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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 -
Frontiers in Surgery 2024Radical nephroureterectomy with concurrent bladder cuff excision (RNUBCE) is the gold standard surgical approach for high-risk primary upper tract urothelial carcinoma...
INTRODUCTION
Radical nephroureterectomy with concurrent bladder cuff excision (RNUBCE) is the gold standard surgical approach for high-risk primary upper tract urothelial carcinoma (UTUC). Given the notably high incidence of bladder tumor recurrence following this procedure, this study aimed to evaluate the effect and safety of intraoperative mitomycin-C (MMC) instillation vs. deferred instillation on overall oncological outcomes following robot-assisted RNUBCE.
METHODS
This is a retrospective chart review study. Patients with non-invasive (N0, not T3/T4) UTUC who underwent robotic RNUBCE combined an intraoperative MMC instillation or a deferred MMC instillation after surgery at a medical center in Taiwan between November 2013 and June 2020 were eligible for inclusion. Patients with prior bladder UC, carcinomas of other origins, received neoadjuvant chemotherapy, and had undergone kidney transplantation were excluded. All surgeries were executed by a single surgical team under the guidance of the same surgeon. The primary outcomes was the risk of bladder tumor recurrence between patients received intraoperative (IO) vs. deferred MMC instillation postoperatively (PO) during one-year follow-up. The secondary outcome was postoperative adverse events assessed by the Clavien-Dindo classification. Univariate and multivariable Cox regression analyses were performed to determine the associations between study variables and the outcomes.
RESULTS
A total of 54 patients were included in the analysis. 12 (22.2%) patients experienced a bladder tumor recurrence during follow-up (IO: 7.7%, PO: 35.7%, < 0.021). After adjustment in the multivariable, intraoperative MMC instillation was significantly associated with lower risk of bladder recurrence [adjusted hazard ratio (aHR) = 0.15, 95% CI: 0.03-0.81, = 0.028]. No MMC-related Clavien-Dindo Grade III-IV adverse events were found in either group.
CONCLUSION
IIntraoperative MMC instillation is safe and associated with a lower bladder tumor recurrence risk in patients undergoing robotic RNUBCE for UTUC than deferred instillation. Future large, prospective studies are still warranted to confirm the findings.
PubMed: 38726470
DOI: 10.3389/fsurg.2024.1366982 -
BJS Open May 2024This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international...
BACKGROUND
This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients.
PATIENTS AND METHODS
Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed.
RESULTS
Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period.
CONCLUSIONS
Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.
Topics: Humans; Colorectal Neoplasms; Male; Female; Hyperthermic Intraperitoneal Chemotherapy; Middle Aged; Peritoneal Neoplasms; Mitomycin; Aged; Oxaliplatin; Cytoreduction Surgical Procedures; Retrospective Studies; Adult; Antineoplastic Combined Chemotherapy Protocols; Propensity Score; Disease-Free Survival; Treatment Outcome; Proportional Hazards Models
PubMed: 38722737
DOI: 10.1093/bjsopen/zrae017 -
International Journal of Ophthalmology 2024To compare the success rate and complications of adjuvant use of mitomycin C and triamcinolone-impregnated biodegradable nasal packing (TABP) in endoscopic...
AIM
To compare the success rate and complications of adjuvant use of mitomycin C and triamcinolone-impregnated biodegradable nasal packing (TABP) in endoscopic dacryocystorhinostomy (DCR). And to evaluate the efficacy of combining intraoperative mitomycin C and TABP for endoscopic DCR.
METHODS
A total of 198 eyes of 148 patients who underwent endoscopic DCR for acquired nasolacrimal duct obstruction were retrospectively analysed. The patients were randomly divided into three groups: Group A included patients treated without intraoperative mitomycin C but with TABP, Group B included patients treated without triamcinolone but with intraoperative mitomycin C and normal saline-impregnated nasal packing, and Group C included patients treated with intraoperative mitomycin C and TABP.
RESULTS
The results revealed no significant difference in the overall success rates between Groups A (86.8%) and B (89.2%; =0.377). However, Group C (97.5%) showed a significantly higher overall success rate than Groups A and B. The incidence of granulomas was significantly lower in group C (5%) than in Groups A (20.8%) and B (15.2%; =0.009). Other complications, such as crust, synechiae, and revision surgery, did not differ significantly among the three groups.
CONCLUSION
The combination of intraoperative mitomycin C and TABP effectively prevents granulomas and enhances surgical success rate. Additionally, there is no statistically significant difference observed between the use of mitomycin C or TABP alone.
