A C57BL/6J Fancg-KO Mouse Model Generated by CRISPR/Cas9 Partially Captures the Human Phenotype.

Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in the repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in the interpretation of genotype-related phenotype. We created a Fancg-KO (KO) mouse model using CRISPR/Cas9 to exclude these confounders. The entire Fancg locus was targeted and maintained on the immunological well-characterized C57BL/6J background. The intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting the loss of FANCG can be embryonically lethal. KO mice displayed infertility and hypogonadism, but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from Fancg-KO mice were hypersensitive to the crosslinking agents cisplatin and Mitomycin C, and Fancg-KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. The reconstitution of these MEFs with Fancg cDNA corrected for the ICL hypersensitivity. This project provides a new, genetically, and immunologically well-defined Fancg-KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.

The Management of Ocular Surface Squamous Neoplasia (OSSN).

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.

National survey of intraoperative mitomycin C use during trabeculectomy surgery in the UK.

PURPOSE: Mitomycin C is a routinely used antimetabolite which effectively limits the scarring process. Conventionally, the intra-operative technique of MMC delivery during trabeculectomy is the direct application of the soaked sponges. The aim of this study is to evaluate the current practice of delivering MMC during trabeculectomy and to see the practices related to a retained MMC swab during trabeculectomy in the UK. METHODS: An electronic questionnaire of 8 questions regarding the intraoperative use of MMC during trabeculectomy surgery was emailed to 69 ophthalmologist members of the UK and Eire glaucoma society (UKEGS) through email in July 2019. RESULTS: 97.2% of the surveyed glaucoma surgeons said they use MMC during trabeculectomy routinely, while 2.9% said they never use MMC for trabeculectomy. In reply to a question 'Have you ever had a retained MMC-soaked sponge/fragment of sponge', 11.76% replied 'yes', 88.24% said 'No'. In response to what technique was employed at the time of retained MMC sponges, all the respondents said they had employed the same technique of 'multiple individual sponges'. 47.1% surgeons said they use multiple individual sponges on being asked what technique they currently employ for delivering MMC during trabeculectomy surgery, while 14.7% surgeons use multiple sponges linked with a 'necklace suture' and 5.9% inject MMC. CONCLUSION: Our survey suggests the intra-operative MMC use in the UK is high and that unintentional MMC-soaked swab retention does occur, albeit rarely. A preference of using the MMC-soaked swabs as a delivery method of MMC is seen in our survey.

Effects of topical mitomycin-C on the tracheal epithelia of rabbits following tracheostomy

Background/aim: We aimed to investigate the topical application of mitomycin-C (MMC) after the conventional tracheostomy in a rabbit model. Materials and methods: Twenty-four male New Zealand White rabbits were randomly divided among 3 equal groups (n: 8). Trache- ostomies were performed on 16 subjects. Group 1 which served as a control for all tracheal measurements. After tracheostomy, we applied sterile saline (group 2) or MMC at 0.8 mg/mL (group 3) around the tracheotomy site for 5 min. At the 3rd week after surgery, all tracheas were subjected to morphometric and histopathological examinations, including tracheal lumen diameter (LD), number of capillary vessels (CV), subepithelial tissue thickness (SETT), fibroblasts, and inflammatory cells (IC). Results: There was a statistically significant difference between the two tracheostomy groups themselves and the control group for LD (p = 0.035), CV (p = 0.006), SETT, fibroblasts, and IC (p < 0.001). Histopathological analysis showed the decreased LD, CV, SETT, IC, and fibroblasts compared to MMC with tracheostomy groups. MMC was more effective than saline for LD, CV, SETT, IC, and fibroblasts. Conclusion: Wound healing modulation may prevent scar formation. Fibrosis decreased following tracheostomy in the group treated with MMC. Fibroblasts appear to be key cells mediating these effects.

Effect of mitomycin C on X-ray repair cross complementing group 1 expression and consequent cytotoxicity regulation in human gastric cancer cells.

