Efficacy and safety of intraoperative injection of mitomycin C during trabeculectomy: a systematic review and meta-analysis.

PURPOSE: Trabeculectomy, a primary surgical treatment for glaucoma, often employs mitomycin C (MMC) to reduce scar formation and improve surgical outcomes. However, the optimal application method of MMC, whether by injection or sponge, remains a subject of debate. This meta-analysis aims to compare injectable and sponge-based MMC application in terms of efficacy and safety, focusing on various clinical outcomes in glaucoma patients. METHODS: A comprehensive literature search of Scopus, MEDLINE, EMBASE, Ovid, Chinese biomedical literature database, China National Knowledge Infrastructure, and Cochrane Library was done for eligible studies that report data of glaucoma patients who were administered MMC by injection or sponge application during trabeculectomy. Outcomes of interest included intraocular pressure (IOP) reduction, bleb appearance grading (height, extent, vascularity), use of anti-glaucoma medications, and rates of complete success, qualified success, and failure. Data were reported as weighted mean differences (WMD) or odds ratios (OR) with confidence intervals (CI). The random-effects inverse-variance model with DerSimonian-Laird estimate of tau2 was employed, with continuity correction applied where necessary. RESULTS: A total of 15 studies with 1276 participants were included. The meta-analysis revealed no significant difference in IOP reduction between patients treated by MMC injection and sponge application (WMD = - 0.434). Significant differences were observed in bleb appearance grading scores for height (WMD = - 0.170) and extent (WMD = 0.174), with substantial heterogeneity. The use of anti-glaucoma medications was significantly lower in the injection group (WMD = - 0.274). However, there were no significant differences in the rates of complete success, qualified success, and failure. The study demonstrated moderate to high heterogeneity across various outcomes. CONCLUSION: This meta-analysis indicated that while both injection and sponge methods of MMC application during trabeculectomy were equally effective for IOP reduction, they differ in their impact on bleb morphology and postoperative medication requirement. The findings highlight the need for individualized treatment approaches in glaucoma surgery, taking into account the specific needs and characteristics of each patient.

Evaluation of Macular Thickness in Glaucoma Patients Using Prostaglandin Analog Eye Drops Undergoing Trabeculectomy with Mitomycin C: Prospective, Comparative, Randomized, Masked Examiner Study.

INTRODUCTION: The aim of the study was to evaluate the macular thickness of glaucomatous patients undergoing trabeculectomy (TREC) with mitomycin C (MMC) with or without the use of prostaglandin analog (PA) eye drops. METHODS: In this prospective, comparative clinical trial, patients with glaucoma and indications for TREC with MMC using PA and without previous macular changes were randomized into 2 groups: the study group (SG) and the control group (CG). In the CG, PA was suspended between 30 and 60 days after the preoperative exams. The subjects were evaluated, including optical coherence tomography (OCT) with the Cirrus 4000 macular protocol preoperatively and in the postoperative period on 3 occasions: 1-3 days ("PO1"), 6-9 days ("PO7"), and 27-30 days ("PO30") after surgery. The results were compared between groups. RESULTS: Thirty-five eyes of 35 patients were included (17 in the CG and 18 in the SG). There was no statistically significant difference in age (p = 0.2), the preoperative visual field mean deviation (p = 0.08), or the preoperative intraocular pressure (SG: 24.8 ± 7.8 mm Hg vs. CG: 22.8 ± 6.0 mm Hg, p = 0.4). The preoperative macular OCT parameters were equivalent between the groups (p > 0.05). When comparing the variation of parameters between the groups between preop and PO30 there was equivalence in all of the comparisons evaluated. The presence (or absence) of the lens did not affect the results. CONCLUSION: PA eye drops did not affect macular thickness after TREC with MMC in glaucomatous patients.

Alkylating agents-induced gonadotoxicity in prepubertal males: Insights on the clinical and preclinical front.

Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.

Effect of ripasudil after trabeculectomy with mitomycin C: a multicentre, randomised, prospective clinical study.

BACKGROUND: To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors. METHODS: This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups. RESULTS: A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success. CONCLUSION: Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.

Oncometabolite 2-hydroxyglutarate suppresses basal protein levels of DNA polymerase beta that enhances alkylating agent and PARG inhibition induced cytotoxicity.

