Targeting myeloid-derived suppressor cells for cancer immunotherapy.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with an immune suppressive phenotype. They represent a critical component of the immune suppressive niche described in cancer, where they support immune escape and tumor progression through direct effects on both the innate and adaptive immune responses, largely by contributing to maintenance of a high oxidative stress environment. The number of MDSCs positively correlates with protumoral activity, and often diminishes the effectiveness of immunotherapies, which is particularly problematic with the emergence of personalized medicine. Approaches targeting MDSCs showed promising results in preclinical studies and are under active investigation in clinical trials in combination with various immune checkpoint inhibitors. In this review, we discuss MDSC targets and therapeutic approaches targeting MDSC that have the aim of enhancing the existing tumor therapies.

Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol.

BACKGROUND: There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial. METHODS: These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow. DISCUSSION: This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010.

Two-Port Pars Plana Anterior and Central Core Vitrectomy (Lam Floaterectomy) in Combination With Phacoemulsification and Intraocular Lens Implantation Under Topical Anesthesia for Patients with Cataract and Significant Floaters: Results of the First 50 Consecutive Cases.

PURPOSE: To study the safety and efficacy of 2-port pars plana anterior and central core vitrectomy (Lam floaterectomy) in combination with phacoemulsification (phaco) and intraocular lens implantation (IOL) for patients with cataract and significant floaters under topical anesthesia. DESIGN: Retrospective review of the first 50 consecutive cases. METHODS: A standardized treatment protocol was used for patients with cataract and significant (moderate to severe) floaters (duration > 3 months). Data analysis included intraoperative and postoperative complications, floater status, and patient satisfaction. RESULTS: There were 50 eyes (38 patients) with a male-to-female ratio of 1 to 2.3. Twelve patients had bilateral eye surgeries. Mean age was 58.10 ± 9.85 years (range, 39-83). All patients completed the 3-month follow-up. One eye had mild vitreous hemorrhage at the end of surgery arising from sclerotomy wound oozing. No other intraoperative compli-cations were encountered. Postoperatively, there was 1 case of transient hypotony and 1 case of congestion at sclerotomy wound. No cases of retinal break or detachment, or clinically significant macular edema, were reported. There were 5 cases (10%) of mild residual floaters and 1 case (2%) of floater recurrence. Total floater clearance rate was 88%. Patient satisfaction rates were 80%, 14%, 6%, and 0% for very satisfied, satis-fied, acceptable, and unsatisfied, respectively. CONCLUSIONS: The 3-month results in terms of safety and efficacy of the Lam floaterectomy in combination with phaco and IOLfor patients with cataract and significant floaters under topical anesthesia are encouraging. Further larger-scale, prospective, multicenter studies seem warranted.

Clinical characteristics of intermediate uveitis in Chinese patients.

PURPOSE: To describe the clinical characteristics of Chinese patients with intermediate uveitis (IU). METHODS: Retrospective review of patients with IU with at least 6 months follow-up. RESULTS: Seventy patients were identified and the mean follow-up was 59.7 months. The mean age at presentation was 33.1 years. Fifteen (21.4%) patients had disease onset before the age of 18 years; 91.4% of IU cases were considered idiopathic after investigations. At the last follow-up, 85 (74.6%) eyes retained vision of at least 20/40. Poor visual outcome was significantly associated with poor presenting visual acuity (p = .002), presence of epiretinal membrane or atrophic macular changes (p = .003), persistent cystoid macular edema (p = .015), and increased disease duration (odds ratio = 1.015 per month, p = .002). Pediatric patients were more likely to have bilateral (p = .003) and chronic disease (p < .001). CONCLUSIONS: IU in Chinese patients was mainly idiopathic, with good visual outcomes in most patients after appropriate treatment.

Combined high-dose sub-tenon triamcinolone, intravitreal bevacizumab, and laser photocoagulation for refractory diabetic macular edema: a pilot study.

