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To describe visual field outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. Cohort analysis. A total of 155 eyes (155 subjects) randomly assigned to treatment with tube shunt surgery (n = 84) or trabeculectomy with mitomycin C (n = 71). The PTVT Study was a multicenter randomized clinical trial comparing the safety and efficacy of trabeculectomy and tube shunt surgery in eyes without previous intraocular surgery. Subjects underwent standard automated perimetry (SAP) at baseline and annually for 5 years. Standard automated perimetry tests were deemed reliable if the false-positive rate was ≤ 15%. Tests were excluded if visual acuity was ≤ 20/400 or loss of ≥ 2 Snellen lines from baseline because of a nonglaucomatous etiology. Linear mixed-effects models were used to compare rates of change in SAP mean deviation (MD) between the 2 groups. Intraocular pressure (IOP) control was assessed by percentage of visits with IOP < 18 mmHg and mean IOP. Rate of change in SAP MD during follow-up. A total of 730 SAP tests were evaluated (average of 4.7 tests per eye). The average SAP MD at baseline was –12.8 ± 8.3 decibels (dB) in the tube group and –12.0 ± 8.4 dB in the trabeculectomy group (P = 0.57). The mean rate of change in SAP MD was –0.32 ± 0.39 dB/year in the trabeculectomy group and –0.47 ± 0.43 dB/year in the tube group (P = 0.23). Eyes with mean IOP 14 to 17.5 mmHg had significantly faster rates of SAP MD loss compared with eyes with mean IOP < 14 mmHg (–0.59 ± 0.13 vs. –0.27 ± 0.08 dB/year; P = 0.012), and eyes with only 50% to 75% of visits with IOP < 18 mmHg had faster rates than those with 100% of visits with IOP < 18 mmHg (–0.90 ± 0.16 vs. –0.29 ± 0.08 dB/year; P < 0.001). Multivariable analysis identified older age and worse IOP control as risk factors for faster progression in both treatment groups. No statistically significant difference in mean rates of visual field change was observed between trabeculectomy and tube shunt surgery in the PTVT Study. Worse IOP control was significantly associated with faster rates of SAP MD loss during follow-up. Older patients were also at risk for faster progression. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

We continue our review of on punctal stenosis by providing a detailed discussion of management modalities, their complications, and outcomes. There is a significant change in the understanding of punctal and peripunctal anatomy, puncto-canalicular junction, and the lacrimal pump mechanisms. While the snip punctoplasty procedures are still practiced, there is an increasing trend toward nonincisional procedures. The nonincisional procedures in select cases appear to be equally effective as the incisional ones. Although simple to use, punctal plugs never became the mainstay of treatment because of design issues and the inability to address the coexisting canalicular stenosis. Placing stents only in the lower punctum in cases of upper and lower punctal stenosis should be discouraged, and management needs to address punctal stenosis and not which punctum is involved. Several types of stents are used in the management of punctal stenosis, mostly based on surgeon's preference. The benefits of adjuvant mitomycin C are uncertain. In view of literature on how stent biofilms can themselves cause chronic inflammation, placing them for prolonged periods should be reviewed and debated. Enhanced understanding of the molecular pathogenesis of punctal stenosis and addressing the current controversies in management would help standardize the therapeutic interventions available in the lacrimal armamentarium. [ABSTRACT FROM AUTHOR]

• Hyperthermia-assisted chemotherapy offers a promising approach for NMIBC treatment. • COMBAT and BR-TRG-I show potential in reducing recurrence in NMIBC patients. • Unithermia's efficacy appears inferior to BCG in high-risk NMIBC. • Conduction hyperthermia devices present varied outcomes in NMIBC treatment. • Further research with standardized protocols is essential for conclusive results. Intravesical treatment for non-muscle invasive bladder cancer (NMIBC) aims to reduce recurrences and stop progression. Hyperthermia-enhanced chemotherapy with devices like COMBAT BRS, Unithermia, and BR-TRG-I is a promising alternative to conventional Bacillus de Calmette Guerin (BCG) therapy. To systematically review the efficacy of hyperthermia generated by conduction devices in the treatment of NMIBC. The review followed the preferred reporting items for systematic reviews and meta-analyses guidelines. A search was performed in the PubMed, Cochrane Library, Scopus, and ClinicalTrials.gov databases. Two reviewers independently assessed the eligibility of candidate studies and abstracted data from studies that met the inclusion criteria. The primary endpoint was assessment of recurrence. Secondary objectives included evaluation of treatment progression and safety. Thirty studies meeting inclusion criteria underwent data extraction. In intermediate-risk NMIBC patients, COMBAT versus mitomycin C (MMC) in normothermia revealed no superiority in reducing recurrence or progression. High-risk NMIBC patients using COMBAT achieved similar or superior outcomes to BCG. BR-TRG-I demonstrated superior results over normothermia in intermediate- and high-risk NMIBC patients. Unithermia proved less effective than BCG in high-risk NMIBC. Progression outcomes were promising with COMBAT and BR-TRG-I, but comprehensive analysis was limited due to inconsistent assessment across studies. Adverse events were primarily mild-moderate, with some device-specific differences. Studies on conduction hyperthermia present great variability, which do not allow us to determine the superiority of 1 device over another in terms of recurrence, progression, and/or adverse effects. Further research with consistent administration protocols is crucial for definitive conclusions [ABSTRACT FROM AUTHOR]

The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine‐Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P <.05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P =.05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P =.46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P >.05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P =.02), increased PFS (HR, 0.66 [0.51-0.87]; P =.003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P =.004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P =.009). Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC. [ABSTRACT FROM AUTHOR]

To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). Prospective, randomized, multicenter trial conducted in the United States and Europe. Adult patients (aged 40–85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

To evaluate the recently published literature on the efficacy and safety of the use of aqueous shunts with extraocular reservoir for the management of adult open-angle glaucomas (OAGs). A search of peer-reviewed literature was last conducted in April 2023 of the PubMed database and included only articles published since the last aqueous shunt Ophthalmic Technology Assessment, which assessed articles published before 2008. The abstracts of these 419 articles were examined, and 58 studies were selected for full-text analysis. After inclusion and exclusion criteria were applied, 28 articles were selected and assigned ratings by the panel methodologist according to the level of evidence. Twenty-five articles were rated level I and 3 articles were rated level II. There were no level III articles. Implantation of aqueous shunts with extraocular reservoir can lower intraocular pressure (IOP) by between one-third and one-half of baseline IOP, depending on whether it is undertaken as the primary or secondary glaucoma surgery. Success rates for aqueous shunts were found to be better than for trabeculectomies in eyes with prior incisional surgery. Conversely, in eyes without prior incisional surgery, implantation of aqueous shunts was found to have an overall lower success rate as the primary glaucoma procedure compared with trabeculectomy. Although both valved and nonvalved aqueous shunts with extraocular reservoir were effective, the nonvalved device generally achieved slightly lower long-term IOPs with fewer glaucoma medications and less need for additional glaucoma surgery. Both devices slow the rates of visual field progression with efficacy comparable with that of trabeculectomy. Early aqueous humor suppression after aqueous shunt implantation is recommended for the management of the postoperative hypertensive phase and long-term IOP control. No strong evidence supports the routine use of mitomycin C with aqueous shunt implantation for OAG. Implantation of aqueous shunts with extraocular reservoir, including valved or nonvalved devices, has been shown to be an effective strategy to lower IOP. Strong level I evidence supports the use of aqueous shunts with extraocular reservoir by clinicians for the management of adult OAG. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette–Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy. • Erdafitinib prolonged RFS versus intravesical chemotherapy in papillary-only FGFR -altered BCG-treated high-risk NMIBC. • At median follow-up of 13.4 months, median RFS was not reached for erdafitinib and was 11.6 months for chemotherapy. • The observed RFS benefit for erdafitinib was further reflected by the 6- and 12-month RFS rates and subgroups tested. • In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. • These trial results validate FGFR inhibition as a promising treatment approach for NMIBC. [ABSTRACT FROM AUTHOR]

Stridor is a clinical sign of an underlying disease and a common reason for pediatric emergency department (PED) consultation. Patients presenting with stridor must be evaluated to determine the origin of this abnormality. We present the case of a 7-year-old female patient who presented to our Pediatric Emergency Department with a history of recurrent episodes of stridor with increasing frequency over the previous 4 years, for this reason she was previously admitted to the pediatric intensive care unit. Findings from the otorhinolaryngologic assessment with flexible fiber-optic endoscopy led to a diagnosis of congenital synechia of the vocal cords. The cervical CT scan evidenced critical stenosis of the airway. An initial cordectomy and placement of a silicone device for fixation were performed. Subsequently, the patient required 6 additional interventions for progressive dilation of the glottic space at the level of the vocal cords and injections of mitomycin C injections (an antineoplastic that inhibits collagen proliferation). This case highlights the importance of additional studies (especially examination of the upper airway) when atypical or recurrent findings are revealed by the clinical history, physical examination, or disease course in patients with croup to prioritize cases severe enough to require pediatric intensive care unit admission. [ABSTRACT FROM AUTHOR]

