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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 -
Cell Reports May 2023Activation of the Fanconi anemia (FA) pathway after treatment with mitomycin C (MMC) is essential for preventing chromosome translocations termed "radials." When...
Activation of the Fanconi anemia (FA) pathway after treatment with mitomycin C (MMC) is essential for preventing chromosome translocations termed "radials." When replication forks stall at MMC-induced interstrand crosslinks (ICLs), the FA pathway is activated to orchestrate ICL unhooking and repair of the DNA break intermediates. However, in FA-deficient cells, how ICL-associated breaks are resolved in a manner that leads to radials is unclear. Here, we demonstrate that MMC-induced radials are dependent on DNA polymerase theta (POLθ)-mediated alternative end joining (A-EJ). Specifically, we show that radials observed in FANCD2 cells are dependent on POLθ and DNA ligase III and occur independently of classical non-homologous end joining. Furthermore, treatment of FANCD2 cells with POLθ inhibitors abolishes radials and leads to the accumulation of breaks co-localizing with common fragile sites. Uniformly, these observations implicate A-EJ in radial formation and provide mechanistic insights into the treatment of FA pathway-deficient cancers with POLθ inhibitors.
Topics: Humans; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Chromosomes; DNA End-Joining Repair; Mitomycin; DNA Repair
PubMed: 37086407
DOI: 10.1016/j.celrep.2023.112428 -
Cornea Apr 2021To study the possible changes in Scheimpflug corneal densitometry 6 months after mitomycin C-augmented trabeculectomy and to compare these measurements with healthy... (Comparative Study)
Comparative Study
PURPOSE
To study the possible changes in Scheimpflug corneal densitometry 6 months after mitomycin C-augmented trabeculectomy and to compare these measurements with healthy controls.
METHODS
Corneal densitometry was monitored with the Pentacam HR3 before and 6 months after first-time uncomplicated mitomycin C-augmented trabeculectomy in 42 eyes of 42 white patients with open-angle glaucoma and in 22 healthy age-matched controls. Preoperative intraocular pressure (IOP), central corneal thickness, known duration of the disease, gender, the type and number of substances, applications and amount of benzalkonium chloride per day, and postoperative topical cortisone use were tested for possible correlations in the trabeculectomy group.
RESULTS
There was a statistically significant reduction of mean diurnal IOP from 19.0 ± 7.7 to 11.1 ± 7.7 mm Hg (P = 0.003) and the amount of pressure-lowering substances from 3.7 ± 1.0 to 0.1 ± 0.5 (P < 0.001). Densitometry measurements decreased in the entire cornea from 25.5 ± 5.7 to 23.1 ± 5.8 grayscale units (P = 0.001) with emphasis in the anterior layer. They returned close to normal 6 months after trabeculectomy and were not statistically significantly different compared with a healthy control group (22.8 ± 3.4 grayscale unit; P = 0.824). No correlations could be found with these observations and possible causing factors studied.
CONCLUSIONS
Corneal densitometry, an objective and sensitive measure of corneal transparency, returned close to normal 6 months after trabeculectomy. Although the observations cannot be associated with any causing factor in this study, the significant IOP reduction and the nearly complete cessation of topical antiglaucomatous substances including benzalkonium chloride seem to be the most plausible reasons for this finding.
Topics: Aged; Alkylating Agents; Cell Count; Cornea; Densitometry; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Mitomycin; Organ Size; Tonometry, Ocular; Trabeculectomy; Visual Acuity
PubMed: 32732700
DOI: 10.1097/ICO.0000000000002439 -
Cancers Mar 2021Prior to the 1980s, the primary management of localized anal cancer was surgical resection. Dr. Norman Nigro and colleagues introduced neoadjuvant chemoradiotherapy... (Review)
Review
Prior to the 1980s, the primary management of localized anal cancer was surgical resection. Dr. Norman Nigro and colleagues introduced neoadjuvant chemoradiotherapy prior to abdominoperineal resection. Chemoradiotherapy 5-fluorouracil and mitomycin C afforded patients complete pathologic response and obviated the need for upfront surgery. More recent studies have attempted to alter or exclude chemotherapy used in the Nigro regimen to mitigate toxicity, often with worse outcomes. Reductions in acute adverse effects have been associated with marked advancements in radiotherapy delivery using intensity-modulated radiation therapy (IMRT) and image-guidance radiation delivery, resulting in increased tolerance to greater radiation doses. Ongoing trials are attempting to improve IMRT-based treatment of locally advanced disease with efforts to increase personalized treatment. Studies are also examining the role of newer treatment modalities such as proton therapy in treating anal cancer. Here we review the evolution of radiotherapy for anal cancer and describe recent advances. We also elaborate on radiotherapy's role in locally persistent or recurrent anal cancer.