Gastric cancer is the fourth most common cancer and ranks as the second leading cause of cancer-related deaths across the world. The combination therapy of surgery with chemotherapeutic drugs, that is, mitomycin C (MMC), is becoming a major strategy for patients with advanced gastric cancer. However, drug resistance is a major factor that limits the effectiveness of chemotherapy, which ultimately leads to the failure of cancer chemotherapy. X-ray repair cross complementing group 1 (XRCC1), a scaffold protein of the base excision repair process, has been implicated in the development of tumor chemoresistance. Thus, this study aimed to explore whether XRCC1 expression could be regulated, its role in gastric AGS cancer cells treated with MMC, and the underlying mechanism. The results of this study demonstrate that XRCC1 expression could be upregulated in AGS cells treated with MMC, and this upregulation could subsequently reduce the cytotoxicity of MMC in AGS cells. Furthermore, MMC-upregulated XRCC1 expression was regulated by MAPK signaling through activating the transcription factor Sp1. These results indicate the role of XRCC1 in the development of drug resistance to MMC in gastric AGS cells. Elucidating the mechanism concerning the MAPKs and transcription factor Sp1 may provide another notion for the development of a clinical chemotherapy strategy for gastric cancers in the future.

The Use of TAT Peptide-Functionalized Graphene as a Highly Nuclear-Targeting Carrier System for Suppression of Choroidal Melanoma.

Tumorous metastasis is a difficult challenge to resolve for researchers and for clinicians. Targeted delivery of antitumor drugs towards tumor cells' nuclei can be a practical approach to resolving this issue. This work describes an efficient nuclear-targeting delivery system prepared from trans-activating transcriptional activator (TAT) peptide-functionalized graphene nanocarriers. The TAT peptide, originally observed in a human immunodeficiency virus 1 (HIV-1), was incorporated with graphene via an edge-functionalized ball-milling method developed by the author's research group. High tumor-targeting capability of the resulting nanocarrier was realized by the strong affinity between TAT and the nuclei of cancer cells, along with the enhanced permeability and retention (EPR) effect of two-dimensional graphene nanosheets. Subsequently, a common antitumor drug, mitomycin C (MMC), was covalently linked to the TAT-functionalized graphene (TG) to form a nuclear-targeted nanodrug MMC-TG. The presence of nanomaterials inside the nuclei of ocular choroidal melanoma (OCM-1) cells was shown using transmission electron microscopy (TEM) and confocal laser scanning microscopy. In vitro results from a Transwell co-culture system showed that most of the MMC-TG nanodrugs were delivered in a targeted manner to the tumorous OCM-1 cells, while a very small amount of MMC-TG was delivered in a non-targeted manner to normal human retinal pigment epithelial (ARPE-19) cells. TEM results further confirmed that apoptosis of OCM-1 cells was started from the lysis of nuclear substances, followed by the disappearance of nuclear membrane and cytoplasm. This suggests that the as-synthesized MMC-TG is a promising nuclear-target nanodrugfor resolution of tumorous metastasis issues at the headstream.

Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer.

INTRODUCTION: Bladder cancer (BC) is a severe health burden: and has high recurrence and progression rates. Standard treatment starts with TURB followed by intravesical chemotherapy with Mitomycin C or immunotherapy with BCG. However, successful management still remains a challenge, because approximately 30% of patients have recurrence or progression within 5 years, and treatment has considerable side effects. Anticipating on the upcoming BCG shortage emphasizes, moreover, the necessity to develop and study novel treatments. This review explores emerging and novel salvage treatments as well as approaches of current treatments with decrease side-effects for non muscle-invasive bladder cancer (NMIBC). Areas covered: In this review, the authors provide an overview of the novel and emerging therapies for NMIBC. They also provide the currently available data and ongoing trials. Expert opinion: Key findings in the field of research on emerging intravesical drugs for the treatment of NMIBC are the promising results for device assisted treatments, treatment with intravesical immunotherapy, and treatments to expedite the immunotherapy checkpoint inhibitors. Other novel therapies are still in an experimental stage and have to make the transition towards the clinical setting to determine the benefit in terms of reduced side-effects, recurrence and progression rates.