Mutations in isocitrate dehydrogenase isoform 1 (IDH1) are primarily found in secondary glioblastoma (GBM) and low-grade glioma but are rare in primary GBM. The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent. Fortunately, IDH1 mutant gliomas are sensitive to this treatment, resulting in a more favorable prognosis. However, it's estimated that up to 75 % of IDH1 mutant gliomas will progress to WHO grade IV over time and develop resistance to alkylating agents. Therefore, understanding the mechanism(s) by which IDH1 mutant gliomas confer sensitivity to alkylating agents is crucial for developing targeted chemotherapeutic approaches. The base excision repair (BER) pathway is responsible for repairing most base damage induced by alkylating agents. Defects in this pathway can lead to hypersensitivity to these agents due to unresolved DNA damage. The coordinated assembly and disassembly of BER protein complexes are essential for cell survival and for maintaining genomic integrity following alkylating agent exposure. These complexes rely on poly-ADP-ribose formation, an NAD+-dependent post-translational modification synthesized by PARP1 and PARP2 during the BER process. At the lesion site, poly-ADP-ribose facilitates the recruitment of XRCC1. This scaffold protein helps assemble BER proteins like DNA polymerase beta (Polß), a bifunctional DNA polymerase containing both DNA synthesis and 5'-deoxyribose-phosphate lyase (5'dRP lyase) activity. Here, we confirm that IDH1 mutant glioma cells have defective NAD+ metabolism, but still produce sufficient nuclear NAD+ for robust PARP1 activation and BER complex formation in response to DNA damage. However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polß protein levels. This defines a novel mechanism by which the IDH1 mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.

Mitomycin C 0.2 mg/ml versus Mitomycin C 0.4 mg/ml during the Implantation of an Ab Externo Polystyrene-isobutylene-styrene Microshunt: A Mega-analysis.

PURPOSE: To compare the effectiveness and adverse event profile of standalone polystyrene-isobutylene-styrene (SIBS) microshunt implantation with adjunct mitomycin C (MMC) 0.2 mg/ml and MMC 0.4 mg/ml. DESIGN: Mega-analysis using individual patient data from international prospective and retrospective clinical studies. PARTICIPANTS: Patients with glaucoma who underwent implantation of a SIBS microshunt with MMC as a standalone procedure. METHODS: A comparison of eyes that received MMC 0.2 mg/ml or 0.4 mg/ml. MAIN OUTCOMES MEASURES: Primary outcome was complete success defined as the proportion of eyes at 1 year with all of the following: (1) no 2 consecutive intraocular pressures (IOPs) > 17 mmHg; (2) no clinical hypotony; (3) ≥ 20% IOP reduction from baseline; and (4) no use of glaucoma medications. Secondary outcomes included IOP thresholds of 12 mmHg, 14 mm Hg, and 21 mmHg, median IOP, number of medications, risk factors for failure, interventions, adverse events, and reoperations. RESULTS: At 1 year, the complete success rate was significantly higher (71.3% vs. 50.46%; P < 0.001) and the median IOP was significantly lower (13.0 vs 14.2 mmHg; P < 0.05) in the MMC 0.4 mg/ml group. Mitomycin C 0.2 mg/ml was found to be a significant risk factor for failure (hazard ratio 1.75; 95% confidence interval 1.14-2.67). Needling and surgical revision occurred at a lower rate in the MMC 0.4 mg/ml group (7% vs 18.8%; P = 0.002 and 4.3% vs 13.7% P = 0.0087, respectively). Adverse events occurred at a similar frequency in both groups (26.6% MMC 0.2 mg/ml vs 29.6% MMC 0.4 mg/ml; P = 0.46), most of which were early and transient. CONCLUSION: Polystyrene-isobutylene-styrene microshunt implantation with MMC 0.4 mg/ml resulted in a higher success rate with greater IOP reduction compared with MMC 0.2 mg/ml. Higher MMC concentration was not associated with increased serious adverse events. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Alkylating agents are possible inducers of glioblastoma and other brain tumors.

Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.

Investigation of Melphalan interaction as an alkylating agent with nucleotides by using surface enhanced Raman spectroscopy (SERS).