RecN, a bacterial structural maintenance of chromosomes-like protein, plays an important role in maintaining genomic integrity by facilitating the repair of DNA double-strand breaks (DSBs). However, how RecN-dependent chromosome dynamics are integrated with DSB repair remains unclear. Here, we investigated the dynamics of RecN in response to DNA damage by inducing RecN from the PBAD promoter at different time points. We found that mitomycin C (MMC)-treated ΔrecN cells exhibited nucleoid fragmentation and reduced cell survival; however, when RecN was induced with arabinose in MMCexposed ΔrecN cells, it increased a level of cell viability to similar extent as WT cells. Furthermore, in MMC-treated ΔrecN cells, arabinose-induced RecN colocalized with RecA in nucleoid gaps between fragmented nucleoids and restored normal nucleoid structures. These results suggest that the aberrant nucleoid structures observed in MMC-treated ΔrecN cells do not represent catastrophic chromosome disruption but rather an interruption of the RecA-mediated process. Thus, RecN can resume DSB repair by stimulating RecA-mediated homologous recombination, even when chromosome integrity is compromised. Our data demonstrate that RecA-mediated presynapsis and synapsis are spatiotemporally separable, wherein RecN is involved in facilitating both processes presumably by orchestrating the dynamics of both RecA and chromosomes, highlighting the essential role of RecN in the repair of DSBs. [ABSTRACT FROM AUTHOR]

To review the literature on the adjuvant use of mitomycin C (MMC) during dacryocystorhinostomy (DCR) in adults with primary nasolacrimal duct obstructions (NLDOs) to determine the efficacy in improving functional and anatomic outcomes with an acceptable level of risk. A literature search conducted in November 2020 and updated in November 2022 yielded 137 articles. Twenty-four articles met the inclusion criteria and were rated for level of evidence by the panel methodologist. Inclusion criteria required controlled studies on the effect of MMC on outcomes of external, endoscopic endonasal, or diode laser-assisted transcanalicular DCR in adults with primary acquired nasolacrimal obstruction with 6 months minimum follow-up and at least 10 participants. Six of the 24 articles were rated level I evidence, 15 level II , and 3 level III. In primary external DCR, MMC significantly improved functional outcomes in 3 of 9 series. In primary endoscopic endonasal DCR, MMC significantly improved functional outcomes in 1 of 9 series. In revision endoscopic endonasal DCR, MMC significantly improved functional success in 1 of 3 series. The use of MMC did not improve outcomes statistically in any diode laser-assisted transcanalicular DCR studies. Concentrations of MMC ranged from 0.05 to 1 mg/ml, with 0.2 mg/ml used most frequently in 12 series, with duration of application ranging from 2 to 30 minutes. Ostium size was significantly larger in MMC groups than in control groups at 6 months after surgery in 4 of 5 reporting studies. However, these larger ostia did not confer higher functional success rates. Reporting of adverse events related to MMC were rare, with delayed cutaneous wound healing reported in 1 of 750 patients. Intraoperative use of MMC in external and endoscopic endonasal DCR has been shown to improve functional and anatomic outcomes compared with controls in some series, but there is no agreement on the recommended concentration or application time for MMC in DCR. The data support that MMC use can result in a larger ostium size, decreased granulation tissue formation, and a decreased number of postoperative nasal debridements compared with controls, but this does not translate into improved functional success. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Treatment of recurrent low-volume low-risk NMIBC include: TURBT, office fulguration and active surveillance. The clinical significance of post-office fulguration single dose mitomycin C instillation is unknown. In a single-institution retrospective cohort of 108 patients, we found that single-dose post-office fulguration MMC was associated with longer recurrence-free-survival (median RFS 20 months 95% CI 4-36) compared to the controlled group that did not receive adjuvant mitomycin C instillation (median RFS 9 months 95% CI 5-13) (P = .038). The treatment was safe and well-tolerated. Prospective evaluation is warranted. Introduction: Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. Patients and Methods: A retrospective analysis of medical records of patients with recurrent small-volume (=1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). Results: Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P = .038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR = 0.552, 95% CI 0.320-0.955, P = .034) and multifocality was associated with shorter RFS (OR = 1.866, 1.078-3.229, P = .026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P = .048). No complications grade 3 or higher were observed. Conclusion: A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy followed by surgery for locoregionally advanced penile carcinoma (LAPSCC) is associated with severe toxicity and a 1-year survival probability of ∼50%. We aimed to evaluate the safety and efficacy of chemoradiotherapy (CRT) as the primary treatment for LAPSCC and the association of high-risk human papillomavirus (hrHPV) with the outcome. This was a prospective, single-center, single-arm study of CRT in LAPSCC, defined as a large/inoperable primary tumor, large palpable nodes, suspicion of extranodal extension or pelvic nodal involvement, and no distant metastases. CRT consisted of 49.5 Gy (33 × 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and positron emission tomography/computed tomography–positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). The response was evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. If feasible, patients with residual/recurrent disease underwent salvage surgery. The primary endpoint was 1-year progression-free survival (PFS), reached when 1-year PFS was ≥50%. Other endpoints were 2-year PFS, overall survival, and toxicity rates. Kaplan-Meier survival curves were compared using the log-rank test. Thirty-three patients were included: 29 (88%) with stage IV disease (T4 any-N M0 and/or any-T N3 M0) and 8 (24%) with hrHPV-positive disease. Median follow-up was 41 months. Thirty-two completed CRT. Eleven (33%) experienced ≥1 grade 3 treatment-related adverse event. There were no grade 4 or 5 treatment-related events. Twenty-four patients (73%) responded, including 13 (39%) complete responses. Nine patients (27%) underwent salvage surgery, and an additional 8 patients underwent later surgery (together 52%). One- and 2-year PFS were 34% and 31%, respectively. One- and 2-year overall survival were 73% and 46%, respectively. No significant difference between patients with hrHPV-positive and -negative tumors was observed. CRT is a viable treatment option for LAPSCC with acceptable toxicity. CRT can result in an enduring response. If patients have residual tumor, salvage surgery is feasible. HrHPV status was not associated with outcomes. [ABSTRACT FROM AUTHOR]

To demonstrate a technique for minimally invasive endoscopic management of posterior urethral strictures, including those at the bladder neck and vesicourethral anastomosis. Herein, we have included endoscopic video footage from 3 patients with posterior urethral strictures, including 1 at the bladder neck, 1 at the vesicourethral anastomosis, and 1 in the bulbomembranous urethra. In each patient, we perform a direct visualization internal urethrotomy (DVIU) with incisions at the 5 and 7 o'clock positions to widen the urethral lumen, followed by injection of 2 mg mitomycin C (MMC) in a total volume of 5 mL sterile water. Herein, we describe our technique for the endoscopic management of posterior urethral strictures, including those in the prostatic urethra and bladder neck. MMC injection, in conjunction with traditional DVIU, adds minimally to the complexity and length of the procedure but may substantially improve long-term surgical outcomes. Bladder outlet obstruction due to stenosis or stricture of the posterior urethra is a common urologic diagnosis whose etiology can often be traced to prior urethral manipulation or iatrogenic trauma. While Americal Urological Assicuation (AUA) guidelines state that dilation or direct visualization internal urethrotomy (DVIU) should be offered for bulbar strictures measuring less than 2 cm in length, recent evidence suggests that DVIU with or without MMC injection may have utility in the management of bladder neck or vesicourethral anastomotic contractures. We have found that DVIU with subsequent MMC injection is a viable minimally invasive approach for the treatment of posterior urethral strictures. While more data are needed to better understand the long-term success rates of these procedures, this approach should be considered for patients with a bladder outlet obstruction secondary to a short stricture of the posterior urethra, bladder neck, or vesicourethral anastomosis. [ABSTRACT FROM AUTHOR]