Clinical validation of a novel thermophysical bladder model designed to improve the accuracy of hyperthermia treatment planning in the pelvic region.

PURPOSE: Hyperthermia treatment planning for deep locoregional hyperthermia treatment may assist in phase and amplitude steering to optimize the temperature distribution. This study aims to incorporate a physically correct description of bladder properties in treatment planning, notably the presence of convection and absence of perfusion within the bladder lumen, and to assess accuracy and clinical implications for non muscle invasive bladder cancer patients treated with locoregional hyperthermia. METHODS: We implemented a convective thermophysical fluid model based on the Boussinesq approximation to the Navier-Stokes equations using the (finite element) OpenFOAM toolkit. A clinician delineated the bladder on CT scans obtained from 14 bladder cancer patients. We performed (1) conventional treatment planning with a perfused muscle-like solid bladder, (2) with bladder content properties without and (3) with flow dynamics. Finally, we compared temperature distributions predicted by the three models with temperature measurements obtained during treatment. RESULTS: Much higher and more uniform bladder temperatures are predicted with physically accurate fluid modeling compared to previously employed muscle-like models. The differences reflect the homogenizing effect of convection, and the absence of perfusion. Median steady state temperatures simulated with the novel convective model (3) deviated on average -0.6 °C (-12%) from values measured during treatment, compared to -3.7 °C (-71%) and +1.5 °C (+29%) deviation for the muscle-like (1) and static (2) models, respectively. The Grashof number was 3.2 ± 1.5 × 105 (mean ± SD). CONCLUSIONS: Incorporating fluid modeling in hyperthermia treatment planning yields significantly improved predictions of the temperature distribution in the bladder lumen during hyperthermia treatment.

The effect of air pockets in the urinary bladder on the temperature distribution during loco-regional hyperthermia treatment of bladder cancer patients.

PURPOSE: Loco-regional hyperthermia combined with mitomycin C is used for treatment of nonmuscle invasive bladder cancer (NMIBC). Air pockets may be present in the bladder during treatment. The aim of this study is to quantify the effect of air pockets on the thermal dose of the bladder. METHODS: We analysed 16 patients treated for NMIBC. Loco-regional hyperthermia was performed with the in-house developed 70 MHz AMC-4 hyperthermia device. We simulated treatments with the clinically applied device settings using Plan2Heat (developed in-house) including the air pockets delineated on CT scans made following treatment, and with the same volume filled with urine. Temperature distributions simulated with and without air pockets were compared. RESULTS: The average air and fluid volumes in the bladder were 6.0 ml (range 0.8 - 19.3 ml) and 183 ml (range 47-322 ml), respectively. The effect of these air pockets varied strongly between patients. Averaged over all patients, the median bladder wall temperature (T50) remained unchanged when an air pocket was present. Temperature changes exceeded ±0.2 °C in, on average, 23% of the bladder wall volume (range 1.3-59%), in 6.0% (range 0.6-20%) changes exceeded ±0.5 °C and in 3.2% (range 0.0-7.4%) changes exceeded ±1.0 °C. There was no correlation between the differences in temperature and the air pocket or bladder volume. There was a positive correlation between air pocket surface and temperature heterogeneity. CONCLUSION: Presence of air causes more heterogeneous bladder wall temperatures and lower T90, particularly for larger air pockets. The size of air pockets must therefore be minimized during bladder hyperthermia treatments.

Long-term outcome of amniotic membrane transplantation combined with mitomycin C for conjunctival reconstruction after ocular surface squamous neoplasia excision.