PubMed: 33801992
DOI: 10.3390/cancers13061208 -
European Urology Oct 2021Urethral stricture disease (USD) is initially managed with minimally invasive techniques such as urethrotomy and urethral dilatation. Minimally invasive techniques are... (Meta-Analysis)
Meta-Analysis
CONTEXT
Urethral stricture disease (USD) is initially managed with minimally invasive techniques such as urethrotomy and urethral dilatation. Minimally invasive techniques are associated with a high recurrence rate, especially in recurrent USD. Adjunctive measures, such as local drug injection, have been used in an attempt to reduce recurrence rates.
OBJECTIVE
To systematically review evidence for the efficacy and safety of adjuncts used alongside minimally invasive treatment of USD.
EVIDENCE ACQUISITION
A systematic review of the literature published between 1990 and 2020 was conducted in accordance with the PRISMA checklist.
EVIDENCE SYNTHESIS
A total of 26 studies were included in the systematic review, from which 13 different adjuncts were identified, including intralesional injection (triamcinolone, n = 135; prednisolone, n = 58; mitomycin C, n = 142; steroid-mitomycin C-hyaluronidase, n = 103, triamcinolone-mitomycin C-N-acetyl cysteine, n = 50; platelet-rich plasma, n = 44), intraluminal instillation (mitomycin C, n = 20; hyaluronic acid and carboxymethylcellulose, n = 70; captopril, n = 37; 192-iridium brachytherapy, n = 10), application via a lubricated catheter (triamcinolone, n = 124), application via a coated balloon (paclitaxel, n = 106), and enteral application (tamoxifen, n = 30; deflazacort, n = 36). Overall, 13 randomised controlled trials were included in the meta-analysis. Use of any adjunct was associated with a lower rate of USD recurrence (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.27-0.50; p < 0.001) compared to no adjunct use. Of all the adjuncts, mitomycin C was associated with the lowest rate of USD recurrence (intralesional injection: OR 0.23, 95% CI 0.11-0.48; p < 0.001; intraluminal injection: OR 0.11, 95% CI 0.02-0.61; p = 0.01). Urinary tract infection (2.9-14%), bleeding (8.8%), and extravasation (5.8%) were associated with steroid injection; pruritis of the urethra (61%) occurred after instillation of captopril; mild gynaecomastia (6.7%) and gastrointestinal side effects (6.7%) were associated with oral tamoxifen.
CONCLUSIONS
Adjuncts to minimally invasive treatment of USD appear to lower the recurrence rate and are associated with a low adjunct-specific complication rate. However, the studies included were at high risk of bias. Mitomycin C is the adjunct supported by the highest level of evidence.
PATIENT SUMMARY
We reviewed studies on additional therapies (called adjuncts) to minimally invasive treatments for narrowing of the urethra in men. Adjuncts such as mitomycin C injection result in a lower recurrence rate compared to no adjunct use. The use of adjuncts appeared to be safe and complications are uncommon; however, the studies were small and of low quality.
Topics: Captopril; Humans; Injections, Intralesional; Male; Mitomycin; Recurrence; Tamoxifen; Triamcinolone; Urethra; Urethral Stricture
PubMed: 34275660
DOI: 10.1016/j.eururo.2021.06.022 -
Investigative Ophthalmology & Visual... Sep 2022To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
PURPOSE
To characterize and pharmacologically influence subconjunctival lymphatics in rabbit and mouse eyes.
METHODS
Rabbits received subconjunctival injections of trypan blue or fixable fluorescent dextrans. Bleb-related outflow pathways were quantified. Immunofluorescence for vessel-specific markers (lymphatics [podoplanin and LYVE-1] and blood vessels [CD31]) were performed in native rabbit conjunctiva and after fixable fluorescent dextran injection. Vascular endothelial cell growth factor-C (VEGFC) was injected subconjunctivally in rabbits. mRNA and protein were assessed for the above markers using RT-PCR and Western blot. Alternatively, mouse studies used Prox1-tdTomato transgenic reporter mice. Subconjunctival injection conditions included: no injection, balanced salt solution (BSS), VEGFC, 5-fluorouracil (5FU) and two concentrations of mitomycin-C (MMC). Two mouse injection protocols (short and long) with different follow-up times and number of injections were performed. Mouse eyes were enucleated, flat mounts created, and subconjunctival branching and length assessed.