We evaluated the use of BCG and Mitomicin C instillations administered with Electromotive Drug Administration (EMDA) in patients with nonmuscle invasive bladder cancer in whom Bacillus Calmette-Guerin (BCG) therapy had failed, in order to provide bladder preservation for these patients. We evaluated the oncological outcomes and tolerability in a long follow up This treatment seems to be safe and to provide good responses in well selected patients, without a high progression rate. Background: Nowadays, there is no standard non-surgical treatment for patients with nonmuscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Güerin (BCG) therapy has failed.Objectives: To assess the clinical and oncological outcomes of sequential treatment with Bacillus Calmette-Guerin (BCG) and Mitomycin C (MMC) administered with Electromotive Drug Administration (EMDA) in patients with high-risk NMIBC who fail BCG immunotherapy. Material and Methods: We retrospectively studied patients with NMIBC who failed BCG and received alternating BCG and Mitomycin C with EMDA between 2010 and 2020. Treatment schedule consisted in an induction therapy with 6 instillations (BCG, BCG, MMC + EMDA, BCG, BCG, MMC + EMDA) and a 1-year maintenance. Complete response (CR) was defined as the absence of high-grade (HG) recurrences during follow-up, and progression was defined as the occurrence of muscle invasive or metastatic disease. CR rate was estimated at 3, 6, 12, and 24 months. Progression rate and toxicity were also assessed. Results: Twenty-two patients were included with a median age of 73 years. Fifty percent of tumors were single, 90% were smaller than 1.5cm, 40% were GII (HG) and 40% were Ta. CR rate was 95.5%, 81% and 70% at 3 and 6 months, 12 months and 24 months, respectively. With a median follow-up of 28.8 months, 6 patients (27%) presented HG recurrence and only 1 patient (4.5%) progressed and ended in cystectomy. This patient died due to metastatic disease. Treatment was well tolerated and 22% of the patients presented adverse effects, being dysuria the most frequent one. Conclusion: Sequential treatment with BCG and Mitomycin C with EMDA achieved good responses and low toxicity in selected patients who did not respond to BCG. Only 1 patient ended in cystectomy and died due to metastatic disease, therefore, cystectomy was avoided in most cases. [ABSTRACT FROM AUTHOR]

To measure the changes in treatment patterns for non-muscle invasive bladder cancer before and during the Bacillus Calmette-Guerin (BCG) drug shortage. We used a 5% random sample of Medicare beneficiaries and identified 7971 bladder cancer patients (2648 pre-BCG shortage and 5323 during the shortage) ≥66 years of age who received intravesical treatment within 1 year of diagnosis between 2010 and 2017. The BCG shortage period was defined from July 2012 ongoing. Full induction treatment with BCG, mitomycin C, gemcitabine, or other intravesical agents was defined as receiving ≥5 of 6 treatments within 60 days. State-level BCG use before and during the drug shortage was compared in US states reporting at least 50 patients in each period. Independent variables included year of index date, age, sex, race, rurality, and region of residence. BCG utilization rates decreased 5.9% in the shortage period (95% CI (−8.2%)-(−3.7%)). The proportion of patients that completed a full induction course of BCG decreased from 31.0% in the pre-shortage period to 27.6% in the shortage period (P =.002). 84% of reporting states (16 of 19) had decreased BCG utilization ranging between 5% and 36% compared to pre-shortage rates. During the BCG drug shortage, eligible bladder cancer patients were less likely to receive gold standard intravesical BCG with a large variation in treatment patterns between US states. [ABSTRACT FROM AUTHOR]

Results from HIVEC-II show no oncological benefit from chemohyperthermia over the control treatment. Adverse events following chemohyperthermia were low of grade and short-lived, although these patients were less likely to complete their treatment. Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non–muscle-invasive bladder cancer (NMIBC). To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC. HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital. Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min. The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat. A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51–69%) in the CHT arm and 60% (95% CI 50–68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62–1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09–10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83–9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77–8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control). CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment. The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non–muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment. [ABSTRACT FROM AUTHOR]

Background: Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies.Objective: To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors.Method: A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021.Results: The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery.Conclusions: The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy. [ABSTRACT FROM AUTHOR]

To report 5-year treatment outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. Multicenter randomized clinical trial. A total of 242 eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 patients in the tube group and 117 patients in the trabeculectomy group. Patients were enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC) (0.4 mg/ml for 2 minutes). The primary outcome measure was the rate of surgical failure, defined as intraocular pressure (IOP) > 21 mmHg or reduced < 20% from baseline, IOP ≤ 5 mmHg, reoperation for glaucoma, or loss of light perception. Secondary outcome measures included IOP, glaucoma medical therapy, and visual acuity. The cumulative probability of failure after 5 years of follow-up was 42% in the tube group and 35% in the trabeculectomy group (P = 0.21; hazard ratio = 1.31; 95% confidence interval = 0.86–2.01). At 5 years, IOP (mean ± standard deviation) was 13.4 ± 3.5 mmHg in the tube group and 13.0 ± 5.2 mmHg in the trabeculectomy group (P = 0.52), and the number of glaucoma medications (mean ± standard deviation) was 2.2 ± 1.3 in the tube group and 1.3 ± 1.4 in the trabeculectomy group (P < 0.001). Trabeculectomy with MMC and tube shunt surgery produced similar IOPs after 5 years of follow-up in the PTVT Study, but fewer glaucoma medications were required after trabeculectomy. No significant difference in the rate of surgical failure was observed between the 2 surgical procedures at 5 years. [ABSTRACT FROM AUTHOR]

Long-term follow-up in the BC2001 trial confirms the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for muscle-invasive bladder cancer. BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88). There are limited data on long-term recurrence risk. To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer–specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43–0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36–0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60–1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58–1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69–1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59–1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9–21%) with chemoradiotherapy versus 22% (95% CI 16–31%) with radiotherapy alone (HR 0.54, [95% CI 0.31–0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr. [ABSTRACT FROM AUTHOR]

Fanconi Anemia (FA) is an incurable recessive disease caused by mutations in any members of the FA pathway. FA Complementation group C patients (FANCC), one of the most common subtypes, exhibit typical, but more severe symptoms than other subtypes. Gene therapy to repair mutated genes in autologous FA patient-derived hematopoietic stem/progenitor cells (FA-HSPCs) can permanently rescue FA-mediated bone marrow failure (BMF) and overcome the limitations of allogeneic bone marrow transplantation. Here, we demonstrated the feasibility of CRISPR/Cas9- HDR in restoring functions of Fancc-/- HSPCs in vivo. We established a CRISPR/Cas9/AAV6-homology-directed repair (HDR) system to integrate Fancc cDNA into the endogenous Fancc promoter. Of note, along with the reestablished expression of Fancc, corrected HSPCs restored the colony-forming ability and the resistance to mitomycin C (MMC) treatment. We assessed the functions of corrected HSPCs in vivo by transplanting these cells into irradiated Fancc-/- mice. 3 months later, we induced the BMF by MMC treatment. We found that mice transplanted with non-corrected HSPCs developed BMF and died after 5 doses of MMC injection, supported by the hypocellular structure of bone sectioning. However, mice transplanted with corrected HSPCs did not develop BMF and survive. Bone sectioning of survivors showed normal cellular structure. Collectively, we demonstrate that CRISPR/Cas9-HDR rescued functions of Fancc-/- HSPCs both in vitro and in vivo. Although, we can rescue the BMF in Fancc-/- mice, we observed significant cell death after the gene editing, as Fancc-/- cells are susceptible to secondary DNA damage caused by the CRISPR/Cas9. To improve the functions of corrected HSPCs, we are exploiting our established Spacer-Nick approach in Hypoxia that barely introduces double-stranded breaks and DNA damage. Data will be updated at the meeting. [ABSTRACT FROM AUTHOR]

Malignant tumors are a serious threat to human health, and chemotherapy (CT) is one of the most commonly used strategies in cancer treatment. However, CT often suffers from severe side effects and therapeutic inefficiency, due to poor targeting of antitumor drugs and drug resistance with long-term use. Herein, we developed a GSH-responsive prodrug-based nanodrugs, which was internally encapsulated with the mitomycin C (MMC) prodrug and the photosensitizer Chlorin e6 (Ce6), and with surface-modified aptamers specifically targeting tumors. The nanodrugs not only promoted GSH-responsive CT drug release at the tumor site, but also enhanced the efficacy of Ce6-based photodynamic therapy (PDT) due to the severe redox imbalance in the tumor caused by GSH depletion, thereby improving the chemo- photodynamic synergistic treatment of the tumor. In vivo studies confirmed that the nanodrugs exhibited excellent tumor-targeting capabilities and significant anti-tumor therapeutic effects, offers a promising approach for clinical cancer treatment. [Display omitted] • MMC prodrugs are released after GSH-responsive, and simultaneously promote ROS production by depleting GSH. • Aptamer confers good tumor targeting and good cellular uptake of the nanoparticles. • The nanoparticles show the excellent antitumor performance under intraoperative NIR-II image guidance. [ABSTRACT FROM AUTHOR]