The aim of the study is to evaluate the long-term clinical results of amniotic membrane transplantation (AMT) combined with mitomycin C (MMC) for reconstruction of conjunctival defects created during the excision of ocular surface squamous neoplasia (OSSN). Eight consecutive eyes of seven patients (five males and two females; mean age, 64 ± 19 years) treated by one surgeon (KH) were included in this study. AMT was performed after excision of a mass region, along with 0.04 % MMC treatment for the exposed sclera. The tumor size, histopathological retrieval, AM graft size after tumor excision, recurrence, and postoperative complications were recorded. During a mean postoperative follow-up period of 60.9 ± 14.6 months (range 36-78 months), the ocular surfaces completely re-epithelialized in all cases. The median size of the tumor was 44.4 ± 21.2 mm2 (range 13-67 mm2). The histopathological diagnoses were five cases of squamous cell carcinoma in situ (SCC in situ) and three cases of dysplasia. The median size of the AM graft after tumor excision was 100.8 ± 32.7 mm2 (range 49-151 mm2). A case of recurrent SCC in situ with a preoperative history of using MMC eye drops developed further corneal limbal deficiency and was treated with therapeutic soft contact lenses. A case of dysplasia with a history of large pterygial excision developed symblepharon postoperatively was treated with AMT 6 months after tumor excision. The tumors recurred in two eyes with SCC in situ and were successfully treated with continuous AMT and MMC. No severe complications, such as infections, corneal or scleral thinning, or ulceration developed in all cases. The combination of AMT and MMC is effective for safe reconstruction over the long-term after the excision of OSSN with postoperative careful observation and treatment. In recurrent tumor excision cases, AMT is a suitable technique for repeated ocular surface reconstruction.

Safety and oncological outcome of early intraoperative intravesicle mitomycin C vs. deferred instillation in patients receiving robot-assisted radical nephroureterectomy.

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%, p < 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, p = 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.

Regulatory Effects of Senescent Mesenchymal Stem Cells: Endotheliocyte Reaction.

Currently, there is a growing focus on aging and age-related diseases. The processes of aging are based on cell senescence, which results in changes in intercellular communications and pathological alterations in tissues. In the present study, we investigate the influence of senescent mesenchymal stem cells (MSCs) on endothelial cells (ECs). In order to induce senescence in MSCs, we employed a method of stress-induced senescence utilizing mitomycin C (MmC). Subsequent experiments involved the interaction of ECs with MSCs in a coculture or the treatment of ECs with the secretome of senescent MSCs. After 48 h, we assessed the EC state. Our findings revealed that direct interaction led to a decrease in EC proliferation and migratory activity of the coculture. Furthermore, there was an increase in the activity of the lysosomal compartment, as well as an upregulation of the genes P21, IL6, IL8, ITGA1, and ITGB1. Treatment of ECs with the "senescent" secretome resulted in less pronounced effects, although a decrease in proliferation and an increase in ICAM-1 expression were observed. The maintenance of high levels of typical "senescent" cytokines and growth factors after 48 h suggests that the addition of the "senescent" secretome may have a prolonged effect on the cells. It is noteworthy that in samples treated with the "senescent" secretome, the level of PDGF-AA was higher, which may explain some of the pro-regenerative effects of senescent cells. Therefore, the detected changes may underlie both the negative and positive effects of senescence. The findings provide insight into the effects of cell senescence in vitro, where many of the organism's regulatory mechanisms are absent.

Unveiling the Success of Awake Insertion of Supraglottic Airway Device for Ventilation in the Bronchoscopic Management of Tracheal Stenosis.

Tracheal and subglottic stenoses are inflammatory conditions that can arise from a variety of potential etiologies, most commonly as a result of iatrogenic airway injury due to endotracheal intubation. Significant stenosis requires management by endoscopy or surgical resection. We describe a case of recurrent subglottic cuff stenosis with an episode of sudden desaturation in a 25-year-old female. The management involved balloon dilatation, laser ablation, and topical mitomycin C application through a flexible fiberoptic bronchoscope. Ensuring safe gas exchange during bronchoscopy was a priority, and this was achieved by maintaining ventilation with a supraglottic airway device, which was inserted in an awake patient after adequate tropicalization of the oral cavity. The intervention successfully helped in the management of stenosis and also addressed the complication of sudden complete airway collapse due to sedation.

