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Antibiotics (Basel, Switzerland) Feb 2024The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections...
The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of , a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance. These results imply that mitomycin C is a substrate of the RND efflux pumps. Mitomycin C monotherapy successfully treated infected larvae, albeit at doses too high for human administration. Checkerboard and time-kill assays showed that the combination of mitomycin C with pentamidine, or the antibiotic gentamicin, resulted in synergistic inhibition of most strains in vitro. In vivo, administration of a combination therapy of mitomycin C with pentamidine, or gentamicin, to larvae infected with resulted in enhanced efficacy compared with monotherapies for the majority of MDR clinical isolates. Notably, the therapeutic benefit conferred by the combination therapy occurred with doses of mitomycin C close to those used in human medicine. Thus, repurposing mitomycin C in combination therapies to target MDR infections merits further investigation.
PubMed: 38391563
DOI: 10.3390/antibiotics13020177 -
EBioMedicine Mar 2024BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours.
METHODS
RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median).
PRIMARY ENDPOINT
invasive loco-regional control (ILRC); secondary overall survival.
FINDINGS
Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy.
INTERPRETATION
Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial.
FUNDING
Cancer Research UK, NIHR, MRC.
Topics: Humans; Disease-Free Survival; Dose Fractionation, Radiation; Hypoxia; Mitomycin; Biomarkers; Treatment Outcome
PubMed: 38387404
DOI: 10.1016/j.ebiom.2024.105032 -
European Urology Open Science Feb 2024The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed...
Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.
BACKGROUND AND OBJECTIVE
The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes.
METHODS
Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds.
KEY FINDINGS AND LIMITATIONS
Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning.
CONCLUSIONS AND CLINICAL IMPLICATIONS
UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery.
PATIENT SUMMARY
We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.
PubMed: 38375344
DOI: 10.1016/j.euros.2023.12.005 -
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 -
BMC Urology Feb 2024to evaluate the role of urinary URO17® biomarker in the detection of urothelial tumors in haematuria patients and the detection of recurrence in non-muscle invasive...
OBJECTIVE
to evaluate the role of urinary URO17® biomarker in the detection of urothelial tumors in haematuria patients and the detection of recurrence in non-muscle invasive bladder urothelial tumors.
MATERIALS AND METHODS
Our study was formed of two cohorts of patients, group I represents patients presenting with haematuria (n = 98), while group II represents patients with known non-muscle invasive bladder cancers on their scheduled follow up cystoscopic investigation (n = 51). For both groups, patients were asked to provide urine samples before cystoscopy, either primary as part of the haematuria investigation or as a scheduled follow-up. Urine samples were sent anonymously for standard urine cytology and URO17® biomarker immunostaining. Results were compared to cystoscopic findings using Chi-square analysis and Fisher's exact test (P < 0.05).
RESULTS
Group I was formed of 98 patients, with an average age of 60 years. URO17® showed 100% sensitivity and 96.15% specificity with a negative predictive value (NPV) of 100 and a positive predictive value (PPV) of 95.83. The results showed statistical significance with P value < 0.001. Group II was formed of 51 patients, with an average age of 75 years. URO17® was shown to have a sensitivity of 85.71% and NPV of 95.45. Eleven patients of group II were on scheduled BacillusCalmette-Guerin (BCG) and another 5 received Mitomycin C (MMC). The overall results of both groups combined (n = 149) showed statistical significance between flexible cystoscopy results and the results of urinary URO17® and urine cytology.
CONCLUSION
URO17® has a potential to be a reliable test for diagnosis and follow up of urothelial cancer patients and a screening tool adjunct to flexible cystoscopy.
TRIAL REGISTRATION
Not applicable as the current study is not a clinical trial, as per according to the National Institutes of Health, "studies that involve a comparison of methods and that do not evaluate the effect of the interventions on the participant do not meet the NIH clinical trial definition."
Topics: Humans; Middle Aged; Aged; Follow-Up Studies; Hematuria; Urinary Bladder Neoplasms; Urinary Bladder; Cystoscopy; Biomarkers; Neoplasm Recurrence, Local
PubMed: 38336681
DOI: 10.1186/s12894-024-01426-7 -
OncoTargets and Therapy 2024Peritoneal metastases from colorectal cancer (CRC) present a significant clinical challenge with poor prognosis, often unresponsive to systemic chemotherapy....