PURPOSE: To study the efficacy and safety of triple therapy (sub-Tenon triamcinolone [∼70 mg], intravitreal bevacizumab [1.25 mg], and focal/grid laser) for refractory diabetic macular edema. METHOD: Twenty-nine eyes of 29 patients who received triple therapy were monitored for central foveal thickness, best-corrected visual acuity (BCVA), and side effects over a 1-year period. Their results were compared with a focal/grid laser historical control group of 18 eyes (18 patients). RESULTS: In the triple therapy group, mean central foveal thickness significantly reduced from baseline value of 441 µm to 298 µm at Month 12 (P < 0.001), but there was no significant change of BCVA. In the control group, there were no sustained significant changes of central foveal thickness or BCVA. A subgroup analysis of 7 eyes in the triple therapy group with baseline BCVA of ≤20/100 showed significant BCVA improvements from 4 weeks to 9 months. The maximum improvement was achieved at 6 months, when the mean BCVA improved by 9.5 Early Treatment Diabetic Retinopathy Study letters from baseline. Intraocular pressure rise (31.0%), partial ptosis (17.2%), and significant cataractogenesis (8.7%) were encountered in the triple therapy group but not in the control group. CONCLUSION: Sustained reduction of central foveal thickness was achieved with triple therapy over the 1-year study period. Significant visual improvement was seen only in patients with worse baseline BCVA, but not in the triple therapy group as a whole. Significant side effects of intraocular pressure rise, ptosis, and cataractogenesis were encountered in the triple therapy group.

Randomized double-masked controlled trial comparing pain scores with and without the use of supplementary 2% lidocaine gel in LASIK.

PURPOSE: To compare pain scores with and without supplementary topical 2% lidocaine gel in patients undergoing simultaneous bilateral laser-assisted in situ keratomileusis (LASIK) under topical anesthesia using 0.5% proparacaine eye drops. DESIGN: Randomized double-masked placebo-controlled trial. METHODS: Fifty-one Chinese subjects (102 eyes, with 51 eyes in each arm) were included. One eye was randomly allocated to have supplementary 2% lidocaine gel while the other eye received carbomer gel as control, in addition to topical 0.5% proparacaine. The pain scores for each eye during microkeratome flap creation, during laser ablation, and at 15, 30, and 45 minutes after LASIK were assessed. An overall pain score of the LASIK procedure was also obtained. Primary outcome measures were pain scores during and after LASIK. Secondary outcomes included need for additional topical anesthesia, patient cooperation score, and duration and complications of surgery. RESULTS: In the 2% lidocaine gel-treated group, the pain scores were significantly lower during microkeratome flap creation and laser ablation, and postoperatively at 30 and 45 minutes (P<.05 for all). Patients in the lidocaine gel group required less additional topical anesthesia (P=.0004) and were more cooperative (P=.019) as compared to the carbomer gel group. No surgical or postoperative complications were observed. CONCLUSIONS: The use of supplementary 2% lidocaine gel in LASIK is effective in lowering the pain experienced during and up to 45 minutes after LASIK.

Prospective Randomized Comparative Study of the Effect of Pupil Dilation or Miosis in Intraocular Lens Pupillary Capture After Combined Phacoemulsification and Vitrectomy With Intraocular Tamponade.

PURPOSE: The objective of the study was to compare the safety and efficacy of postoperative pharmacological pupil dilation, miosis, and alternate-day pupil dilation and miosis after combined phacoemulsification (phaco), intraocular lens (IOL) implantation, and pars plana vitrectomy (PPV) with intraocular tamponade. DESIGN: This was a prospective, randomized controlled clinical trial. METHODS: Patients who were indicated for phaco with IOL implantation, PPV, and intraocular tamponade were randomly assigned into 3 different groups: (1) pupil dilation using 4% homatropine (dilation group), (2) pupil miosis using 1% pilocarpine (miosis group), and (3) alternate-day pupil miosis and dilation starting with 1% pilocarpine on the first day postoperatively and switched to 4% homatropine thereafter on alternate days (alternate-day group). The main outcome measured was the rate of IOL capture postoperatively. The secondary measurable outcomes were the complication rates, visual acuity, and ease of fundal examination with binocular indirect ophthalmoscopy. RESULTS: Twenty-two, 21, and 20 eyes were allocated to the dilation, miosis, and alternate-day groups, respectively. Intraocular lens capture was found in 7 (11.1%) of 63 eyes. Intraocular lens was captured in 6 (27.3%) of 22 eyes in the dilation, 1 (4.5%) of 21 eyes in the miosis, and none in the alternate-day groups (P = 0.0133). The difference of the visual acuity among the 3 groups was not statistically significant (P = 0.650). Anterior chamber reaction of more than +1 cell in the first week was found in 6 (27.3%) of 22, 13 (61.9%) of 21, and 10 (50%) of 20 eyes in the dilation, miosis, and alternate-day groups, respectively (P = 0.074). Although more eyes were found with posterior synechia in the miosis group, the difference was not statistically significant (P = 0.478). The number of eyes that had suboptimal binocular indirect ophthalmoscopy view was 3 (13.6%) of 22, 12 (57.1%) of 21, and 6 (30%) of 20 in the dilation, miosis, and alternate-day groups, respectively (P = 0.01). CONCLUSIONS: Pupil dilation after combined phaco with IOL implantation, PPV, and intraocular tamponade could lead to a higher chance of IOL capture. Pupil miosis may lead to more anterior chamber inflammation. The regimen of alternate pupil dilation and miosis may cause less chance of IOL capture.