Excision combined with ocular surface reconstruction followed by topical chemotherapy for ocular surface squamous neoplasia.

PURPOSE: To investigate the visual prognosis of ocular surface squamous neoplasia (OSSN) after tumor resection and ocular surface reconstruction, and clarify factors that influence recurrence. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of all patients who underwent surgical treatment for OSSN at our hospital between January 1996 and December 2019 were reviewed. Tumor size/location, histological classification, surgical procedure, intraoperative mitomycin-C use, and postoperative topical 5-fluorouracil (5-FU) administration were examined, and pre and postoperative visual acuity (VA) were compared to elucidate factors that influence disease recurrence. RESULTS: Tumor excision was performed in 70 eyes of 70 cases (43 men, 27 women; average age: 71.6 ± 12.6 years) with dysplasia (8 eyes), carcinoma in situ (26 eyes), and invasive squamous cell carcinoma (36 eyes). Tumors were found in the limbus (N = 59 eyes), palpebral conjunctiva (N = 8 eyes), and from the bulbar to palpebral conjunctiva (N = 3 eyes). Surgical procedures performed were limbal transplantation/keratoepithelioplasty (N = 29 eyes), cultivated oral mucosal epithelial transplantation (N = 3 eyes), and auto-conjunctival epithelium transplantation (N = 2 eyes). Ocular surface was reconstructed using amniotic membrane, donor cornea, or cultivated epithelial sheet. The mean follow-up was 38.6 ± 38.6 months (range, 2 months to 13.8 years). VA postoperatively improved in 25 (61.0%) cases. Recurrence occurred in 19 (27.1%) cases at from 2 to 50 months (median: 12.5 months) postoperative. Uni- and multivariate analyses revealed that presurgical tumor size and postoperative administration of 5-FU were significantly related to recurrence. CONCLUSION: Combined surgical excision and postoperative topical 5-FU administration effectively prevented OSSN recurrence, and ocular surface reconstruction contributed to improvement of VA.

Beyond Traditional Approaches: A Pilot Study Exploring the Role of Injection Mitomycin C on the Surgical Resection Bed in Oral Cancer Treatment.

Background Oral cavity cancer ranks sixth among all cancers worldwide. India has the most oral cancer cases and accounts for one-third of the global oral cancer burden. Oral cavity cancer is known to be associated with an elevated likelihood of locoregional recurrences, which account for the bulk of post-surgery and radiotherapy treatment failures. Mitomycin C (MMC) is an antineoplastic and antibiotic agent that is administered topically rather than intravenously to treat bladder and intraperitoneal tumors to avoid recurrences. This study aimed to investigate the use of injection MMC as a local application on surgical resection beds for patients undergoing surgery for oral cancer and to assess its efficacy in preventing regional recurrences. Methodology In this prospective, interventional, pilot study, patients were assigned randomly to two groups using simple randomization. Group A involved the application of two gauze pieces soaked with MMC injection. Group B involved the application of two gauze pieces soaked with a 10% betadine solution. During the pectoralis major myocutaneous flap harvest procedure for reconstruction, two gauze pieces soaked with either injection MMC solution (20 mg MMC in 20 mL of 0.9% normal saline) or 10% betadine solution were placed on the surgical resection bed for a 45-minute contact period. Patients were evaluated daily in the postoperative period for local complications. Regular follow-up visits were scheduled for 15 months of follow-up. Results After exclusions at various phases, the final analysis included 50 patients in Group A and 50 patients in Group B. Minor complications, specifically blackening of the skin flap in the neck resulting in surgical site infections, were observed in 16% (eight patients) of the MMC group and in 6% (three patients) of the betadine group (p = 0.1997) patients. In the MMC group, two (4%) patients experienced locoregional recurrences at three months, four (8%) patients at six months, six (12%) patients at nine months, eight (16%) patients at 12 months, and 10 (20%) patients at 15 months of follow-up. In contrast, locoregional recurrences occurred in two (4%) patients in the betadine group at three months, six (12%) patients at six months, nine (18%) patients at nine months, 12 (24%) patients at 12 months, and 15 (30%) patients at 15 months. Although the difference in locoregional recurrences between the two groups was not statistically significant, there was a trend of decreasing locoregional recurrences in the MMC group relative to the betadine group as the duration of follow-up increased. In the subgroup analysis of patients with pathological extranodal extension (ENE), only 10 of 18 patients with ENE in Group A (55.55%) experienced a recurrence, whereas all 12 patients with ENE in Group B (100%) experienced a recurrence within the same time frame. This difference in locoregional recurrence rates between the two groups was statistically significant, with a p-value of 0.0100. Conclusions Our study demonstrated that the local administration of MMC on surgical resection beds may lower the risk of locoregional recurrences in patients with oral cancer, especially those with ENE. These findings contribute to the ongoing efforts to enhance treatment strategies and patient outcomes for this challenging malignancy.