For peritoneal metastases from a primary appendiceal mucinous neoplasm to exist, the thin wall of the appendix must perforate to allow mucus or mucus plus tumor cells to gain access to the peritoneal spaces. The proportion of specimens containing tumor cells within mucus as compared to mucus only outside the appendix may have prognostic significance. The histopathology of tumor masses was determined from the specimens resected at the cytoreductive surgery (CRS). The presence versus absence of tumor cells in mucus and the proportion of specimens with tumor cells was determined and correlated with the overall survival of these patients. In 418 patients with a complete cytoreduction for a low-grade appendiceal mucinous neoplasm (LAMN), the cellularity of all resected specimens was determined. The hazard ratio of overall survival of patients whose specimens had no cells as compared to specimens with cells in mucus by histology was 4.41 (1.61, 12.1) (p = 0.0039). If overall survival of patients with all specimens without tumor cells was compared to patients with specimens with 1–99 % tumor and compared to patients with 100 % of specimens with tumor cells, the hazard ratios were 4.3 (1.34, 13.8) (p = 0.0143) and 9.62 (2.93, 31.6) (p = 0.0002), respectively. The cellularity of mucus within the specimens removed by a complete CRS has strong prognostic implications in LAMN patients. LAMN with acellular specimens (LAMNa) as compared to LAMN with tumor cells in specimens (LAMNb) should be staged as different histologic subtypes of mucinous appendiceal neoplasms. [ABSTRACT FROM AUTHOR]

An 8-month-old girl referred from her pediatrician with a diagnosis of neurofibromatosis type 1 (NF1) presented with an enlarged cloudy cornea of the left eye and a swollen left side of the face. Her left eye had intraocular pressure (IOP) of 21 mm Hg, corneal diameter of 16 mm, ectropion uvea, cup:disk ratio of 0.9, axial length of 28.06 mm, and S-shaped upper lid deformity. Uneventful combined trabeculotomy-trabeculectomy with mitomycin C was performed. On postoperative day 1, there was a new total hyphema that persisted for 2 weeks. An anterior chamber washout was performed, revealing the source of bleeding to be a persistent tunica vasculosa lentis along the zonules of the lens. Viscotamponade was performed, and the corneal wounds were closed, with the ocular tension slightly elevated. Bleeding did not recur for the following 5 months, and IOP was controlled until final follow-up. [ABSTRACT FROM AUTHOR]

Methicillin resistant Staphylococcus aureus (MRSA) is a pathogen to humans causing life-threatening infections. MRSA have the capability to grow resistance to many antibiotics, and phage therapy is one treatment option for this infection. The aim of the present study was to isolate and characterize the lytic bacteriophages specific to MRSA from domestic sewage water at a tertiary care hospital in Egypt. Thirty MRSA strains were isolated from different clinical samples admitted to the microbiology lab at Theodor Bilharz Research institute (TBRI) hospital, Giza, Egypt. They were confirmed to be MRSA through phenotypic detection and conventional PCR for mecA gene. They were used for the isolation of phages from sewage water of TBRI hospital. Plaque assay was applied to purify and quantify the titer of the isolated phages. The host range of the isolated phages was detected using the spot test assay. The morphology of phages was confirmed using transmission electron microscope (TEM). Digestion of DNA extracted from phages with endonuclease enzymes including EcoRI and SmaI was performed. SDS-PAGE was performed to analyze MRSA specific phage proteins. As a positive control prophages were isolated from a mitomycin C (MitC) treated culture of S. aureus strain ATCC25923. Further characterization using conventional polymerase chain reaction (PCR) was used to select three known Staphylophages by detecting the endolysin gene of phage K, the polymerase gene of phage 44AHJD, and the minor tail gene of phage P68. Isolated phages in this research displayed a wide host range against MRSA using the spot test, out of thirty tested MRSA isolates 24 were sensitive and got lysed (80%). The titer of the phages was estimated to be 1.04 × 106 pfu/ml using plaque test. Identification of head and tail morphology of the phages was achieved using TEM and they were designated to tailed phages of order Caudovirales , they composed an icosahedral capsid. Prophages were isolated through MitC induction. DNA of phages was digested by endonuclease enzymes. Conventional PCR yielded 341 bp of phage K endolysin gene and phage P68 minor tail protein gene 501 bp. Protein analysis using SDS-PAGE showed 4 proteins of sizes between 42 kDa and 140 kDa. Phages isolated here are alike to others mentioned in previous studies. The high broad host range of the isolated phages is promising to control MRSA and can be in the future commercially suitable for treatment as lysate preparations. Animal models of phage-bacterial interaction will be our next step that may help in resolving the multidrug resistant crisis of MRSA in Egypt. [ABSTRACT FROM AUTHOR]

Intravesical instillation (IVI) of Bacillus Calmette-Guerin (BCG) can prevent bladder cancer recurrence, but this agent has been out of stock in recent years. IVI of other agents, like chidamide, a histone deacetylase (HDAC) inhibitor, may have the potential to exert a therapeutic effect against bladder cancer by modifying the gene expression profiles associated with histone modifications that occur during cancer tumorigenesis. Here, we investigated the in vitro therapeutic effect of chidamide and/or mitomycin C in bladder cancer cell lines and screened related molecular pathways using an antibody array. We also quantitatively analyzed the synergistic effect of IVI of chidamide and mitomycin C in vivo in an N-methyl-N-nitrosourea (MNU)-induced rat bladder cancer model. The synergistic cytotoxic effect of chidamide plus mitomycin C was confirmed in both T24 and UMUC3 cells, with significantly greater induction of apoptosis elicited with chidamide plus mitomycin C than with either drug alone. The antibody array identified the Axl signaling pathway as the key target of the synergistic effect. Expression of Axl and its related downstream molecules, including claspin and survivin, was significantly suppressed. In the rat bladder cancer model, IVI of chidamide plus mitomycin C reduced tumor burden (Ki67 index) to a greater extent than either drug alone. Our results suggest that chidamide and mitomycin act synergistically to reduce MNU-induced bladder cancer. These findings provide new insights into a new and potentially effective approach to treating bladder cancer. [ABSTRACT FROM AUTHOR]

• Multicentric cohort of n = 605 patients treated with definitive chemoradiotherapy for anal cancer. • Overall, T-category, N-category, age and KPS were associated with worse DFS. • In early stage disease, T-category, HIV status, age, performance status and elevated platelets were associated with worse DFS. Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC. Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004–2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors. After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p < 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7). Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC. [ABSTRACT FROM AUTHOR]

To compare the effectiveness and safety of the MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG). One-year results from a 2-year, prospective, randomized, multicenter, noninferiority study (NCT01881425) conducted in the United States and Europe. Eligible patients were aged 40–85 years with intraocular pressure (IOP) ≥15 and ≤40 mmHg and mild-to-severe POAG inadequately controlled on maximum tolerated medical therapy. Patients were randomized 3:1 to undergo stand-alone MicroShunt implantation or trabeculectomy, both performed with adjunctive mitomycin C (0.2 mg/ml for 2 minutes). The primary effectiveness end point was surgical success, defined as ≥20% reduction in mean diurnal IOP from baseline (no medication washout) at year 1 without increasing the number of glaucoma medications. Secondary effectiveness end points at year 1 were the mean IOP change from baseline and requirement for postoperative intervention. Additional end points included glaucoma medication use and adverse events. Overall, 395 (MicroShunt) and 132 (trabeculectomy) patients were randomized (mean Humphrey visual field mean deviation, −12.34 decibels [dB]). At year 1, probability of success was lower in the MicroShunt group compared with the trabeculectomy group (53.9% vs. 72.7%, respectively; P < 0.01). In the MicroShunt group, mean IOP ± standard deviation decreased from 21.1 ± 4.9 mmHg at baseline to 14.3 ± 4.3 mmHg (−29.1%; P < 0.01) at year 1, with a mean of 0.6 ± 1.1 glaucoma medications (baseline 3.1 ± 1.0; P < 0.01). In the trabeculectomy group, mean IOP decreased from 21.1 ± 5.0 mmHg to 11.1 ± 4.3 mmHg (−45.4%; P < 0.01), with a mean of 0.3 ± 0.9 glaucoma medications (baseline 3.0 ± 0.9; P < 0.01). Postoperative interventions, including laser suture lysis, were reported in 40.8% (MicroShunt) versus 67.4% (trabeculectomy) of patients (P < 0.01). Reported incidence of transient hypotony was higher in the trabeculectomy group versus the MicroShunt group (49.6% vs. 28.9%; P < 0.01). Vision-threatening complications were uncommon and reported in 1.0% of MicroShunt versus 0.8% of trabeculectomy patients. Probability of success was lower with MicroShunt compared with trabeculectomy. Although reductions in IOP and glaucoma medications over 1 year were observed in both groups, the trabeculectomy group had a lower mean IOP on fewer medications. [ABSTRACT FROM AUTHOR]