SERS (Surface Enhanced Raman Spectroscopy) is a new Raman spectroscopy which relies on Surface Plasmon Resonance (SPR) of metal nanoparticles. We have applied colloidal silver and gold nanoparticles as amplifier agents to enhance nucleotide Raman signals. It is observed that without these enhancing agents, it is impossible to investigate nucleotide spectrum due to weak Raman signals. Interaction mechanism of Melphalan, an anticancer drug with four nucleotides (Adenine, Cytosine, Guanine, Thymine) was investigated using SERS to detect and identify changes due to alkylating process in Raman spectra. After incubating Melphalan drug with nucleotides for 24 h at 37 °C, some changes occurred in SERS spectrum and interpretation of SERS spectra revealed the influence of the alkyl substitution on peaks and Raman shifts. After incubation of Melphalan with each nucleotide, intensity of relevant SERS signals assigned to Amid III group of Cytosine and Amid I of Thymine decreased significantly, confirming alkylating taking place. In this study, we also investigated the effect of nanoparticles type on nucleotide spectrum. We could not obtain useful information in the cases of guanine nucleotide. The SERS spectrum of Cytosine as an example of nucleotides in aqueous solution compared to solid state and results demonstrated that in solid state better signals were obtained than in liquid state.

The effect of adjuvant Mitomycin C during vitrectomy on functional and anatomical outcomes in patients with severe diabetic tractional retinal detachment.

PURPOSE: To evaluate the effect of adjuvant Mitomycin C (MMC) use on the anatomical and functional success of vitreoretinal surgery (VRS) in severe diabetic tractional retinal detachment (dTRD) patients. METHODS: A retrospective analysis of consecutive patients undergoing VRS due to severe dTRD was conducted. Patients were categorized into those who received 20 µg/0.1 mL MMC via MMC sandwich method (Group 1) and those who did not (Group 2). Demographics, surgical characteristics, visual outcomes, and complications that may related to MMC were analyzed. RESULTS: A total of 25 eyes were included, 13 in Group 1 and 12 in Group 2. No statistical difference was observed in baseline characteristics between the groups. The mean best-corrected visual acuity was 1.90 ± 0.43 logMAR and 1.93 ± 0.41 logMAR preoperatively and 1.60 ± 0.78 logMAR and 1.56 ± 0.78 logMAR postoperatively in Groups 1 and 2, respectively (p = 0.154). The postoperative mean intraocular pressure was 16.23 ± 2.55 mmHg and 13.08 ± 4.94 mmHg in Groups 1 and 2, respectively (p = 0.225). The rate of re-surgery was significantly lower in Group 1 (0% vs. 41.7% in Group 2, p = 0.015). Retina was attached in all patients at the last visit. No MMC-related complication was recorded. CONCLUSION: Intraoperative adjuvant MMC application for severe dTRD significantly reduces re-surgery rates with good anatomical and functional outcomes safely.

Pigtail with self-retaining bicanalicular intubation combined with Mitomycin C for the treatment of acquired lower punctal stenosis.

BACKGROUND: The pigtail was used to create an opening at the lower punctal site in grade 0 stenosis with insertion of self-retaining tube and Mitomycin C (MMC). METHODS: The patients with acquired lower punctal stenosis (grade 0) were divided randomly into equal groups, Group A: were treated with pigtail and MMC 0.02% and Group B: were treated with pigtail alone. The pigtail was inserted through the upper punctum until its tip reached the occluded punctum, this site was incised with a scalpel (No. 11). A self-retaining bicanalicular tube was then placed. RESULTS: Results of 36 eyes from 26 patients were included. No differences were observed between both groups regarding epiphora score, FDD test and punctal size preoperatively. The postoperative epiphora score, there were significant differences at 1 month (P = 0.035), 3 months (P = 0.005), and 6 months after removal (P < 0.001). The FDD test, there were significant differences at 6 months (P = 0.045), 1 month (P = 0.021), 3 months (P = 0.012), and 6 months post tube removal (P = 0.005). The punctal size, both groups differed at 1 month (P = 0.045), 3 months (P = 0.03), and 6 months post tube removal (P = 0.005). Only one case (5.5%) at each group showed extrusion of the tube. CONCLUSION: The pigtail probe, bicanalicular stent and MMC can be an effective method in treatment of severe punctal stenosis.

Efficacy of Ab Interno Revision for Trabeculectomy Bleb Failure Using a Minimally Invasive Approach: A Prospective Study.

