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Diagnostic Microbiology and Infectious... Mar 2024Gepotidacin (GSK2140944) is a novel, bactericidal, first in class triazaacenaphthylene bacterial type II topoisomerase inhibitor in development for the treatment of...
Intermethod comparability analyses of gepotidacin antimicrobial susceptibility tests using a large collection of globally collected Escherichia coli and Staphylococcus saprophyticus clinical isolates.
Gepotidacin (GSK2140944) is a novel, bactericidal, first in class triazaacenaphthylene bacterial type II topoisomerase inhibitor in development for the treatment of uncomplicated urinary tract infections and gonorrhea. The performance of several antimicrobial susceptibility methods (broth microdilution, gradient diffusion, and disk diffusion) for gepotidacin were evaluated using over 5800 recent Escherichia coli and Staphylococcus saprophyticus clinical isolates. Reference broth microdilution gepotidacin MICs showed an essential agreement of 95.9 % and 98.1 % with MICs by gradient diffusion for E. coli and S. saprophyticus isolates, respectively. Gepotidacin susceptibility using disks produced by 2 manufacturers had good agreement with an R values of 0.95 and 99.2 % of overall zone diameters agreeing within 3 mm. A correlation with an overall R value of 0.72 between MICs by broth microdilution and zone diameters by disk diffusion was observed. This data should assist in the clinical development of gepotidacin and provide reliable susceptibility methods to evaluate its activity.
Topics: Humans; Escherichia coli; Staphylococcus saprophyticus; Anti-Bacterial Agents; Acenaphthenes; Mitomycin; Microbial Sensitivity Tests; Heterocyclic Compounds, 3-Ring
PubMed: 38215519
DOI: 10.1016/j.diagmicrobio.2024.116181 -
Journal of Clinical Medicine Dec 2023The XEN45 is a minimally invasive glaucoma surgery device commonly used in clinical practice. This retrospective study included consecutive patients with open-angle...
The XEN45 is a minimally invasive glaucoma surgery device commonly used in clinical practice. This retrospective study included consecutive patients with open-angle glaucoma who underwent a XEN45 implant with mitomycin C, either alone or in combination with phacoemulsification, between June 2015 and March 2021. The primary end point was the mean change in intraocular pressure (IOP) from the baseline to month 6. A total of 677 eyes, 395 (58.3%) in the XEN alone group and 282 (41.7%) in the XEN+Phaco group, were included in this study. The preoperative IOP was significantly lowered from 28.7 ± 8.6 mmHg and 25.4 ± 6.9 mmHg to 13.5 ± 5.0 mmHg and 13.5 ± 4.1 mmHg at month 6 in the XEN solo and XEN+Phaco groups, respectively, with < 0.0001 each. The mean (95% confidence interval) number of ocular hypotensive medications was significantly reduced from 3.3 (3.2-3.4) to 0.2 (0.1-0.2) and from 3.1 (2.9-3.2) to 0.2 (0.1-0.2) in the XEN solo and XEN+Phaco groups, respectively, with < 0.0001 each. Needling was performed in 228 (33.7%) eyes. Conclusions: the XEN implant significantly reduces both IOP and the number of ocular hypotensive medications. IOP lowering was higher in the XEN solo group than in the XEN+Phaco one, although such a difference was only evident during the first month after surgery.
PubMed: 38202164
DOI: 10.3390/jcm13010157 -
Ophthalmology Jul 2024To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in patients with advanced glaucoma.
DESIGN
Multicenter randomized controlled trial.
PARTICIPANTS
Between June 3, 2014, and May 31, 2017, 453 adults with newly diagnosed advanced open-angle glaucoma in at least 1 eye (Hodapp classification) were recruited from 27 secondary care glaucoma departments in the United Kingdom. Two hundred twenty-seven were allocated to trabeculectomy, and 226 were allocated medical management.
METHODS
Participants were randomized on a 1:1 basis to have either mitomycin C-augmented trabeculectomy or escalating medical management with intraocular pressure (IOP)-reducing drops as the primary intervention and were followed up for 5 years.