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. To systematically review evidence for the efficacy and safety of adjuncts used alongside minimally invasive treatment of USD. A systematic review of the literature published between 1990 and 2020 was conducted in accordance with the PRISMA checklist. 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. 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. 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. Adjuncts to minimally invasive treatment of urethral strictures may reduce recurrence rates and thereby avoid the need for urethroplasty. Further adequately powered studies are needed to establish the safety, efficacy, and cost effectiveness of adjuncts and optimal drug dosing and delivery protocols. [ABSTRACT FROM AUTHOR]

Mitomycin C (MC) is an anti-cancer drug which functions by forming interstrand crosslinks (ICLs) between opposing DNA strands. MC analog, 10-decarbamoyl mitomycin C (DMC), unlike MC, has stronger cytotoxic effects on cancer cells with TP53 mutation. We previously demonstrated that MC/DMC could activate p21WAF1/CIP1 in MCF-7 (TP53-proficient) and K562 (TP53 deficient) cells in a TP53-independent mode. We also found that MC/DMC regulate AKT activation in a TP53-dependent manner and that AKT deactivation is not associated with the activation of p21WAF1/CIP1 in response to MC/DMC treatment. RAS proteins are known players in the upstream mediated signaling of p21WAF1/CIP1 activation that leads to control of cell proliferation and cell death. Thus, this prompted us to investigate the effect of both drugs on the expression of RAS proteins and regulation of the MAPK/ERK signaling pathways in MCF-7 and K562 cancer cells. To accomplish this goal, we performed comparative label free proteomics profiling coupled to bioinformatics/complementary phosphoprotein arrays and Western blot validations of key signaling molecules. The MAPK/ERK pathway exhibited an overall downregulation upon MC/DMC treatment in MCF-7 cells but only DMC exhibited a mild downregulation of that same pathway in TP53 mutant K562 cells. Furthermore, treatment of MCF-7 and K562 cell lines with oligonucleotides containing the interstrand crosslinks (ICLs) formed by MC or DMC shows that both ICLs had a stronger effect on the downregulation of RAS protein expression in mutant TP53 K562 cells. We discuss the implication of this regulation of the MAPK/ERK pathway in relation to cellular TP53 status. [Display omitted] • Mitomycin C (MC) and its major ICL downregulate MAPK/ERK pathway in MCF-7. • MC analog (DMC) and its major ICL downregulate MAPK/ERK pathway in K562. • The stereochemistry of ICLs contributes to the differential regulation of MAPK/ERK. • JAK/STAT pathway is downregulated by MC/DMC treatment in both MCF-7 and K562. • RAB8A and RAB13 are potential molecular targets of MC/DMC ICLs. [ABSTRACT FROM AUTHOR]

Cytogenetic studies have shown that human chromosomes 1, 9, and 16, with a large heterochromatic region of highly methylated classical satellite DNA, are prone to induction of chromatid breaks and interchanges by mitomycin C (MMC). A couple of studies have indicated that material from chromosome 9, and possibly also from chromosomes 1 and 16, are preferentially micronucleated by MMC. Here, we further examined the chromosome-specific induction of micronuclei (MN; with and without cytochalasin B) and chromosomal aberrations (CAs) by MMC. Cultures of isolated human lymphocytes from two male donors were treated (at 48 h of culture, for 24 h) with MMC (500 ng/ml), and the induced MN were examined by a pancentromeric DNA probe and paint probe for chromosome 9, and by paint probes for chromosomes 1 and 16. MMC increased the total frequency of MN by 6–8-fold but the frequency of chromosome 9 -positive (9+) MN by 29–30-fold and the frequency of chromosome 1 -positive (1+) MN and chromosome 16 -positive (16+) MN by 12–16-fold and 10–17-fold, respectively. After treatment with MMC, 34–47 % of all MN were 9+, 17–20 % 1+, and 3–4 % 16+. The majority (94–96 %) of the 9+ MN contained no centromere and thus harboured acentric fragments. When MMC-induced CAs aberrations were characterized by using the pancentromeric DNA probe and probes for the classical satellite region and long- and short- arm telomeres of chromosome 9, a high proportion of chromosomal breaks (31 %) and interchanges (41 %) concerned chromosome 9. In 83 % of cases, the breakpoint in chromosome 9 was just below the region (9cen-q12) labelled by the classical satellite probe. Our results indicate that MMC specifically induces MN harbouring fragments of chromosome 9, 1, and 16. CAs of chromosome 9 are highly overrepresented in metaphases of MMC-treated lymphocytes. The preferential breakpoint is below the region 9q12. • Mitomycin C-induced human micronuclei and chromosome aberrations were characterized. • Fluorescence in situ hybridization and chromosome paints in human lymphocytes were used. • Chromosomes 9, 1 and 16 are over-represented in induced micronuclei. • Chromosome 9 is highly involved in induced chromatid breaks and exchanges. • The preferential breakpoint in chromosome 9 is right below long arm band 9cen-q12. [ABSTRACT FROM AUTHOR]

Due to patient or surgeon preference many patients diagnosed with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) are not treated according to AUA, EAU or NCCN guidelines. Data suggests that delaying or forgoing radical cystectomy may put patients at risk for disease progression and inferior oncologic outcomes. However, the natural history of bladder-sparing therapy (BST) in patients with BCG-unresponsive disease is not well defined. Alternate intravesical, and recently systemic, treatment options are given to patients without full knowledge of the oncologic risks over time with the first and subsequent lines of BST. The primary aim of this retrospective study is to determine the oncologic risks of BST over time in patients with BCG-unresponsive NMIBC who do not undergo radical cystectomy. Data for this study came from a larger multi-center, international cohort of patients with BCG-unresponsive disease that included 594 patients who underwent either upfront radical cystectomy or upfront BST. Patients were included if they had BCG-unresponsive disease after adequate BCG therapy according to FDA criteria, defined as 1) ≥; T1 high-grade (HG) disease on the first assessment following adequate BCG, 2) high grade recurrence with papillary NMIBC within 6 months of adequate induction and maintenance BCG therapy, or 3) any component of CIS within 12 months of adequate induction and maintenance BCG. Adequate BCG was defined as 5/6 doses for induction and 2/3 doses for maintenance. Patients with upper tract disease or who were pathologic T2, node-positive, or metastatic at time of BCG-unresponsiveness were excluded. BSTs at time of BCG-unresponsiveness were collected, in addition to subsequent lines of BST. Survival analysis was performed to create life tables and time-to-event calculations. 422 patients with BCG unresponsive disease underwent at least 1 BST. The most common initial BST was BCG or alternate BCG in 204 (48.3%) patients (Table 1). Alternative intravesical agents, including sequential intravesical gemcitabine and docetaxel, intravesical Mitomycin C, or various experimental clinical trial therapies were given in 151 (35.8%) patients. For all patients undergoing at least 1 BST, intravesical HG recurrence occurred in 22% and 37% of patients at 6 and 12 months after BCG-unresponsiveness, respectively (Table 2). Rates of cystectomy, metastasis, bladder cancer death, and all-cause mortality were low at 6 months at 2%, 1%, 0%, and 1%, respectively. However, at 12 months, these rates rose to 12%, 3%, 2%, and 4%, respectively. 90 patients received 2nd and third lines of BST. In this group, rates of cystectomy, metastasis, bladder cancer death, and all-cause mortality were also low at 6 months with 1% in each outcome and started to rise 9 months after BCG-unresponsiveness. This study reviewed oncologic outcomes from a large retrospective multi-center cohort of patients with BCG-unresponsive NMIBC. Patients who underwent initial BST appeared to have acceptable oncologic outcomes 6-9 months after BCG-unresponsive diagnosis. In clinical practice, this may translate to initial trial of BST in well-selected patients in which BCG is ineffective. Worse oncologic outcomes arise 12 months after being deemed BCG-unresponsive, particularly in patients treated with second and third lines of BST. The results from this study provide important reference data which may aid in patient counseling. Larger prospective patient cohorts are required to validate these data and confirm the safety of delaying cystectomy in select patients with BCG-unresponsive NMIBC. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy, effect of radiotherapy, and complications of direct visual internal urethrotomy (DVIU) and intralesional mitomycin C (MMC) for recurrent bladder neck contracture/vesicourethral anastomotic stenosis (BNC/VUAS).Methods: Patients who underwent DVIU with intralesional MMC for recurrent BNC/VUAS between 2007 and 2019 at 2 institutions were included. Cold knife incisions were performed in a reproducible fashion followed by injection of 0.3-0.4 mg/mL MMC at each incision site. Those with evidence of complete urethral obliteration, stenosis of the entire posterior urethra, or <3 months follow-up were excluded. Success was defined as the ability to pass a 17-French cystoscope postoperatively without the need for catheterization or additional procedures.Results: Eighty-six patients were analyzed over a median follow-up of 21.1 months. Around 91% had at least 1 prior DVIU, 56% had at least 1 prior dilation, and 44% presented with an indwelling catheter or performed intermittent catheterization. Success was achieved in 65% after 1 procedure, an additional 18% after 2 procedures, and another 7% after 3 or more procedures (90% overall success rate). Nonradiated patients showed a higher overall success rate compared to radiated patients (94% vs 76%, P = 0.04). Of the 9 cystoscopic failures, 5 were asymptomatic and pursued observation. Only 2 (5%) patients with a history of catheterization required this postoperatively. Two patients underwent subsequent urinary diversion surgery. No long-term complications were seen.Conclusion: DVIU with low-dose MMC remains a safe and effective BNC/VUAS treatment. A patent bladder neck was achieved in >90% of nonradiated patients and >75% of radiated patients. [ABSTRACT FROM AUTHOR]