PRCIS: Ab interno bleb revision using the Grover and Fellman spatula offers potential benefits in improved intraocular pressure control and spares the conjunctiva for enhanced bleb management. PURPOSE: This study aimed to evaluate the safety and effectiveness of Ab-Interno Bleb Revision (AIBR) for treating failed trabeculectomy blebs. METHODS: This noncomparative case series enrolled glaucoma patients with failed trabeculectomy blebs who underwent AIBR and were followed up for 1 year. Eligible patients received subconjunctival Mitomycin C 0.1 mL of 0.2 mg/mL (20 µg) 5 days before the AIBR, performed using the Grover and Fellman spatula. The primary outcome measures were intraocular pressure (IOP) and the usage of IOP-lowering medications 1 year after the procedure. Secondary outcomes included the procedure's failure rate and complications. Complete success was defined as achieving an IOP between 5 and 21 mm Hg without medication, while qualified success required additional medical treatment. RESULTS: The study comprised 23 eyes from 23 patients, having a mean age of 59.66±14.93 years. Preoperatively, the mean IOP was 23.54±10.7 mm Hg, and the mean antiglaucoma medication requirement was 3.99±0.65, both significantly reduced to 15.7±6.9 mm Hg ( P =0.009) and 1.26±1.2 ( P <0.001) at 1 year, respectively. Overall, 19 eyes (82.6%) achieved success (complete success: 39.2%, qualified success: 43.4%), while in 4 (17.4%) patients, the procedure failed (IOP >21 mm Hg). 5 patients had transient hyphema, but there were no sight-threatening complications such as hypotony or choroidal detachment. CONCLUSIONS: Ab-Interno Bleb Revision (AIBR) is a safe, effective, and minimally invasive intervention for managing failed trabeculectomy blebs. By eliminating the need to reopen the conjunctiva, this technique offers a promising alternative for the treatment of this challenging condition.

Outcomes of a Second Ahmed Glaucoma Implant With Mitomycin-C in Pediatric Glaucoma After Initial Valve Failure.

PRCIS: After the failure of a glaucoma drainage device in children, implantation of a second Ahmed glaucoma valve with mitomycin-C allows a significant reduction of intraocular pressure and number of medications with good medium-term and long-term survival. INTRODUCTION: The effectiveness of glaucoma drainage devices (GDD) is limited in time. There is little literature regarding the optimal management strategy after failure of a GDD in pediatric glaucoma. PURPOSE: To report the outcomes of Ahmed glaucoma valve implantation (AGV) with mitomycin-C (MMC) after failure of a GDD in children. METHODS: Retrospective chart review of patients with a history of at least 1 GDD receiving an AGV implantation with MMC between 2000 and 2019. We defined complete success as an IOP of 5-21 mm Hg without glaucoma medication and qualified success as a final IOP of 5-21 mm Hg with one or more glaucoma medication, without loss of vision. RESULTS: Twenty-one patients (22 eyes) met the inclusion criteria. The intraocular pressure and number of medications were significantly reduced. The probability of complete success was 47% [95% CI: 29%-75%] at 2 years and 34% [95% CI: 18%-65%] at 4 years. The probability of qualified success was 74% [95% CI: 56%-97%] at 2 years, and 54% [95% CI: 34%-84%] at 5 years. Failure happened in 10 eyes after a mean time of 4.3 years ±3.6 (6 mo to 15 y), 5 of which (23%) for severe complications or loss of vision. DISCUSSION: This study of implantation of a second valve with MMC reports a significant decrease in IOP and medications with medium-term and long-term success rates close to those reported for first valve implantation, although with a high risk of complications.

Conformational Modulation of Tissue Transglutaminase via Active Site Thiol Alkylating Agents: Size Does Not Matter.

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme's dysregulated activity has been implicated in a variety of pathologies (e.g., celiac disease, fibrosis, cancer), leading to the development of a wide range of inhibitors. Our group has primarily focused on the development of peptidomimetic targeted covalent inhibitors, the nature and size of which were thought to be important features to abolish TG2's conformational dynamism and ultimately inhibit both its activities. However, we recently demonstrated that the enzyme was unable to bind guanosine triphosphate (GTP) when catalytically inactivated by small molecule inhibitors. In this study, we designed a library of models targeting covalent inhibitors of progressively smaller sizes (15 to 4 atoms in length). We evaluated their ability to inactivate TG2 by measuring their respective kinetic parameters kinact and KI. Their impact on the enzyme's ability to bind GTP was then evaluated and subsequently correlated to the conformational state of the enzyme, as determined via native PAGE and capillary electrophoresis. All irreversible inhibitors evaluated herein locked TG2 in its open conformation and precluded GTP binding. Therefore, we conclude that steric bulk and structural complexity are not necessary factors to consider when designing TG2 inhibitors to abolish G-protein activity.

