 and 24 weeks after stopping treatment was seen in all (100%) patients. Asthenia and fatigue were the most common adverse events (11.2%). No patients reported on-treatment virologic failure or discontinuation of treatment because of adverse events. The prevalence of HCV infection in this population was 14.1%, and treatment of HCV infection using sofosbuvir-velpatasvir or sofosbuvir-daclatasvir regimens was well tolerated and effective.
Topics: Humans; Male; Female; Middle Aged; Sofosbuvir; Imidazoles; Renal Dialysis; Kidney Failure, Chronic; Carbamates; Valine; Pyrrolidines; Antiviral Agents; Heterocyclic Compounds, 4 or More Rings; Drug Combinations; Adult; Prevalence; Treatment Outcome; Hepatitis C; Aged; Hepacivirus; Sustained Virologic Response; Saudi Arabia; Hepatitis C, Chronic
PubMed: 38725207
DOI: 10.4103/sjkdt.sjkdt_19_23 -
Nature Communications May 2024The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of...
The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI's capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
Topics: Adenosine; Transcriptome; 5-Methylcytosine; Humans; Methylation; Sequence Analysis, RNA; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA
PubMed: 38724548
DOI: 10.1038/s41467-024-47953-7 -
Phytomedicine : International Journal... Jul 2024Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in...
BACKGROUND
Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown.
PURPOSE
This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer.
METHODS
Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression.
RESULTS
Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro.
CONCLUSION
Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.
Topics: Gemcitabine; Deoxycytidine; Forkhead Box Protein M1; Humans; Animals; Pancreatic Neoplasms; Neoplastic Stem Cells; Cell Line, Tumor; Cell Proliferation; Mice, Nude; Mice; Mice, Inbred BALB C; Xenograft Model Antitumor Assays; Drugs, Chinese Herbal; Complex Mixtures; Trametes
PubMed: 38723529
DOI: 10.1016/j.phymed.2024.155656 -
CNS Oncology Jun 2024Treatment for refractory or relapsed primary CNS lymphoma (r/r PCNSL) is challenging. Salvage whole-brain radiation therapy (WBRT) is an option but has a short duration...
Treatment for refractory or relapsed primary CNS lymphoma (r/r PCNSL) is challenging. Salvage whole-brain radiation therapy (WBRT) is an option but has a short duration of disease control, so additional treatment modalities are warranted. A 75-year-old female with r/r PCNSL who had multiple progressions after multiple lines of treatment underwent salvage WBRT. The patient received ibrutinib, a Bruton's tyrosine kinase inhibitor, as maintenance therapy for 18 months following WBRT with the intention of increasing survival duration after salvage WBRT. She survived 81 months from diagnosis, including 57 months after completion of WBRT. This case presentation describes the experience of using ibrutinib as maintenance therapy in treating r/r PCNSL after salvage WBRT.
Topics: Humans; Piperidines; Adenine; Female; Aged; Central Nervous System Neoplasms; Pyrazoles; Pyrimidines; Neoplasm Recurrence, Local; Salvage Therapy; Remission Induction; Lymphoma
PubMed: 38722227
DOI: 10.1080/20450907.2024.2345579 -
Turkish Journal of Haematology :... May 2024Bruton tyrosine kinase inhibition in cardiac tissue causes inhibition of the PI3K-AKT signaling pathway, which is responsible for protecting cardiac tissue during...
OBJECTIVE
Bruton tyrosine kinase inhibition in cardiac tissue causes inhibition of the PI3K-AKT signaling pathway, which is responsible for protecting cardiac tissue during stress. Therefore, there is an increase in the risk of arrhythmia. This study explores the prediction of that risk with the Age-Creatinine-Ejection Fraction (ACEF) score as a simple scoring system based on the components of age, creatinine, and ejection fraction.
MATERIALS AND METHODS
Patients diagnosed with chronic lymphocytic leukemia (CLL) and receiving ibrutinib treatment for at least 1 year were evaluated with echocardiography and Holter electrocardiography and the results were compared with a control group of CLL patients who had not received treatment. ACEF score was calculated with the formula age/left ventricular ejection fraction+1 (if creatinine >2.0 mg/dL).
RESULTS
When the arrhythmia development of the patients was evaluated, no statistically significant difference was found between the control and ibrutinib groups in terms of types of arrhythmias other than paroxysmal atrial fibrillation (PAF). PAF was found to occur at rates of 8% versus 22% (p=0.042) among ibrutinib non-users versus users. For patients using ibrutinib, an ACEF score of >1.21 predicted the development of PAF with 77% sensitivity and 75% specificity (area under the curve: 0.830, 95% confidence interval: 0.698-0.962, p<0.001).
CONCLUSION
The ACEF score can be used as a risk score that predicts the development of PAF in patients diagnosed with CLL who are scheduled to start ibrutinib.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Adenine; Piperidines; Male; Female; Aged; Middle Aged; Arrhythmias, Cardiac; Creatinine; Pyrimidines; Aged, 80 and over; Protein Kinase Inhibitors
PubMed: 38721568
DOI: 10.4274/tjh.galenos.2024.2024.0045