Trabeculectomy has been performed since the mid-1960s and remains the gold standard for glaucoma surgery. Newer surgical options have evolved, collectively referred to as minimally invasive glaucoma surgeries. Despite producing large intraocular pressure decreases, full-thickness procedures into the subconjunctival space may be limited by fibrosis. Mitomycin C (MMC) and 5-fluorouracil have been in use with trabeculectomy with good evidence of significantly increased success at the cost, however, of an increased risk of complications. Off-label MMC application can be found in almost all clinical trials, including in combination with minimally invasive glaucoma surgeries. We explore current evidence for MMC use in trabeculectomy and how this may differ for minimally invasive glaucoma surgery devices and analyze the range of agents and doses that are used. Although we found that most studies could not show any correlation between MMC dosage and the surgical outcome, the success rates with the Xen® microshunt seemed to be higher when using 20 mcg of MMC than when using 10 mcg. Certain important methodological considerations make this hard to confirm definitively, and other factors such as placement of the device may play a more substantial role. For the PreserFlo® microshunt, preliminary data suggest higher success rates with higher MMC dosage at the cost of higher device-related adverse events and reoperations. Although the ideal dose still needs to be established, it seems very likely that MMC provides significant improvement in outcomes in bleb-forming minimally invasive glaucoma procedures. [ABSTRACT FROM AUTHOR]

The MCM8/9 complex is implicated in aiding fork progression and facilitating homologous recombination (HR) in response to several DNA damage agents. MCM9 itself is an outlier within the MCM family containing a long C-terminal extension (CTE) comprising 42% of the total length, but with no known functional components and high predicted disorder. In this report, we identify and characterize two unique motifs within the primarily unstructured CTE that are required for localization of MCM8/9 to sites of mitomycin C (MMC)-induced DNA damage. First, an unconventional "bipartite-like" nuclear localization (NLS) motif consisting of two positively charged amino acid stretches separated by a long intervening sequence is required for the nuclear import of both MCM8 and MCM9. Second, a variant of the BRC motif (BRCv) similar to that found in other HR helicases is necessary for localization to sites of MMC damage. The MCM9-BRCv directly interacts with and recruits RAD51 downstream to MMC-induced damage to aid in DNA repair. Patient lymphocytes devoid of functional MCM9 and discrete MCM9 knockout cells have a significantly impaired ability to form RAD51 foci after MMC treatment. Therefore, the disordered CTE in MCM9 is functionally important in promoting MCM8/9 activity and in recruiting downstream interactors; thus, requiring full-length MCM9 for proper DNA repair. [ABSTRACT FROM AUTHOR]

Instillation therapy for non–muscle-invasive bladder cancer (NMIBC) reduces recurrences but is associated with side effects. Preoperative instillation of chemotherapy could potentially be associated with fewer side effects compared with adjuvant instillations and in some patients make tumour resection (transurethral resection of the bladder tumour [TURBT]) superfluous. To investigate tumour response and adverse events related to short-term, intensive chemoresection with mitomycin C compared with adjuvant instillations in patients with recurrent NMIBC. A randomised, controlled trial was conducted in two urological departments in Denmark from January 2018 to June 2019. In total, 120 participants with a history of Ta bladder tumours, low grade or high grade, were included upon recurrence. Intravesical mitomycin C (40 mg/40 ml) three times a week for 2 wk in the intervention group (59 patients) was compared with TURBT and six weekly adjuvant instillations in the control group (61 patients). Tumour response was evaluated in the intervention group by flexible cystoscopy after 4 wk. Side effects were prospectively registered in both groups using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Groups were compared using χ2 or Fisher's exact test. Complete tumour response was seen in 33 participants (57%) in the intervention group. Fewer adverse events were reported in the intervention group than in the control group. Two patients in each group ceased instillation treatment due to adverse events. The main limitation is the current lack of long-term follow-up. Short-term, intensive chemoresection yields a tumour response of 57%. Hence, only half of those treated with chemoresection needed TURBT. The treatment was furthermore associated with fewer clinically significant side effects. Owing to small numbers, further investigations on Ta high-grade tumours are needed. We compared a nonsurgical treatment with standard treatment in patients with superficial bladder tumours. We found it to be safe and able to avoid surgery in more than half of the patients. Short-term, intensive chemoresection for recurrent intermediate- or high-risk Ta non–muscle-invasive bladder cancer is feasible with a complete tumour response in 57% of patients. Hence, only half of the patients treated with chemoresection needed transurethral resection of the bladder tumour. The treatment was furthermore associated with fewer clinically significant side effects. Long-term follow-up will demonstrate whether chemoresection may serve as a standard nonsurgical treatment option. [ABSTRACT FROM AUTHOR]

• DNA damage was assessed using in vitro and in vivo comet assay on one- and two-cell mouse embryos. • The use of a protocol with three layers of agarose reduces the embryo loss. • DNA damage induced in maternal germ cells persists, which can be detected in embryos. DNA damage quantified as the comet tail length was assessed using in vitro and in vivo comet assay on one- and two-cell mouse embryos obtained by natural mating. The use of a protocol with three layers of agarose reduces the embryo loss and makes it possible to study a small number of embryos. A significantly lower level of basal, but not induced DNA damage was found in embryos with cleaved zona pellucida compared to embryos with intact zona pellucida. There were no significant differences in the length of the comet's tail between embryos lysed in different lysis solutions, both in cases of basal and induced DNA damage. A significant increase in the comet tail length was detected in one-cell embryos of mice treated with methyl methanesulfonate and etoposide compared to the control. The data show that DNA damage induced in maternal germ cells persists, which can be detected in embryos using the comet assay. [ABSTRACT FROM AUTHOR]

Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1∗2 , NQO1∗3 , and POR∗28 with the efficacy of CRS + HIPEC with MMC in patients with CPM. A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1∗2 , NQO1∗3 , and POR∗28 were tested for association. A total of 253 patients were included. In NQO1∗3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1∗3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03–4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66–3.07]). Carriership of the NQO1∗3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial. • NQO1∗3 polymorphism is associated with a higher peritoneal recurrence rate • NQO1∗3 polymorphism is associated with worse disease-free survival • This polymorphism is a potential biomarker for the efficacy of mitomycin C HIPEC • Individualized CRS + HIPEC treatment based upon biomarkers may be beneficial [ABSTRACT FROM AUTHOR]