Nontoxic Natural Polymeric Particle Vehicles Derived from Hyaluronic Acid and Mannitol as Mitomycin C Carriers for Bladder Cancer Treatment.

Hyaluronic acid/mannitol (HA/MN)-based particles were designed as mitomycin c (MMC) delivery vehicles through the crosslinking of 1:0, 3:1, 1:3, and 0:1 mole ratios of HA/MN to investigate their potential use in bladder cancer therapy. The HA/MN-MMC particles prepared by the microemulsion crosslinking method were of 0.5-10 µm size with a zeta potential value of -36.7 mV. The MMC carrier potential of the HA/MN-MMC particles was investigated by changing HA/MN ratios in the particle structure. The MMC loading capacity of neat HA particles was 5.3 ± 1.1 mg/g, whereas HA/MN (1:3) particles could be loaded with about three times more drug, for example, 18.4 ± 0.8 mg/g. The kinetic of MMC drug delivery from the HA/MN-MMC particles were tested in vitro in bladder cancer conditions for example, pH 4.5, 6, and 7.4. The HA-MMC particles released approximately 70% of the loaded drug in 300 h, while 43% of the loaded drug was released from the HA/MN-MMC particles within 600 h under physiological conditions, pH 7.4, 37 °C. The cytotoxicity of HA-based particles on healthy L929 fibroblast cells and HTB-9 human bladder cancer cells was investigated in vitro via MTT tests. Bare MMC inhibited about 90% of L929 fibroblast cells even at 100 µg/mL, but the cell viabilities in the presence of HA-MMC and HA/MN-MMC particles were 85 ± 5 and 109 ± 7% at 1000 µg/mL, respectively. The HA/MN-MMC (1:3) particles at 1000 µg/mL were found capable of destroying half of HTB-9 human bladder cancer cells within 24 h. Interestingly, the same particles at 50 µg/mL destroyed almost all the cancer cells with 8 ± 5% cell viability in 72 h of incubation time. The designed HA/MN-MMC (1:3) particles were found to afford a chemotherapeutic effect on the tumor cancers while reducing the toxicity of MMC against L929 fibroblast cells.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods: This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m2) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results: The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions: This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

Survey of glaucoma surgical preferences among glaucoma specialists in Spain.