PubMed: 38721511
DOI: 10.18240/ijo.2024.03.09 -
Translational Andrology and Urology Apr 2024
PubMed: 38721287
DOI: 10.21037/tau-23-569 -
Journal of Translational Medicine May 2024To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation...
PURPOSE
To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation by transforming growth factor (TGF)-β1 in rat Tenon's capsule fibroblasts.
METHODS
Cultured rat Tenon's capsule fibroblasts were treated with TGF-β1 and analyzed with microarrays for mRNA profiling to validate miR-146a as the target. The Tenon's capsule fibroblasts were then respectively treated with lentivirus-mediated transfection of miR-146a mimic or inhibitor following TGF-β1 stimulation in vitro, while GFS was performed in rat eyes with respective intraoperative administration of miR-146a, mitomycin C (MMC), or 5-fluorouracil (5-FU) in vivo. Profibrotic genes expression levels (fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin) were determined through qPCR, Western blotting, immunofluorescence staining and/or histochemical analysis in vitro and in vivo. SMAD4 targeting siRNA was further used to treat the fibroblasts in combination with miR-146a intervention to confirm its role in underlying mechanisms.
RESULTS
Upregulation of miR-146a reduced the proliferation rate and profibrotic changes of rat Tenon's capsule fibroblasts induced by TGF-β1 in vitro, and mitigated subconjunctival fibrosis to extend filtering blebs survival after GFS in vivo, where miR-146a decreased expression levels of NF-KB-SMAD4-related genes, such as fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin(α-SMA). Additionally, SMAD4 is a key target gene in the process of miR-146a inhibiting fibrosis.
CONCLUSIONS
MiR-146a effectively reduced TGF-β1-induced fibrosis in rat Tenon's capsule fibroblasts in vitro and in vivo, potentially through the NF-KB-SMAD4 signaling pathway. MiR-146a shows promise as a novel therapeutic target for preventing fibrosis and improving the success rate of GFS.
Topics: Animals; MicroRNAs; Fibrosis; Glaucoma; Filtering Surgery; Fibroblasts; Rats, Sprague-Dawley; Male; Tenon Capsule; Cell Proliferation; Transforming Growth Factor beta1; Rats; Smad4 Protein; NF-kappa B; Mitomycin; Gene Expression Regulation
PubMed: 38720358
DOI: 10.1186/s12967-024-05170-2 -
Dose-response : a Publication of... 2024We have been conducting a collaborative study on the thresholds of mutagens. In our previous examinations of cell activity and cell proliferation as endpoints, both...
BACKGROUND
We have been conducting a collaborative study on the thresholds of mutagens. In our previous examinations of cell activity and cell proliferation as endpoints, both displayed hormesis. This time, we conducted experiments to determine thresholds using the micronucleus test as an endpoint.
METHODS
The micronucleus test was conducted using Chinese hamster CHL/IU cells and mouse lymphoid L5178Y cells. Additionally, we conducted preliminary investigations into the gene expression using human TK6 cells.
RESULTS
When adhesive CHL/IU cells were treated with mitomycin C (MMC), and the hormetic response was examined, hormesis was not observed clearly. When L5178Y cells were treated with methyl methanesulfonate (EMS), AF-2, MMC, and colchicine, all of them exhibited an adaptive response. Additionally, cross-adaptive responses using AF-2 and MMC or EMS and MMC were conducted, both combinations showed a cross-adaptive response. When the gene expression patterns of six genes were investigated by RT-PCR after treatment with MMC, EMS, and HO using TK6 cells, two genes, and , were induced in a dose- and time-dependent manner.
CONCLUSION
Adaptive responses arise from preconditioning. As hormesis is inherently linked to preconditioning, adaptive responses observed in this study strongly suggest that hormesis was induced, hence existence of thresholds.
PubMed: 38715588
DOI: 10.1177/15593258241252040 -
Frontiers in Oncology 2024DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences...
BACKGROUND
DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.
METHODS
RFWD3 expression and association with clinical features was assessed using analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry. RFWD3 expression was modulated in cell lines using siRNA and CRISPR/cas9 gene editing, and cells were characterised using cytotoxicity and proliferation assays, flow cytometry, and live cell microscopy.