In the Netherlands, limited variability exists in performance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) among centers treating colorectal peritoneal metastases (PM), except for the intraperitoneal drug administration. This offers a unique opportunity to investigate any disparities in survival between the two most frequently used HIPEC regimens worldwide: mitomycin C (MMC) and oxaliplatin. This was a comparative, population-based cohort study of all Dutch patients diagnosed with synchronous colorectal PM who underwent CRS-HIPEC between 2014 and 2017. They were retrieved from the Netherlands Cancer Registry. Main outcome was overall survival (OS). The effect of the intraperitoneal drug on OS was investigated using multivariable Cox regression analysis. In total, 297 patients treated between 2014 and 2017 were included. Among them, 177 (59.6%) received MMC and 120 (40.4%) received oxaliplatin. Only primary tumor location was different between the two groups: more left-sided colon in the Oxaliplatin group (47.5% vs. 33.3%, respectively, p=0.048). The 1-, 2- and 3-year OS were 84.6% vs. 85.8%, 61.6% vs. 63.9% and 44.7% vs. 53.5% in patients treated with MMC and oxaliplatin, respectively. Median OS was 30.7 months in the MMC group vs. 46.6 months in the oxaliplatin group (p=0.181). In multivariable analysis, no influence of intraperitoneal drug on survival was observed (adjusted HR 0.77 [0.53–1.13]). Long-term survival between patients treated with either MMC or oxaliplatin during CRS-HIPEC was not significantly different. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases (CRPM) a favorable long-term survival. While cytoreductive techniques are standardized, there remains great variability in HIPEC drugs with mitomycin C or oxaliplatin use based largely on institute preference. In this study, we compared outcomes based on mitomycin C or oxaliplatin use after complete cytoreduction.Methods: This is a retrospective analysis over a 7-year period of all patients undergoing complete cytoreduction with HIPEC.Results: Seventy-eight patients underwent complete cytoreduction with HIPEC during this time. Forty-six patients received oxaliplatin as HIPEC, and 32 received mitomycin C. There was no difference in patient characteristics, resections, or major morbidity between the two groups. Superficial wound infections were higher in the mitomycin C group (37.5% v 15.2%, p = 0.02). Median overall and disease-free survival for the entire cohort was 40 and 14 months, respectively. There was no difference in overall survival or disease-free survival between the two HIPEC groups (HR 0.50, 95% CI 0.11-2.28).Conclusion: Complete cytoreduction and HIPEC can offer selected patients a favorable survival. The choice of mitomycin C or oxaliplatin for HIPEC had no influence on survival. Prospective studies are needed to explore this important issue. [ABSTRACT FROM AUTHOR]

Ganglion cysts are among the most common benign soft tissue masses. Although surgery has been shown to be effective, ∼12% to 42% of cases with long-term follow-up have been reported to recur. The purpose of this study was to determine the impact of the topical application of mitomycin C used as an adjuvant to surgery on recurrence rate of ganglion cysts. A retrospective analysis was done on all patients surgically treated by 1 surgeon for ganglion cysts. The primary end point was local recurrence after the procedure, determined clinically and by ultrasound. Secondary outcomes included wound complication rate, adverse effects, and overall patient satisfaction. A total of 98 consecutive patients were included in this study and assigned to a study group in a nonrandomized manner. The control group (n = 52) consisted of patients who underwent surgical resection only. The study group (n = 46) consisted of patients who underwent surgical resection with application of topical mitomycin C. No patients were lost to follow-up. Of the 52 patients in the control group, 13 (25.0%) had recurrence of the ganglion cyst. In contrast, in the experimental study group, 2 patients (4.3%) had a recurrence. There was no difference in superficial wound infections between the 2 groups. In this study, we found that the use of topical mitomycin C as an adjuvant to surgical resection significantly reduced the recurrence rate. Wound infection and overall nonrecurrence complication rates were similar to those of other studies. [ABSTRACT FROM AUTHOR]

• vulgaris and A.alba showed genotoxic and strong protective-proapoptotic activity. • alba showed cytotoxic activity on colon cancer without effects on stem cells. • Compounds in the extracts could be responsible for achieved biological activity. The aim of the study was to investigate genotoxic and cytotoxic activities of Artemisia vulgaris L. and Artemisia alba Turra methanol extracts concerning their chemical composition, separately and in co-treatment with a known mutagen (mitomycin C, MMC). For these evaluations, the cytokinesis-block micronucleus (CBMN) assay as the method for measuring MN frequency in human peripheral blood lymphocytes (PBLs) and MTT assay as the proliferation test in SW-480 human colon cancer cells and human periodontal ligament stem cells (PDLSCs) as normal control, were performed. The total phenol and flavonoid contents were determined using the spectrophotometric method, and identification and quantification of polyphenols were performed using high-performance liquid chromatography (HPLC-PDA). Cytokinesis-block micronucleus assay showed that both extracts significantly increased micronucleus (MN) frequency in the PBLs treated with all tested concentrations (10, 50, 100 and 250 μg/mL), except the lowest concentration (10 μg/mL) of A. vulgaris. All the concentrations of A. alba significantly influence the nuclear division index (NDI). In treatment against MMC, the extracts dose-dependently reduced MN frequencies and NDI values in comparison with the positive control. A. alba extract exhibits significant cytotoxic activity in SW-480 cells, while A. vulgaris induces cytotoxic activity only in co-treatment with MMC after long-term exposure. Both extracts did not significantly affect the viability of the PDLSCs. The phytochemical analysis showed that the extracts contained large amounts of total phenols and flavonoids. The most abundant polyphenolic compounds were chlorogenic acid and quercetin-3- O -glucopyranoside, while 2,5-dihydroxybenzoic acid present in higher amount and detected only in A. alba extract. High concentrations of certain polyphenolic compounds detected in A. vulgaris and A. alba extracts can be a significant factor for obtaining genotoxic, cytotoxic and protective activities. [ABSTRACT FROM AUTHOR]

Phosphoglycerate kinase 1 (PGK1) plays metabolic, kinase and translational roles in Peritoneal metastasis (PM) of gastric origin and is associated with chemoresistance. Silencing PGK1 might potentiate the effect of chemotherapy. In an orthoptic xenograft nude mice model, human gastric cancer cells (MKN45) were grown in 22 donor animals. Solid tumors were then grafted into the gastric subserosa of 102 recipient animals and allowed to grow for 10 days. Animals were randomized into 7 groups: Five test groups: 1) Mitomycin C (MMC), 2) MMC and small hairpin RNA silencing of PGK1 with an adenoviral vector (Adv-shPGK1), 3) 5-fluorouracil (5-FU), 4) 5-FU and Adv-shPGK1, 5) Adv-shPGK1 alone; two control groups: 1) Sham (NaCl 0.9%), 2) empty viral vector. Intraperitoneal therapy was administered on postoperative day (POD) 11 and 18. Animals were sacrificed at POD 21, analysis was blinded to therapy. Adding Adv-shPGK1 to 5-FU reduced the number (0.23 ± 0.43 vs. 1.36 ± 1.00, p = 0.005) and weight (0,005 ± 0.012 mg vs. 0.05 ± 0.08 mg, p = 0.002) of PM as compared to 5-FU alone. The effect of adding Adv-shPGK1 to MMC did not reach statistical significance. Mortality was not increased by adding Adv-shPGK1 to chemotherapy but was increased by Adv-shPGK1 alone as compared to sham. In this experimental model, combined therapy with chemotherapy and Adv-shPGK1 improves control of PM of gastric origin as compared to chemotherapy alone and might counteract chemoresistance of PM. A systemic toxicity of Adv-shPGK1 cannot be excluded. In an orthoptic xenograft model of gastric cancer, combination of small hairpin RNA inhibition of Phosphoglycerate-kinase 1 (PGK1) and intraperitoneal chemotherapy reduces growth of peritoneal metastasis as compared to chemotherapy alone. [ABSTRACT FROM AUTHOR]

To report 3-year results of the Primary Tube Versus Trabeculectomy (PTVT) Study. Unmasked multicenter randomized clinical trial. Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. Patients were enrolled at 16 clinical centers and were assigned randomly to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC; 0.4 mg/ml for 2 minutes). The primary outcome measure was the rate of surgical failure, defined as intraocular pressure (IOP) of more than 21 mmHg or reduced less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures included IOP, glaucoma medical therapy, visual acuity, and surgical complications. The cumulative probability of failure after 3 years of follow-up was 33% in the tube group and 28% in the trabeculectomy group (P = 0.17; hazard ratio, 1.39; 95% confidence interval, 0.9–2.2). Mean ± standard deviation IOP was 14.0±4.2 mmHg in the tube group and 12.1±4.8 mmHg in the trabeculectomy group at 3 years (P = 0.008), and the number of glaucoma medications was 2.1±1.4 in the tube group and 1.2±1.5 in the trabeculectomy group (P < 0.001). Serious complications requiring reoperation or producing loss of 2 or more Snellen lines developed in 3 patients (2%) in the tube group and 9 patients (8%) in the trabeculectomy group (P = 0.11). There was no significant difference in the rate of surgical failure between the 2 surgical procedures at 3 years. Trabeculectomy with MMC achieved lower IOP with use of fewer glaucoma medications compared with tube shunt surgery after 3 years of follow-up in the PTVT Study. Serious complications producing vision loss or requiring reoperation occurred with similar frequency after both surgical procedures. [ABSTRACT FROM AUTHOR]