INTRODUCTION
Peritoneal metastases from colorectal cancer (CRC) present a significant clinical challenge with poor prognosis, often unresponsive to systemic chemotherapy. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment approach for select patients. The use of curcumin, a natural compound with antitumor properties, in HIPEC is of interest due to its lower side effects compared to conventional drugs and potential for increased efficacy through direct delivery to the peritoneal cavity.
METHODS
An in vitro hyperthermic model was developed to simulate clinical HIPEC conditions. Three colon cancer cell lines (SK-CO-1, COLO205, SNU-C1) representing different genetic mutations (p53, KRAS, BRAF) were treated with either curcumin (25 µM) or mitomycin-C (1 µM) for 1, 2, or 3 hours. Post-treatment, cells were incubated at 37°C (normothermia) or 42°C (hyperthermia). Cell viability and proliferation were assessed at 24, 48 and 72 hours post-treatment using Annexin V/PI, MTT assay, trypan blue exclusion, and Hoffman microscopy.
RESULTS
Hyperthermia significantly enhanced the antitumor efficacy of curcumin, evidenced by a two-fold reduction in cell viability compared to normothermia across all cell lines. In the SNU-C1 cell line, which harbors a p53 mutation, mitomycin-C failed to significantly impact cell viability, unlike curcumin, suggesting mutation-specific differences in treatment response.
DISCUSSION
The findings indicate that hyperthermia augments the antitumor effects of curcumin in vitro, supporting the hypothesis that curcumin could be a more effective HIPEC agent than traditional drugs like mitomycin-C. Mutation-associated differences in response to treatments were observed, particularly in p53 mutant cells. While further studies are needed, these preliminary results suggest that curcumin in HIPEC could represent a novel therapeutic strategy for CRC patients with peritoneal metastases. This approach may offer improved outcomes with fewer side effects, particularly in genetically distinct CRC subtypes.
PubMed: 38313386
DOI: 10.2147/OTT.S448024 -
Sensing chemical-induced DNA damage using CRISPR/Cas9-mediated gene-deletion yeast-reporter strains.Applied Microbiology and Biotechnology Feb 2024Microorganism-based genotoxicity assessments are vital for evaluating potential chemical-induced DNA damage. In this study, we developed both chromosomally integrated...
Microorganism-based genotoxicity assessments are vital for evaluating potential chemical-induced DNA damage. In this study, we developed both chromosomally integrated and single-copy plasmid-based reporter assays in budding yeast using a RNR3 promoter-driven luciferase gene. These assays were designed to compare the response to genotoxic chemicals with a pre-established multicopy plasmid-based assay. Despite exhibiting the lowest luciferase activity, the chromosomally integrated reporter assay showed the highest fold induction (i.e., the ratio of luciferase activity in the presence and absence of the chemical) compared with the established plasmid-based assay. Using CRISPR/Cas9 technology, we generated mutants with single- or double-gene deletions, affecting major DNA repair pathways or cell permeability. This enabled us to evaluate reporter gene responses to genotoxicants in a single-copy plasmid-based assay. Elevated background activities were observed in several mutants, such as mag1Δ cells, even without exposure to chemicals. However, substantial luciferase induction was detected in single-deletion mutants following exposure to specific chemicals, including mag1Δ, mms2Δ, and rad59Δ cells treated with methyl methanesulfonate; rad59Δ cells exposed to camptothecin; and mms2Δ and rad10Δ cells treated with mitomycin C (MMC) and cisplatin (CDDP). Notably, mms2Δ/rad10Δ cells treated with MMC or CDDP exhibited significantly enhanced luciferase induction compared with the parent single-deletion mutants, suggesting that postreplication and for nucleotide excision repair processes predominantly contribute to repairing DNA crosslinks. Overall, our findings demonstrate the utility of yeast-based reporter assays employing strains with multiple-deletion mutations in DNA repair genes. These assays serve as valuable tools for investigating DNA repair mechanisms and assessing chemical-induced DNA damage. KEY POINTS: • Responses to genotoxic chemicals were investigated in three types of reporter yeast. • Yeast strains with single- and double-deletions of DNA repair genes were tested. • Two DNA repair pathways predominantly contributed to DNA crosslink repair in yeast.
Topics: Saccharomyces cerevisiae; CRISPR-Cas Systems; DNA Damage; Mitomycin; Luciferases; DNA
PubMed: 38300351
DOI: 10.1007/s00253-024-13020-w -
American Journal of Ophthalmology Case... Mar 2024To present the clinical outcome of mitomycin intravascular chemoembolization (MICE) as a prophylactic treatment in a patient with HSV-induced corneal neovascularization...