MAIN OUTCOME MEASURES
The primary outcome was vision-specific QoL measured with the 25-item Visual Function Questionnaire (VFQ-25) at 5 years. Secondary outcomes were general health status, glaucoma-related QoL, clinical effectiveness (IOP, visual field, and visual acuity), and safety.
RESULTS
At 5 years, the mean ± standard deviation VFQ-25 scores in the trabeculectomy and medication arms were 83.3 ± 15.5 and 81.3 ± 17.5, respectively, and the mean difference was 1.01 (95% confidence interval [CI], -1.99 to 4.00; P = 0.51). The mean IOPs were 12.07 ± 5.18 mmHg and 14.76 ± 4.14 mmHg, respectively, and the mean difference was -2.56 (95% CI, -3.80 to -1.32; P < 0.001). Glaucoma severity measured with visual field mean deviation were -14.30 ± 7.14 dB and -16.74 ± 6.78 dB, respectively, with a mean difference of 1.87 (95% CI, 0.87-2.87 dB; P < 0.001). Safety events occurred in 115 (52.2%) of patients in the trabeculectomy arm and 124 (57.9%) of patients in the medication arm (relative risk, 0.92; 95% CI, 0.72-1.19; P = 0.54). Serious adverse events were rare.
CONCLUSIONS
At 5 years, the Treatment of Advanced Glaucoma Study demonstrated that primary trabeculectomy surgery is more effective in lowering IOP and preventing disease progression than primary medical treatment in patients with advanced disease and has a similar safety profile.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Trabeculectomy; Male; Intraocular Pressure; Female; Quality of Life; Visual Acuity; Aged; Antihypertensive Agents; Visual Fields; Glaucoma, Open-Angle; Middle Aged; Mitomycin; Surveys and Questionnaires; Follow-Up Studies; Treatment Outcome; Tonometry, Ocular; Sickness Impact Profile; Ophthalmic Solutions; Alkylating Agents; Aged, 80 and over
PubMed: 38199528
DOI: 10.1016/j.ophtha.2024.01.007 -
Breast Cancer Research : BCR Jan 2024Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
BACKGROUND
Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
METHODS
We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.
RESULTS
Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.
CONCLUSIONS
This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
Topics: Humans; Male; BRCA1 Protein; Breast Neoplasms; Exons; Fanconi Anemia; Mitomycin; Phenotype
PubMed: 38195559
DOI: 10.1186/s13058-023-01755-9 -
EMBO Reports Feb 2024FANCJ, a DNA helicase linked to Fanconi anemia and frequently mutated in cancers, counteracts replication stress by dismantling unconventional DNA secondary structures...
FANCJ, a DNA helicase linked to Fanconi anemia and frequently mutated in cancers, counteracts replication stress by dismantling unconventional DNA secondary structures (such as G-quadruplexes) that occur at the DNA replication fork in certain sequence contexts. However, how FANCJ is recruited to the replisome is unknown. Here, we report that FANCJ directly binds to AND-1 (the vertebrate ortholog of budding yeast Ctf4), a homo-trimeric protein adaptor that connects the CDC45/MCM2-7/GINS replicative DNA helicase with DNA polymerase α and several other factors at DNA replication forks. The interaction between FANCJ and AND-1 requires the integrity of an evolutionarily conserved Ctf4-interacting protein (CIP) box located between the FANCJ helicase motifs IV and V. Disruption of the CIP box significantly reduces FANCJ association with the replisome, causing enhanced DNA damage, decreased replication fork recovery and fork asymmetry in cells unchallenged or treated with Pyridostatin, a G-quadruplex-binder, or Mitomycin C, a DNA inter-strand cross-linking agent. Cancer-relevant FANCJ CIP box variants display reduced AND-1-binding and enhanced DNA damage, a finding that suggests their potential role in cancer predisposition.
Topics: Humans; DNA; DNA Replication; Genomic Instability; Minichromosome Maintenance Proteins; Neoplasms
PubMed: 38177925
DOI: 10.1038/s44319-023-00044-y -
Cureus Dec 20235-fluorouracil (5-FU) is a well-known chemotherapeutic agent used for the treatment of colon cancer and other solid malignancies. Dihydropyrimidine dehydrogenase (DPD)...