PURPOSE: To evaluate the spectrum of glaucoma surgery undertaken among members of the Spanish Glaucoma Society (SEG). METHODS: A 10 question web-based anonimous survey was mailed through the Annals of the Spanish Glaucoma Society to all its members on January, February and July 2019 to determine their preferred surgical approach. MAIN OUTCOME MEASURES: Age, type of Glaucoma, surgery undertaken, type of anti-scarring strategy and prothesis introduced for the last 10 surgeries since the survey was received. The surgeon experience was registered in years of practice. RESULTS: A total of 97 SEG members across the country answered the survey. Sixty-two (63.4%) responders had more than 10 years of experience. Primary open angle glaucoma was the most frequent type of glaucoma (60.6%). The most popular surgery was deep-sclerectomy (37.3%) followed by trabeculectomy (17,6%) and the collagen microshunt (XEN® Allergan Inc., Irvine, CA) (14.1%). Glaucoma drainage device (GDD) was used in 10.5% of the cases. Up to 21.7% of surgeries were reinterventions, where GDD was used in 27.3% and trabeculectomy in 20.3% of the cases. Glaucoma surgery was combined with phacoemulsification in 47.3% of the eyes. Mitomycin C (MMC) was used in 54,8% of the cases, collagen matrix (Ologen®, Aeon Astron Corporation, Taipei, Taiwan) was used alone in 8.2% of the cases and in 13,7% combined with MMC. MMC was used in a soaked sponge in 79% of cases (concentrations of 0.02% in 99% and 0.04% in 1%) and in 21% of cases MMC was injected subconjunctivally (concentrations of 0,01% in 81% and 0.02% in 19%). CONCLUSIONS: Although the glaucoma surgeon performs a wide range of surgical techniques, deep sclerectomy remains the most widely used surgical technique in Spain. Combined cataract and glaucoma surgery is performed almost in half of the patients and MMC is the most frequently selected antifibrotic agent, alone or combined with collagen matrix. The new minimal invasive surgical techniques represent the 20% of the total.

Mitomycin C application after photorefractive keratectomy in high, moderate, or low myopia: Systematic review and meta-analysis.

Photorefractive keratectomy (PRK) is considered a safe approach laser procedure with a clinical significance in correcting myopia results. PRK requires removing the whole superficial epithelium. The integrity of the epithelial basement membrane and the deposition of abnormal extracellular matrix can put the cornea in a probable situation for corneal haze formation. Mitomycin C (MMC) is applied after excimer laser ablation as a primary modulator for wound healing, limiting corneal haze formation. We aim to summarize the outcomes of MMC application after laser ablation. We searched Scopus, PubMed, Cochrane CENTRAL, and Web of Science till December 2020 using relevant keywords. The data were extracted and pooled as mean difference (MD) or risk ratio (RR) with a 95% confidence interval (CI), using Review Manager software (version 5.4). Our analysis demonstrated a statistically significant result for MMC application over the control group in terms of corneal haze formation postoperatively (RR = 0.29, 95% CI: [0.19, 0.45], P < 0.00001). Regarding corrected distance visual acuity (CDVA), no significant difference was observed between the MMC group and the control group (MD = 0.02; 95% CI: [-0.04, 0.07]; P = 0.56). Regarding the uncorrected distance visual acuity (UDVA), the analysis favored the MMC application with (MD -0.03, 95% CI: [-0.06, -0.00]; P = 0.05). There was no statistically significant increase in complications with MMC. In conclusion, MMC application after PRK is associated with a lower incidence of corneal haze formation with no statistically significant side effects. The long term effect can show improvement regarding UDVA favoring MMC. However, there is no significant effect of MMCs application regarding CDVA, and SE.

Severe long-term progressive corneal remodeling after bilateral simultaneous prophylactic crosslinking and topography-guided surface ablation with mitomycin.

To report a case of a 20-year-old woman who developed massive and progressive corneal remodeling in both eyes after bilateral PRK with mitomycin and CXL as an elective refractive procedure for mild keratoconus. The patient had 6 years of follow up, initially presenting with focal steepening of up to 20 diopters on both eyes one-and-a-half- years postoperatively that spontaneously reversed over the next five years while the high order aberrations worsened. At the present time, the patient depends on bilateral scleral contact lenses for her day-to-day activities. The use of combined elective PRK with mitomycin and prophylactic CXL could lead to progressive corneal deformation. Additional reports would help to establish the role of this combination procedure among the armamentarium to visually rehabilitate patients with keratoconus.