PURPOSE
To present the clinical outcome of mitomycin intravascular chemoembolization (MICE) as a prophylactic treatment in a patient with HSV-induced corneal neovascularization (NV) before penetrating keratoplasty (PKP).
OBSERVATIONS
A 53-year-old male patient presented with a medical history of recurrent herpes simplex virus (HSV) corneal infection. The patient reported worsening visual acuity despite maintenance treatment with systemic antivirals and topical corticosteroids. After the appearance of corneal NV, subconjunctival triamcinolone and bevacizumab injections were given with limited and temporary improvement. Due to worsening corneal NV, MICE was subsequently performed, resulting in the elimination of corneal NV from the visual axis, which allowed for successful PKP 4 months later. Cataract surgery was performed 6 months after PKP.
CONCLUSIONS AND IMPORTANCE
This report describes the potential efficacy of MICE as a prophylactic treatment for corneal NV prior to PKP.
PubMed: 38298265
DOI: 10.1016/j.ajoc.2024.101993 -
European Urology Oncology Jan 2024Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non-muscle-invasive...
BACKGROUND
Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non-muscle-invasive bladder cancer (NMIBC). The implementation of a quality performance indicator (QPI) programme in Scotland's National Health Service (NHS) aimed to improve cancer outcomes and reduce nationwide variance.
OBJECTIVE
To evaluate the effect of hospitals achieving benchmarks for two specific QPIs on time to recurrence and progression in NMIBC.
DESIGN, SETTING, AND PARTICIPANTS
QPIs for bladder cancer (BC) were enforced nationally in April 2014. NHS health boards collected prospective data on all new BC patients. Prospectively recorded surveillance data were pooled from 12 collaborating centres.
INTERVENTION
QPIs of interest were (1) hospitals achieving detrusor muscle (DM) sampling target at initial transurethral resection of bladder tumour (TURBT) and (2) use of single instillation of mitomycin C after TURBT (SI-MMC).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary and secondary endpoints were time to recurrence and progression, respectively. Kaplan-Meier and Cox multivariable regression analyses were performed.
KEY FINDINGS AND LIMITATIONS
Between April 1, 2014 and March 31, 2017, we diagnosed 3899 patients with new BC, of which 2688 were NMIBC . With a median follow up of 60.3 mo, hospitals achieving the DM sampling target had a 5.4% lower recurrence rate at 5 yr than hospitals not achieving this target (442/1136 [38.9%] vs 677/1528 [44.3%], 95% confidence interval [CI] = 1.6-9.2, p = 0.005). SI-MMC was associated with a 20.4% lower recurrence rate (634/1791 [35.4%] vs 469/840 [55.8%], 95% CI = 16.4-24.5, p < 0.001). On Cox multivariable regression, meeting the DM target and SI-MMC were associated with significant improvement in recurrence (hazard ratio [HR] 0.81, 95% CI = 0.73-0.91, p = 0.0002 and HR 0.66, 95% CI = 0.59-0.74, p < 0.004, respectively) as well as progression-free survival (HR 0.62, 95% CI = 0.45-0.84, p = 0.002 and HR 0.65, 95% CI = 0.49-0.87, p = 0.004, respectively). We did not have a national multicentre pre-QPI control.
CONCLUSIONS
Within a national QPI programme, meeting targets for sampling DM and SI-MMC in the real world were independently associated with delays to recurrence and progression in NMIBC patients.
PATIENT SUMMARY
Following the first 3 yr of implementing a novel quality performance indicator programme in Scotland, we evaluated compliance and outcomes in non-muscle-invasive bladder cancer. In 2688 patients followed up for 5 yr, we found that achieving targets for sampling detrusor muscle and the single instillation of mitomycin C during and after transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression.
PubMed: 38296735
DOI: 10.1016/j.euo.2024.01.012 -
Ophthalmology Science 2024Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic...
PURPOSE
Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery.
DESIGN
Preclinical study using a rabbit model of glaucoma filtration surgery.
SUBJECTS
Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes.
METHODS
Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring.
MAIN OUTCOME MEASURES
The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology.
RESULTS
Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, < 0.01). Bleb histology did not reveal any significant toxicity in verteporfin-treated eyes. There were no significant differences in inflammation or scarring across groups.
CONCLUSIONS
Although verteporfin remained inferior to MMC with regard to surgical survival, there was a trend toward increased survival compared with BSS control and it had an excellent safety profile. Further studies with variations in verteporfin dosage and/or application frequency are needed to assess whether this may be a useful adjunct to glaucoma surgery.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38261964
DOI: 10.1016/j.xops.2023.100448