Dans un contexte de défaut de production du BCG et en l'absence d'alternatives validées, la cystectomie est désormais recommandée dans les TVNIM à haut risque en échec du BCG. La thermochimiothérapie de Mitomycine C (MMC) pourrait être une alternative thérapeutique à la prévention des récidives des TVNIM à risque intermédiaire et élevé en échec ou intolérants au BCG. L'objectif était de réaliser une mise au point pratique de la thermochimiothérapie par l'HIVEC™. Une revue de la littérature a été réalisée sur la base de données PubMed en mars 2019 en utilisant les mots clés « bladder cancer; non-muscle invasive; Mitomycin C; chemohyperthermia; HIVEC; high risk ». Nous rapportons notre expérience de mise en place du système BRS Medical dans notre centre. La thermochimiothérapie serait efficace chez des patients ayant une TVNIM de risque intermédiaire et élevé, naïfs ou en échec du BCG. Un essai comparatif de phase III a rapporté que l'HIVEC™ était non inférieur au BCG après un suivi médian de 24 mois. Il pourrait exister une indication de l'HIVEC dans un schéma néoadjuvant où un essai de phase III a mis en évidence un taux de réponse complète à 62,5 % avant RTUV. Concernant la tolérance, la plupart des effets indésirables de l'HIVEC rapportés étaient mineurs sans toxicité de grade 3 ou plus. Nous rapportons notre expérience de mise en place. La pompe est mise à disposition par l'industrie et le consommable a un coût total de 1500 euros par patient (6 séances). Le tarif du GHS est de 406 euros et l'organisation des séances en hôpital de jour est rentable dès la quatrième séance. Le schéma d'administration comprend 6 instillations endovésicales à un rythme hebdomadaire. La durée de chaque séance est de 1 heure. Un sondage urinaire est pratiqué et la sonde est connectée aux tubulures du consommable. Après avoir purgé le système, la MMC est réchauffée à l'extérieur du patient par une fiche en aluminium avant mise en circulation à une température de 43 °C. À la fin de la séance, une alarme signale la fin de la procédure. L'HIVEC™ peut être une alternative dans la prévention du risque de récidive des TVNIM en échec ou intolérants au BCG. La mise en place du système dans notre centre a été facile, rapide et attractive pour les patients. In a context of BCG production failure and in the absence of validated alternatives, cystectomy is now recommended in high-risk NMIBC with BCG failure. The thermochemotherapy of Mitomycin C (MMC) may be a therapeutic alternative to the prevention of recurrence of intermediate and high risk NMIBC who fail or are intolerant to BCG. The aim was to achieve a practical development of thermochemotherapy with HIVEC™. A review of the literature was conducted on the PubMed database in March 2019 using the keywords "bladder cancer; non-invasive muscle; Mitomycin C; chemohyperthermia; HIVEC; high risk". We report our experience implementing the BRS Medical system in our center. Thermochemotherapy would be effective in patients with intermediate and high risk NMIBC, naive or in BCG failure. A phase III comparative trial reported that HIVEC™ was no lower than BCG after a median follow-up of 24 months. There may be an indication of HIVEC in a neoadjuvant protocol where a phase III trial demonstrated a complete response rate of 62.5% before TUVR. Regarding tolerance, most reported adverse effects of HIVEC were minor with no grade 3 or higher toxicity. We report our experience of setting up. The pump is made available by the industry and the consumable has a total cost of 1500 euros per patient (6 sessions). The price of GHS is 406 euros and the organization of sessions in day hospital is profitable from the fourth session. The administration scheme includes 6 instillations at a weekly rate. The duration of each session is 1 hour. A urine test is performed and the probe is connected to the tubing of the consumable. After purging the system, the MMC is warmed to the outside of the patient by an aluminum plug before circulating at a temperature of 43 °C. At the end of the session, an alarm signals the end of the procedure. HIVEC™ may be an alternative in preventing the risk of recurrence of NMBIC in failure or intolerant to BCG. The implementation of the system in our center was easy, fast and attractive for the patients. [ABSTRACT FROM AUTHOR]

Several liposome products have been approved for the treatment of cancer. In all of them, the active agents are encapsulated in the liposome water phase passively or by transmembrane ion gradients. An alternative approach in liposomal drug delivery consists of chemically modifying drugs to form lipophilic prodrugs with strong association to the liposomal bilayer. Based on this approach, we synthesized a mitomycin c-derived lipidic prodrug (MLP) which is entrapped in the bilayer of PEGylated liposomes (PL-MLP, Promitil®), and activated by thiolytic cleavage. PL-MLP is stable in plasma with thiolytic activation of MLP occurring exclusively in tissues and is more effective and less toxic than conventional chemotherapy in various tumor models. PL-MLP has completed phase I clinical development where it has shown a favorable safety profile and a 3-fold reduction in toxicity as compared to free mitomycin c. Clinical and pharmacokinetic studies in patients with advanced colo-rectal carcinoma have indicated a significant rate of disease stabilization (39%) in this chemo-refractory population and significant prolongation of median survival in patients attaining stable disease (13.9 months) versus progressive disease patients (6.35 months). The pharmacokinetics of MLP was typically stealth with long T½ (~1 day), slow clearance and small volume of distribution. Interestingly, a longer T½, and slower clearance were both correlated with disease stabilization and longer survival. This association of pharmacokinetic parameters with patient outcome suggests that arrest of tumor growth is related to the enhanced tumor localization of long-circulating liposomes and highlights the importance of personalized pharmacokinetic evaluation in the clinical use of nanomedicines. Another important area where PL-MLP may have an added value is in chemoradiotherapy, where it has shown a strong radiosensitizing effect in animal models based on a unique mechanism of enhanced prodrug activation and encouraging results in early human testing. Unlabelled Image [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the in vivo efficacy of a novel regenerative collagen-based scaffold developed by the Royal College of Surgeons in Ireland in a chronic tympanic membrane perforation (TMP) using a chinchilla model. Bilateral TMPs were induced in 17 mixed gender chinchillas using tympanic membrane resection followed by a mixture of topical Mitomycin C and dexamethasone for 3 days. These were monitored with weekly otoscopy for 8 weeks. Animals were excluded if signs of infection developed in the follow up period (n = 8). At 8 weeks, intervention began and 18 TMPs were assigned to either treatment with the collagen-based scaffold (treated group) or spontaneous healing (control group). Animals were euthanized 6 weeks post-intervention. Otoscopic imaging and auditory brain response (ABR) were conducted at baseline, 8 weeks post-TMP induction and 6 weeks post-intervention. All TMPs were then evaluated at 6 weeks post-intervention and bullae underwent histologic evaluation. At 6 weeks post-intervention, otoscopic imaging demonstrated various degrees of healing in the treated ears. The treated group was noted to have an increased rate of healing when compared to the control group. Histologic evaluation demonstrated a variation in the degree of perforation healing within groups, with some animals in the treated group showing high levels of perforation healing. At 8 weeks after the TMP procedure, most of the animals had worsened hearing response. At 6-week post the collagen-based scaffold treatment, about 50 % (4/8) of the treated ears had improved in hearing response as compared to those of non-treated ears. Given the initial histologic evidence of partial healing in scaffold-treated ears, the post-intervention period should be extended to monitor the potential for complete healing. Given the overall positive findings related to healing with the scaffold-treated ears, this material warrants further investigation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel graphene quantum dots-polyfluorene (GQD@PF) hybrid was synthesized. • GQD@PF was used to modify pencil graphite electrode (PGE) surface. • Modified electrode was used as a DNA biosensor to test MC-dsDNA interactions. • 24 fold enhance in electroactive surface area was achieved with GQD@PF modification. • GQD@PF-PGE allows an approximately 56 times more sensitive DNA analysis. A novel graphene quantum dots (GQD) / polyfluorene (PF) nanocomposite was deposited on the disposable pencil tip graphite electrode (PGE) and proven to be an efficient nanosensor for analysis of the electrochemical interaction between the antitumor compound mitomycin C (MC) with double stranded DNA (ds-DNA). This modified electrode (GQD@PF-PGE) was prepared in four steps: hydrothermal, chemical oxidation, ultrasonication and electro-oxidation processes. GQD, PF, GQD@PF and GQD@PF-PGE have been characterized by different analytical techniques such as SEM, TEM, XRD, FTIR, UV–Vis, EIS. Compared to bare PGE, GQD@PF modified PGE performed approximately 56 times more sensitive analysis when evaluating the guanine oxidation signals measured by DPV. CV and EIS measurements also showed that GQD@PF-PGE possesses a fast electron transfer as compared to bare electrode and exhibit a remarkable electrocatalytic activity towards both guanine and MC electrooxidation. Comprehensive optimization studies have also been carried out for the developed new nanobiosensor. [ABSTRACT FROM AUTHOR]