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Ophthalmology Mar 2024To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG).
DESIGN
Prospective, randomized, multicenter trial conducted in the United States and Europe.
PARTICIPANTS
Adult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg.
METHODS
Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes.
MAIN OUTCOME MEASURES
The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions.
RESULTS
At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups.
CONCLUSION
At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Adult; Humans; Glaucoma; Glaucoma, Open-Angle; Intraocular Pressure; Mitomycin; Prospective Studies; Trabeculectomy; Middle Aged; Aged; Aged, 80 and over
PubMed: 37769852
DOI: 10.1016/j.ophtha.2023.09.023 -
Annals of Medicine and Surgery (2012) Nov 2023Urinary bladder tumor recurrence following transurethral resection of bladder tumor (TURBT) is a common issue. This study aims to determine how urine alkalinization...
BACKGROUND
Urinary bladder tumor recurrence following transurethral resection of bladder tumor (TURBT) is a common issue. This study aims to determine how urine alkalinization affects bladder tumor recurrence after surgery.
MATERIALS AND METHODS
Sixty patients receiving mitomycin C (MMC) therapy after TURBT were divided into two groups based on mean pH values. Twenty-six patients were in group A, whose urine pH was below 5.5. However, there were 34 patients in group B, and their urine pH was higher than 5.5. Both groups of patients were given intravesical MMC once weekly for 6 weeks following TURBT. A cystoscopy was performed as a follow-up at 3, 6, and 12 months. Urine pH and the recurrence-free survival rate were compared using Kaplan-Meier survival analysis and the COX proportional hazard model.
RESULTS
The mean time to tumor recurrence in group A (intravesical MMC in acidic urine) and group B (intravesical MMC in alkaline urine) was 12.48 versus 16.84 months, respectively. Alkaline urine pH was identified as an independent predictor of preventing the recurrence of superficial bladder tumors by univariate COX regression analysis. Age, sex, and mean tumor size did not affect the likelihood of tumor recurrence. However, smoking had an association with increased tumor recurrence.
CONCLUSION
Tumor recurrence post-TURBT is delayed in patients with alkaline urine pH. Smoking is an independent risk factor for bladder tumors.
PubMed: 37915689
DOI: 10.1097/MS9.0000000000001350 -
Antimicrobial Agents and Chemotherapy Jul 2023Cefepime has been reported to cause concentration-related neurotoxicity, especially in critically ill patients with renal failure. This evaluation aimed to identify a...
Cefepime has been reported to cause concentration-related neurotoxicity, especially in critically ill patients with renal failure. This evaluation aimed to identify a dosing regimen providing a sufficient probability of target attainment (PTA) and the lowest justifiable risk of neurotoxicity in critically ill patients. A population pharmacokinetic model was developed based on plasma concentrations over four consecutive days obtained from 14 intensive care unit (ICU) patients. The patients received a median dose of 2,000 mg cefepime by 30-min intravenous infusions with dosing intervals of every 8 h (q8h) to q24h. A time that the free drug concentration exceeds the MIC over the dosing interval () of 65% and an of 100% were defined as treatment targets. Monte Carlo simulations were carried out to identify a dosing regimen for a PTA of 90% and a probability of neurotoxicity not exceeding 20%. A two-compartment model with linear elimination best described the data. Estimated creatinine clearance was significantly related to the clearance of cefepime in nondialysis patients. Interoccasion variability on clearance improved the model, reflecting dynamic clearance changes. The evaluations suggested combining thrice-daily administration as an appropriate choice. In patients with normal renal function (creatinine clearance, 120 mL/min), for the pharmacodynamics target of 100% and a PTA of 90%, a dose of 1,333 mg q8h was found to be related to a probability of neurotoxicity of ≤20% and to cover MICs up to 2 mg/L. Continuous infusion appears to be superior to other dosing regimens by providing higher efficacy and a low risk of neurotoxicity. The model makes it possible to improve the predicted balance between cefepime efficacy and neurotoxicity in critically ill patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01793012).
Topics: Humans; Cefepime; Critical Illness; Creatinine; Anti-Bacterial Agents; Mitomycin; Probability; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 37366614
DOI: 10.1128/aac.00309-23 -
Frontiers in Immunology 2023Colorectal adenocarcinoma (COAD), accounting for the most common subtype of colorectal cancer (CRC), is a kind of malignant digestive tumor. Some cell cycle checkpoints...