5-fluorouracil (5-FU) is a well-known chemotherapeutic agent used for the treatment of colon cancer and other solid malignancies. Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catalyzes 5-FU, and if a patient is deficient, such as through a gene mutation, they can be predisposed to severe toxicity. Although 5-FU-induced neurotoxicity is extremely rare, it can be fatal. We report a case of 5-FU neurotoxicity in a 56-year-old male patient with keratinizing squamous cell carcinoma of the anal canal on concurrent chemoradiation therapy consisting of 5-FU, mitomycin, and radiotherapy. Encephalopathy, dysarthria, and ataxia were noted on day three of treatment. MRI of the brain showed a pattern of global anoxic brain injury. DPD testing was negative for polymorphism, and the patient's symptoms improved after treatment with uridine triacetate, the treatment for 5-FU toxicity.
PubMed: 38174188
DOI: 10.7759/cureus.49898 -
JGH Open : An Open Access Journal of... Dec 2023Transcatheter arterial chemoembolization (TACE) using various anticancer drugs is often performed to treat hepatocellular carcinoma (HCC). We aimed to compare the...
BACKGROUND AND AIM
Transcatheter arterial chemoembolization (TACE) using various anticancer drugs is often performed to treat hepatocellular carcinoma (HCC). We aimed to compare the therapeutic efficacy and side effects of TACE with anticancer drugs transcatheter arterial embolization (TAE) without anticancer drugs for HCC.
METHODS
Patients with HCC were randomized to either the TACE or TAE group. Up to five target nodules were treated in each patient. Lipiodol (Lp; 10 mL), contrast media (CM; 10 mL), epirubicin (40 mg), mitomycin C (10 mg), miliplatin (70 mg), and 1-2-mm 2-day soluble gelatin sponge particles (2D-SGS) were injected into the TACE group, whereas Lp (10 mL), CM (10 mL), and 2D-SGS were injected into the TAE group. Treatment effect (TE) of the target nodules was graded (TE1-TE4) and patient responses were assessed. Three months after treatment, blood tests were performed to compare tumor markers and adverse events.
RESULTS
Fifty-four patients and 161 target nodules were included; 75 nodules in 28 patients were treated by TACE, and 86 nodules in 26 patients were treated by TAE. The number of nodules graded TE1, TE2, TE3, and TE4 was 1, 28, 7, and 39, respectively, in the TACE group and 2, 25, 7, and 52, respectively, in the TAE group. The response rates were 89% (25/28) and 73% (19/26) in the TACE and TAE groups, respectively. There were no significant differences in TE, response rates, or blood test results between the two groups.
CONCLUSION
In hepatic arterial embolization for HCC, anticancer drugs did not have any impact on the therapeutic efficacy or side effects at 3 months after embolization.
PubMed: 38162847
DOI: 10.1002/jgh3.12997 -
Global Health & Medicine Dec 2023Hepatocellular carcinoma (HCC) was featured as spontaneous rupture hemorrhage under intratumoral overpressure. Spontaneous rupture hepatocellular carcinoma (srHCC) has a...
The prophylactic role of mitomycin C-based hyperthermic intraperitoneal chemotherapy (MMC-based HIPEC) on peritoneal metastasis of spontaneously ruptured hepatocellular carcinoma (srHCC): A pilot study.