RESULTS
Rabbit eyes demonstrated clear bleb-related subconjunctival outflow pathways that were distinct from blood vessels and were without nasal/temporal predilection. Immunofluorescence against vessel-specific markers showed lymphatics and blood vessels in rabbit conjunctiva, and these lymphatics overlapped with bleb-related subconjunctival outflow pathways. Subconjunctival VEGFC increased lymphatic (P = 0.004-0.04) but not blood vessel (P = 0.77-0.84) mRNA or protein in rabbits. Prox1-tdTomato transgenic reporter mice demonstrated natively fluorescent lymphatics. Subconjunctival VEGFC increased murine lymphatic branching and length (P ≤ 0.001-0.004) while antimetabolites (P ≤ 0.001-0.043) did the opposite for the long protocol.
DISCUSSION
Subconjunctival lymphatics are pharmacologically responsive to both VEGFC and antimetabolites in two animal models studied using different methodologies. These results may be important for bleb-forming glaucoma surgeries or ocular drug delivery.
Topics: Animals; Mice; Rabbits; Antimetabolites; Conjunctiva; Dextrans; Fluorouracil; Glaucoma; Intraocular Pressure; Mitomycin; RNA, Messenger; Trypan Blue
PubMed: 36166215
DOI: 10.1167/iovs.63.10.16 -
GMS Ophthalmology Cases 2020To present an extremely rare case of corneal melanoma. An 84-year-old female patient presented to our department with a pigmented corneal lesion in her right eye (OD),...
To present an extremely rare case of corneal melanoma. An 84-year-old female patient presented to our department with a pigmented corneal lesion in her right eye (OD), 6x4 mm, complaining of mild pain and inability of complete eyelid closure. Tumor growth had been noted the previous year. She had undergone cataract surgery in her right eye three years before, followed by an unspecified postoperative complication. Her visual acuity was 3/10 OD and 9/10 OS. Ophthalmic evaluation and ultrasonography (A- and B-scan) did not reveal any other pathology. The pigmented lesion was surgically removed and the patient underwent a protocol therapy of topical chemotherapy (mitomycin 0.03%, 2x4 for 2 weeks and dexamethasone 0.1%, 2x4 for the following 2 weeks, followed by another cycle of mitomycin 0.03%, 2x4 for another 2 weeks). The surgical removal of the lesion was uncomplicated, as was the postoperative period. The patient's visual acuity improved to 6/10 three months postoperatively. The histologic examination revealed malignant melanoma. Despite its rarity, primary melanoma of the cornea is an existing entity. Treatment of corneal melanoma consists of surgical removal and postoperative topical chemotherapy. Postoperative follow-up is mandatory.
PubMed: 32269910
DOI: 10.3205/oc000139 -
International Journal of Environmental... Sep 2022The search for the "gold standard" in the surgical treatment of pterygium has been ongoing for over two decades. Despite the development of various surgical techniques,... (Review)
Review
The search for the "gold standard" in the surgical treatment of pterygium has been ongoing for over two decades. Despite the development of various surgical techniques, recurrence rates range from 6.7% to 88% depending on the method used. This review discusses the latest and most commonly used methods for the surgical removal of pterygium, primarily focusing on efficacy and safety. Moreover, this review includes articles that either evaluated or compared surgical methods and clinical trials for primary and recurrent pterygium. Limited data are available on combined methods as well as on the efficacy of adjuvant treatment. The use of adjuvant intraoperative mitomycin C (MMC) and conjunctival autografting (CAU) are the two most highly recommended options, as they have the lowest rates of postoperative recurrence.
Topics: Conjunctiva; Follow-Up Studies; Humans; Mitomycin; Pterygium; Recurrence; Treatment Outcome
PubMed: 36141628
DOI: 10.3390/ijerph191811357 -
Acta Ophthalmologica Aug 2022To assess surgical success and the post-operative development of intraocular pressure between XEN45 gelstent, Preserflo MicroShunt and trabeculectomy with mitomycin C.
PURPOSE
To assess surgical success and the post-operative development of intraocular pressure between XEN45 gelstent, Preserflo MicroShunt and trabeculectomy with mitomycin C.