Transcriptomic correlates of cell cycle checkpoints with distinct prognosis, molecular characteristics, immunological regulation, and therapeutic response in colorectal adenocarcinoma.
BACKGROUNDS
Colorectal adenocarcinoma (COAD), accounting for the most common subtype of colorectal cancer (CRC), is a kind of malignant digestive tumor. Some cell cycle checkpoints (CCCs) have been found to contribute to CRC progression, whereas the functional roles of a lot of CCCs, especially the integrated role of checkpoint mechanism in the cell cycle, remain unclear.
MATERIALS AND METHODS
The Genomic Data Commons (GDC) The Cancer Genome Atlas (TCGA) COAD cohort was retrieved as the training dataset, and GSE24551 and GSE29623 were downloaded from Gene Expression Omnibus (GEO) as the validation datasets. A total of 209 CCC-related genes were derived from the Gene Ontology Consortium and were subsequently enrolled in the univariate, multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, finally defining a CCC signature. Cell proliferation and Transwell assay analyses were utilized to evaluate the functional roles of signature-related CCCs. The underlying CCC signature, molecular characteristics, immune-related features, and therapeutic response were finally estimated. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic responses.
RESULTS
The aberrant gene expression of CCCs greatly contributed to COAD development and progression. Univariate Cox regression analysis identified 27 CCC-related genes significantly affecting the overall survival (OS) of COAD patients; subsequently, LASSO analysis determined a novel CCC signature. Noticeably, , , , , and were first identified to be correlated with the prognosis of COAD, and it was proven that all of them were significantly correlated with the proliferation and invasion of HCT116 and SW480 cells. In TCGA COAD cohort, CCC signature robustly stratified COAD patients into high and low CCC score groups (median OS: 57.24 months vs. unreached, < 0.0001), simultaneously, with the good AUC values for OS prediction at 1, 2, and 3 years were 0.74, 0.78, and 0.77. Furthermore, the prognostic capacity of the CCC signature was verified in the GSE24551 and GSE29623 datasets, and the CCC signature was independent of clinical features. Moreover, a higher CCC score always indicated worse OS, regardless of clinical features, histological subtypes, or molecular subgroups. Intriguingly, functional enrichment analysis confirmed the CCC score was markedly associated with extracellular, matrix and immune (chemokine)-related signaling, cell cycle-related signaling, and metabolisms. Impressively, a higher CCC score was positively correlated with a majority of chemokines, receptors, immunostimulators, and anticancer immunity, indicating a relatively immune-promoting microenvironment. In addition, GSE173839, GSE25066, GSE41998, and GSE194040 dataset analyses of the underlying CCC signature suggested that durvalumab with olaparib and paclitaxel, taxane-anthracycline chemotherapy, neoadjuvant cyclophosphamide/doxorubicin with ixabepilone or paclitaxel, and immunotherapeutic strategies might be suitable for COAD patients with higher CCC score. Eventually, the GDSC database analysis showed that lower CCC scores were likely to be more sensitive to 5-fluorouracil, bosutinib, gemcitabine, gefitinib, methotrexate, mitomycin C, and temozolomide, while patients with higher CCC score seemed to have a higher level of sensitivity to bortezomib and elesclomol.
CONCLUSION
The novel CCC signature exhibited a good ability for prognosis prediction for COAD patients, and the CCC score was found to be highly correlated with molecular features, immune-related characteristics, and therapeutic responses, which would greatly promote clinical management and precision medicine for COAD.
Topics: Humans; Gene Expression Profiling; Colorectal Neoplasms; Adenocarcinoma; Prognosis; Paclitaxel; Cell Cycle Checkpoints; Tumor Microenvironment; Nerve Tissue Proteins; Cell Cycle Proteins; Microtubule-Associated Proteins
PubMed: 38143740
DOI: 10.3389/fimmu.2023.1291859 -
Advanced Science (Weinheim,... Apr 2024Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death....
Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO and Cu in the tumor microenvironment. The exposed CaO further yields hydrogen peroxide (HO) and Ca in a weakly acidic environment to strengthen the Cu-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.