Hepatocellular carcinoma (HCC) was featured as spontaneous rupture hemorrhage under intratumoral overpressure. Spontaneous rupture hepatocellular carcinoma (srHCC) has a high propensity for peritoneal metastasis (PM). Although HIPEC has become standard treatment for malignancies with PM, it has been poorly described in srHCC. We conducted a single-arm, open-label, single-center, prospective study to explore the prophylactic role of MMC-based HIPEC on PM of srHCC. A total of 7 patients were collected from April 1, 2021 to April 30, 2022. HIPEC was conducted 3 times on the first, third and fifth postoperative days. 15 mg/m2 of MMC was used with 60 minutes perfusion at 43°C. The primary end-point was local peritoneum recurrence free survival (RFS), whereas the secondary end-point was systemic RFS and overall survival (OS). The mean hepatectomy operation time was 232 minutes (SD: 124.08 minutes). The median bleeding loss was 200 mL (range 50-400 mL). The mean hospital stay was 13 days (SD: 3.42 days). Only mild abdominal distension was reported in 4 patients (57%). There were no patients who suffered from life-threatening intra-abdominal and extra-abdominal complications (EAC). At the data cut-off (April 30, 2023), one patient (14%) had died due to cachexia. Local peritoneal recurrence occurred in three patients (43%). Median follow-up was 16.1 months (IQR: 12.8-16.6 months). Median local peritoneum RFS was 12.3 months (95% CI: 7.0- 17.5; 4 events) and median overall RFS was 7.5 months (95% CI: 4.2-10.8; 6 events). MMC-based HIPEC was safe and feasible in selected patients of srHCC. It showed a positive tendency in preventing PM, but large-scale research should be continued.
PubMed: 38162434
DOI: 10.35772/ghm.2023.01081 -
Saudi Journal of Ophthalmology :... 2023The purpose of the study was to evaluate the visual outcomes and recurrence rate of patients with macular corneal dystrophy (MCD) who have undergone phototherapeutic...
PURPOSE
The purpose of the study was to evaluate the visual outcomes and recurrence rate of patients with macular corneal dystrophy (MCD) who have undergone phototherapeutic keratectomy (PTK).
METHODS
This retrospective, single-centered study enrolled patients from King Khaled Eye Specialist Hospital who had undergone PTK for MCD between 2000 and 2020. Pre-, intra-, and post-operative data were collected, and the primary outcome measures included uncorrected visual acuity, best-corrected visual acuity (BCVA), spherical equivalent, central keratometry, keratometric astigmatism, recurrence rate, and necessity of subsequent surgery.
RESULTS
This study evaluated 42 eyes of 29 patients. BCVA improved from 0.41 (±0.17) preoperatively to 0.30 (±0.16) postoperatively. Sixteen out of 42 eyes (38%) had the recurrence of macular dystrophy deposits within the stroma; the average time from PTK to recurrence was 37 months (range: 5.5-115.4 months). The overall success rate of PTK at 2 years was 44.8%. Eleven eyes (26%) required subsequent surgery following PTK at an average of 43 months postoperatively. Deeper ablation and longer application of mitomycin C (MMC) were both found to be statistically significant factors associated with visual improvement and lower recurrence rate following PTK.
CONCLUSION
PTK can be considered a treatment modality for younger patients to defer keratoplasty to a later stage. Deeper ablation is associated with improved postoperative visual acuity, and longer application of MMC is associated with lower recurrence rates of MCD.
PubMed: 38155672
DOI: 10.4103/sjopt.sjopt_194_22 -
Indian Journal of Ophthalmology Mar 2024Filtration surgery is one of the most frequently performed surgeries in the management of glaucoma, and trabeculectomy is considered the gold standard surgical technique... (Review)
Review
Filtration surgery is one of the most frequently performed surgeries in the management of glaucoma, and trabeculectomy is considered the gold standard surgical technique for the same. Though trabeculectomy has been reported to have an excellent initial success rate, about 30% of them fail in 3 years, and nearly 50% of them fail in 5 years. The most significant risk of failure still seems to be wound scarring, especially episcleral fibrosis, leading to bleb failure. As a result, it is essential to explore the role of anti-scarring agents, including mitomycin C, and 5-fluorouracil in wound modulation and improving the bleb survival rate. Since these agents are widely used in trabeculectomy, it is crucial to understand the various modes of application, advantages, and adverse effects of these agents. On an evidence-based approach, all these points have been highlighted in this review article. In addition, the newer agents available for wound modulation and their scope for practical application are discussed.
Topics: Humans; Cicatrix; Intraocular Pressure; Glaucoma; Trabeculectomy; Fluorouracil; Mitomycin
PubMed: 38153968
DOI: 10.4103/IJO.IJO_2013_23