Visual Field Outcomes in the Primary Tube Versus Trabeculectomy Study.

PURPOSE: To describe visual field outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Cohort analysis. PARTICIPANTS: A total of 155 eyes (155 subjects) randomly assigned to treatment with tube shunt surgery (n = 84) or trabeculectomy with mitomycin C (n = 71). METHODS: 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. MAIN OUTCOME MEASURES: Rate of change in SAP MD during follow-up. RESULTS: 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. CONCLUSIONS: 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. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.

Safety and long-term survival results of the addition of inotuzumab ozogamicin to the conditioning regimen of allogeneic stem cell transplantation: A single-center phase 1,2 trial.

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.

Risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation in a letermovir-exposed CMV-free population receiving PTCy.

Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%-37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities-especially due to alkylating agents-and immunological elements.

Effects of different alkylating agents on photoreceptor degeneration and proliferative response of Müller glia.

Animal models for retinal degeneration are essential for elucidating its pathogenesis and developing new therapeutic strategies in humans. N-methyl-N-nitrosourea (MNU) has been extensively used to construct a photoreceptor-specific degeneration model, which has served to unveil the molecular process of photoreceptor degeneration as well as the mechanisms regulating the protective responses of remaining cells. Methyl methanesulphonate (MMS), also known to cause photoreceptor degeneration, is considered a good alternative to MNU due to its higher usability; however, detailed pathophysiological processes after MMS treatment remain uncharacterized. Here, we analyzed the time course of photoreceptor degeneration, Müller glial proliferation, and expression of secretory factors after MNU and MMS treatments in rats. While the timing of rod degeneration was similar between the treatments, we unexpectedly found that cones survived slightly longer after MMS treatment. Müller glia reentered the cell cycle at a similar timing after the two treatments; however, the G1/S transition occurred earlier after MMS treatment. Moreover, growth factors such as FGF2 and LIF were more highly upregulated in the MMS model. These data suggest that comparative analyses of the two injury models may be beneficial for understanding the complex regulatory mechanisms underlying the proliferative response of Müller glia.

Evaluating Primary Treatment for People with Advanced Glaucoma: Five-Year Results of the Treatment of Advanced Glaucoma Study.

PURPOSE: To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in patients with advanced glaucoma. DESIGN: Multicenter randomized controlled trial. PARTICIPANTS: Between June 3, 2014, and May 31, 2017, 453 adults with newly diagnosed advanced open-angle glaucoma in at least 1 eye (Hodapp classification) were recruited from 27 secondary care glaucoma departments in the United Kingdom. Two hundred twenty-seven were allocated to trabeculectomy, and 226 were allocated medical management. METHODS: Participants were randomized on a 1:1 basis to have either mitomycin C-augmented trabeculectomy or escalating medical management with intraocular pressure (IOP)-reducing drops as the primary intervention and were followed up for 5 years. MAIN OUTCOME MEASURES: The primary outcome was vision-specific QoL measured with the 25-item Visual Function Questionnaire (VFQ-25) at 5 years. Secondary outcomes were general health status, glaucoma-related QoL, clinical effectiveness (IOP, visual field, and visual acuity), and safety. RESULTS: At 5 years, the mean ± standard deviation VFQ-25 scores in the trabeculectomy and medication arms were 83.3 ± 15.5 and 81.3 ± 17.5, respectively, and the mean difference was 1.01 (95% confidence interval [CI], -1.99 to 4.00; P = 0.51). The mean IOPs were 12.07 ± 5.18 mmHg and 14.76 ± 4.14 mmHg, respectively, and the mean difference was -2.56 (95% CI, -3.80 to -1.32; P < 0.001). Glaucoma severity measured with visual field mean deviation were -14.30 ± 7.14 dB and -16.74 ± 6.78 dB, respectively, with a mean difference of 1.87 (95% CI, 0.87-2.87 dB; P < 0.001). Safety events occurred in 115 (52.2%) of patients in the trabeculectomy arm and 124 (57.9%) of patients in the medication arm (relative risk, 0.92; 95% CI, 0.72-1.19; P = 0.54). Serious adverse events were rare. CONCLUSIONS: At 5 years, the Treatment of Advanced Glaucoma Study demonstrated that primary trabeculectomy surgery is more effective in lowering IOP and preventing disease progression than primary medical treatment in patients with advanced disease and has a similar safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.