Topics: Humans; Hydrogen Peroxide; Reactive Oxygen Species; Neoplasms; Adenosine Triphosphate; Cell Death; Mitomycin; Tumor Microenvironment
PubMed: 38342617
DOI: 10.1002/advs.202306031 -
Urology Journal Dec 2023Intracavitary chemotherapy is one of the current treatment options for kidney-sparing treatment of upper tract urothelial carcinoma (UTUC). The purpose of this... (Meta-Analysis)
Meta-Analysis
PURPOSE
Intracavitary chemotherapy is one of the current treatment options for kidney-sparing treatment of upper tract urothelial carcinoma (UTUC). The purpose of this meta-analysis was to assess the efficacy and safety of intracavitary perfusion.
METHODS
We carefully selected publications for study from four databases (Embase, PubMed, Web of Science, and Scopus) up to January 2023. The R 4.0.4 software was used to calculate the pooled ratio and its 95% confidence intervals (95% CIs). The I2 score was used to test heterogeneity, and the funnel plot was used to estimate the publication bias.
RESULTS
Thirty-four studies with a total of 788 patients were included in this study. The overall survival at a median follow-up of 26.3 months was 87.2% (95% CI 0.80-0.93). The cancer-specific survival at a median follow-up of 30 months was 94.1% (95% CI 0.89-0.98). At a median follow-up of 30 months, the recurrence rate of UTUC was 27.5% (95% CI 0.21-0.34). By subgroup analysis, we found that the recurrence rate in patients with T1 / Ta stage was 35.1% and CIS stage 29.0%. The recurrence rates of BCG, Mitomycin C, and Mitomycin Gel (UGN101) were 31.2%, 41.3% and 12.9%, respectively. The recurrence rates for anterograde and retrograde perfusion were 28.5% and 21.8%, respectively.
CONCLUSION
With the advent of new drugs, including UGN101, patients with UTUC have a better prognosis. Therefore, kidney preservation therapy for patients with UTUC would be promising.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Chemotherapy, Adjuvant; Kidney; Kidney Neoplasms; Mitomycin; Ureteral Neoplasms
PubMed: 37312572
DOI: 10.22037/uj.v20i.7530 -
Investigative and Clinical Urology Nov 2023The clinical effect of neoadjuvant intravesical instillation of chemotherapy immediately before transurethral resection of bladder tumors (TURBT) has been a subject of... (Randomized Controlled Trial)
Randomized Controlled Trial
The effect of immediate neoadjuvant electromotive instillation of mitomycin C with Bacillus Calmette-Guérin versus BCG alone in non-muscle-invasive bladder cancer: A randomized controlled trial.
PURPOSE
The clinical effect of neoadjuvant intravesical instillation of chemotherapy immediately before transurethral resection of bladder tumors (TURBT) has been a subject of recent research. The aim of this study was to assess the effect of immediate neoadjuvant electromotive instillation of mitomycin C before transurethral resection for patients with non-muscle-invasive urothelial bladder cancer.
MATERIALS AND METHODS
Our study was a randomized clinical trial carried out on 50 patients diagnosed with non-muscle-invasive urothelial bladder cancer. Patients were classified into two groups: Group I consisted of 25 patients who received neoadjuvant electromotive drug administration of mitomycin C before TURBT and intravesical bacille Calmette-Guerin (BCG) per week for 6 weeks; Group II consisted of 25 patients who were treated with TURBT followed by intravesical BCG per week for 6 weeks alone (standard of care). Patients were followed up at 3, 6, 12, and 18 months by cystoscopy.
RESULTS
Patients who received neoadjuvant electromotive drug administration of mitomycin C before TURBT in combination with BCG had a low recurrence rate compared with those who received BCG alone (12.0% vs. 48.0%, respectively; p=0.012) and a longer disease-free interval (88.0% vs. 52.0%, respectively; p=0.012). Four patients developed progression to muscle-invasive disease (16.0%) in the BCG alone group. However, this difference was not statistically significant (p=0.516). Regarding adverse effects, there were no statistically significant differences between the groups.
CONCLUSIONS
Neoadjuvant intravesical electromotive drug administration of mitomycin C before TURBT is safe; reduces recurrence rates and enhances the disease-free interval compared with TURBT followed by BCG alone.