METHODS
Data from 105 eyes from 105 patients of matched cases with refractory open-angle glaucoma, who underwent surgery between January 2019, and August 2020, were evaluated. Patients underwent either stand-alone XEN gelstent insertion with Mitomycin C, stand-alone Preserflo with Mitomycin C or trabeculectomy with Mitomycin C. The primary outcome was the proportion of complete surgical success at 6 months post-operatively (i.e. intraocular pressure between 5mmHg and 18mmHg, no revision surgery, no loss of light perception and no post-operative pharmaceutical antiglaucomatous treatment). The reduction of intraocular pressure after 6 months, the classes of antiglaucomatous medication used post-operatively, best-corrected visual acuity, spherical refractive errors and astigmatism were assessed as secondary outcomes.
RESULTS
We included 35 eyes in each group. After 6-month follow-up, complete success was 73.5% [95%-CI: 57.9%-89.2%] in the trabeculectomy group, 51.4% [95%-CI: 34.0%-68.8%] in the XEN group and 74.2% [95%-CI: 57.9%-90.5%] in the Preserflo group (p = 0.08). Regarding secondary outcomes, the reduction of intraocular pressure was 12.1 ± 7.9 mmHg in the trabeculectomy group and was thereby 5.8 [95%-CI: 2.2-9.6] mmHg greater compared with the XEN group (p < 0.001) and 4.8 [95%-CI: 0.9-8.7] mmHg higher than the Preserflo group (p = 0.01).
CONCLUSIONS
No statistically significant differences were found between trabeculectomy, XEN45 gelstent implantation and Preserflo MicroShunt implantation regarding surgical success after 6 months. Yet reduction in intraocular pressure was significantly higher in the trabeculectomy group. However, all three interventions resulted in sufficiently low post-operative intraocular pressure and may therefore be considered individually for glaucoma treatment.
Topics: Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Mitomycin; Retrospective Studies; Tonometry, Ocular; Trabeculectomy; Treatment Outcome
PubMed: 34626093
DOI: 10.1111/aos.15042 -
Translational Vision Science &... Feb 2023The gold standard for managing postoperative ocular fibrosis in glaucoma surgery is the chemotherapeutic mitomycin C (MMC) despite its association with significant...
PURPOSE
The gold standard for managing postoperative ocular fibrosis in glaucoma surgery is the chemotherapeutic mitomycin C (MMC) despite its association with significant adverse effects. This study compares in vitro the antifibrotic efficacy and cytotoxicity of the small-molecule TGFβ1 inhibitor SB-431542 (SB) to MMC.
METHODS
To measure collagen contraction, human Tenon's capsule fibroblasts (HTCFs) embedded in a three-dimensional collagen lattice were exposed to 0.2 mg/mL MMC or 20 µM SB followed by incubation with 2 ng/mL TGFβ1. Total protein extracted from experimentally treated HTCFs underwent immunoblotting for α-smooth muscle actin (α-SMA), matrix metallopeptidase 9 (MMP-9), and EDA splice-variant fibronectin (EDA-FN) expression. Cytotoxicity and cell metabolism were assessed using LIVE/DEAD staining, lactate dehydrogenase (LDH) assay, and methylthiazole tetrazolium (MTT) assay.
RESULTS
Collagen lattice contraction in TGFβ1-induced HTCFs was significantly lowered by SB and MMC. Pretreatment with SB and MMC significantly lowered protein expression of α-SMA, MMP-9, and EDA-FN in HTCFs relative to TGFβ1 alone. HTCF viability in collagen lattices was significantly reduced with MMC pretreatment but not SB pretreatment. MMC-pretreated HTCFs had a significant increase in LDH release after 3 hours and a decrease in MTT activity after 20 minutes, while SB-pretreated HTCFs showed no significant changes via MTT or LDH assay during the same treatment period.
CONCLUSIONS
SB shows comparable efficacy to MMC in reducing expression of fibrosis-promoting proteins in HTCFs and in vitro scarring activity. SB distinguishes itself from MMC by exhibiting less cytotoxicity in both two-dimensional and three-dimensional in vitro assays.
TRANSLATIONAL RELEVANCE
This study demonstrates in vitro the potential of SB as a safer alternative ocular antifibrotic agent.
Topics: Humans; Mitomycin; Tenon Capsule; Cicatrix; Matrix Metalloproteinase 9; Fibroblasts; Collagen; Glaucoma
PubMed: 36826843
DOI: 10.1167/tvst.12.2.31