RESULTS
Expression of RFWD3 RNA and protein varied in HGSOCs. In cell lines, reduction of RFWD3 expression led to increased sensitivity to interstrand crosslinking (ICL) inducing agents mitomycin C and carboplatin. RFWD3 also demonstrated further functionality outside its role in DNA damage repair, with RFWD3 deficient cells displaying cell cycle dysregulation, reduced cellular proliferation and reduced migration. In tumours, low RFWD3 expression was associated with increased tumour mutational burden, and complete response to platinum chemotherapy.
CONCLUSION
RFWD3 expression varies in HGSOCs, which can lead to functional effects at both the cellular and tumour levels.
PubMed: 38711848
DOI: 10.3389/fonc.2024.1389472 -
Tierarztliche Praxis. Ausgabe G,... Apr 2024A 17-year-old Appaloosa mare was referred for evaluation of presumed refractory keratitis of the left eye. Gross examination revealed ocular discomfort and corneal...
A 17-year-old Appaloosa mare was referred for evaluation of presumed refractory keratitis of the left eye. Gross examination revealed ocular discomfort and corneal neovascularization with a nasal focal opacification affecting approximately 40% of the corneal surface. On ophthalmic examination, extensive subepithelial to mid-stromal vascular branching accompanied by a homogeneous white, dense opacification, which affected up to 80% of the total corneal thickness, were apparent. Signs of concurrent uveitis were absent. Deep-stromal lamellar keratectomy with a conjunctival pedicle graft was performed under general anesthesia. Histopathology confirmed a poorly differentiated corneal stromal invasive squamous cell carcinoma (SI-SCC) with neoplastic cell extension to the surgical margins. Postoperatively, 4 topical mitomycin C 0.04% chemotherapy cycles combined with oral firocoxib therapy were initiated. Seven months after surgery, regrowth of the SI-SCC was clinically suspected. A total volume of 1 ml bevacizumab 2.5% was administered in the standing sedated horse via 3 mid-stromal corneal injections. Four weeks later, intrastromal bevacizumab injections (ISBIs) were repeated, however, this time the solution was injected directly into the main corneal vessel branches.Seven weeks after the second ISBIs, the left eye was comfortable and significant remission of corneal vascularization and opacity was recognized. No recurrence has been noted for a follow-up period of more than 53 months.Equine SI-SCC usually has a very poor prognosis for globe maintenance. To the authors' knowledge this is the first report of well-tolerated intrastromal antivascular endothelial growth factor adjunctive therapy with bevazicumab 2.5% and SI-SCC resolution after a multimodal treatment approach.
Topics: Horses; Animals; Bevacizumab; Horse Diseases; Female; Carcinoma, Squamous Cell; Eye Neoplasms; Angiogenesis Inhibitors; Corneal Stroma
PubMed: 38701802
DOI: 10.1055/a-2253-8103 -
Journal of Experimental & Clinical... May 2024Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)...
Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside.
BACKGROUND
Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are still high and there is no consensus on the drug of choice for HIPEC. The aim of this study was to use patient derived organoids (PDO) to build a relevant CRCPM model to improve HIPEC efficacy in a comprehensive bench-to-bedside strategy.
METHODS
Oxaliplatin (L-OHP), cisplatin (CDDP), mitomycin-c (MMC) and doxorubicin (DOX) were used to mimic HIPEC on twelve PDO lines derived from twelve CRCPM patients, using clinically relevant concentrations. After chemotherapeutic interventions, cell viability was assessed with a luminescent assay, and the obtained dose-response curves were used to determine the half-maximal inhibitory concentrations. Also, induction of apoptosis by different HIPEC interventions on PDOs was studied by evaluating CASPASE3 cleavage.
RESULTS
Response to drug treatments varied considerably among PDOs. The two schemes with better response at clinically relevant concentrations included MMC alone or combined with CDDP. L-OHP showed relative efficacy only when administered at low concentrations over a long perfusion period. PDOs showed that the short course/high dose L-OHP scheme did not appear to be an effective choice for HIPEC in CRCPM. HIPEC administered under hyperthermia conditions enhanced the effect of chemotherapy drugs against cancer cells, affecting PDO viability and apoptosis. Finally, PDO co-cultured with cancer-associated fibroblast impacted HIPEC treatments by increasing PDO viability and reducing CASPASES activity.
CONCLUSIONS
Our study suggests that PDOs could be a reliable in vitro model to evaluate HIPEC schemes at individual-patient level and to develop more effective treatment strategies for CRCPM.
Topics: Humans; Colorectal Neoplasms; Peritoneal Neoplasms; Hyperthermic Intraperitoneal Chemotherapy; Organoids
PubMed: 38698446
DOI: 10.1186/s13046-024-03052-5