Topics: Humans; Mitomycin; BCG Vaccine; Neoadjuvant Therapy; Non-Muscle Invasive Bladder Neoplasms; Urinary Bladder Neoplasms
PubMed: 37932566
DOI: 10.4111/icu.20230161 -
Research Square Oct 2023Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug...
BACKGROUND
Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic symptoms. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs for disease modelling remain key challenges to study human nociception . Here, we report a detailed characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol).
METHODS
Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Expression profiling of sensory neurons was performed with Immunocytochemistry and in situ hybridization techniques. Manual patch clamp and high throughput cellular screening systems (Fluorescence imaging plate reader, automated patch clamp and multi-well microelectrode arrays recordings) were applied to functionally characterize the generated sensory neurons.
RESULTS
The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. High throughput systems confirmed functional expression of Na and K ion channels. Multi-well microelectrode recordings display spontaneously active neurons with sensitivity to increased temperature indicating expression of heat sensitive ion channels. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model.
CONCLUSIONS
We validated the efficiency of two differentiation protocols and their potential application for understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.
PubMed: 37961300
DOI: 10.21203/rs.3.rs-3127017/v1 -
Pharmaceutics Oct 2023Mill. (Cs), a plant traditionally employed in nutrition and to treat various respiratory and gastrointestinal infections, possesses cancer chemopreventive...
Mill. (Cs), a plant traditionally employed in nutrition and to treat various respiratory and gastrointestinal infections, possesses cancer chemopreventive characteristics. In particular, Cs bark extract previously demonstrated antiproliferative and pro-apoptotic activities against a leukemic lymphoblastic cell line. Starting from this evidence, the aim of this paper was to investigate the possibility to affect also the earlier phases of the carcinogenic process by evaluating Cs bark extract's antimutagenic properties, in particular using the "In Vitro Mammalian Cell Micronucleus Test" on TK6 cells performed by flow cytometry. For this purpose, since an ideal chemopreventive agent should be virtually nontoxic, the first step was to exclude the extract's genotoxicity. Afterwards, the antimutagenic effect of the extract was evaluated against two known mutagens, the clastogen mitomycin C (MMC) and the aneugen vinblastine (VINB). Our results indicate that Cs bark extract protected cells from MMC-induced damage (micronuclei frequency fold increase reduction from 2.9 to 1.8) but not from VINB. Moreover, we demonstrated that Cs bark extract was a strong antioxidant and significantly reduced MMC-induced ROS levels by over 2 fold. Overall, our research supports the assumption that Cs bark extract can counteract MMC mutagenicity by possibly scavenging ROS production.
PubMed: 37896225
DOI: 10.3390/pharmaceutics15102465 -
Microbiome Research Reports 2023Temperate phages are known to heavily impact the growth of their host, be it in a positive way, e.g., when beneficial genes are provided by the phage, or negatively...
Temperate phages are known to heavily impact the growth of their host, be it in a positive way, e.g., when beneficial genes are provided by the phage, or negatively when lysis occurs after prophage induction. This study provides an in-depth look into the distribution and variety of prophages in (). This species is found in a wide variety of ecological niches and is routinely used as a meat starter culture. Fourty five genomes were screened for prophages. The intact predicted prophages and their chromosomal integration loci were described. Six lysogens were analysed for phage-mediated lysis post induction via UV light and/or mitomycin C. Their lysates were analysed for phage particles via viral DNA sequencing and transmission electron microscopy. Two hundred and six prophage sequences of any completeness were detected within genomes. The 50 as intact predicted prophages show high levels of genetic diversity on an intraspecies level with conserved regions mostly in the replication and head/tail gene clusters. Twelve chromosomal loci, mostly tRNA genes, were identified, where intact phages were integrated. The six analysed lysogens showed strain-dependent lysis in various degrees after induction, yet only four of their lysates appeared to contain fully assembled virions with the siphovirus morphotype. Our data demonstrate that is a (pro)phage-susceptible species, harbouring multiple intact prophages and remnant sequences thereof. This knowledge provides a basis to study phage-host interaction influencing microbial communities in food fermentations.
PubMed: 38045928
DOI: 10.20517/mrr.2023.18