Interactive expressions of HtrA1 and VEGF in human vitreous humors and fetal RPE cells.

PURPOSE: High-temperature requirement factor A1 (HtrA1) is associated with exudative age-related macular degeneration, an angiogenic retinal disease related to vascular endothelial growth factor (VEGF). This study investigates the interactive relationship between the expressions of HtrA1 and VEGF. METHODS; The vitreous humor levels of HtrA1, VEGF, and pigment epithelium-derived factor were determined in 55 unrelated Han Chinese patients who underwent ocular surgeries. Expressions of HTRA1 and VEGFA were studied interactively and under stress conditions in primary human fetal retinal pigment epithelial (RPE) cells to evaluate their regulations. RESULTS: Vitreous levels of HtrA1 were significantly associated with that of VEGF in vitreous samples from all patients (Pearson's correlation coefficient test, r = 0.650, P = 7.91 × 10(-8)) and from patients with retinal detachment (r = 0.835, P = 2.14 × 10(-7)). On stress induction, HTRA1 and VEGFA were upregulated in human fetal RPE cells treated by tunicamycin and dithiothreitol, but reduced after treatment by MG132. However, HtrA1 and VEGF did not regulate each other in their expressions. CONCLUSIONS: This study revealed an association between HtrA1 and VEGF in human vitreous humors and RPE cells. They are both related to stress and inflammatory conditions.

Effectiveness of diode laser trans-scleral cyclophotocoagulation in patients following silicone oil-induced ocular hypertension in Chinese eyes.

We evaluated the effectiveness of diode laser trans-scleral cyclophotocoagulation (TSCPC) on intraocular pressure (IOP) in nine patients having raised IOP following use of silicone oil (SO) for retinal detachment (RD) surgery in a retrospective observational case series. Diode laser TSCPC was applied at a power setting of 1.75 to 2.5 watts, for two sec with a maximum of 30 applications. The patients were followed up for 40 to 312 weeks. The mean pre-laser IOP was 32.06 mm Hg (SD 7.32). The mean post-laser IOP at one month, three months and six months was 17.89 mm Hg (SD 8.23), 21.89 mm Hg (SD 8.16) and 21.67 mm Hg (SD 7.55) respectively. The final IOP (at the last follow-up) was 19.56 mm Hg (SD 7.85) (P=0.021). Seven of them had undergone SO removal. In our observation, effectiveness of TSCPC in long-term control of SO-induced ocular hypertension was limited as compared to short-term control of IOP.

Randomized controlled trial on the safety of intracameral cephalosporins in cataract surgery.

OBJECTIVE: To compare the safety profiles of intracameral cephalosporins in cataract surgery. PATIENTS AND METHODS: In this controlled trial, 129 patients were randomized to one of four groups to receive 1 mg of one of three cephalosporins - cefazolin, cefuroxime, or ceftazidime, or normal saline - given intracamerally during cataract surgery. Central endothelial cell density (ECD) and retinal center point thickness (CPT) were determined by specular microscopy and ocular coherence tomography, respectively, before and at 3 months after surgery. RESULTS: There were no statistical significant differences in the changes of ECD and CPT between eyes receiving intracameral cephalosporin and control. CONCLUSION: The use of intracameral cefazolin, cefuroxime, or ceftazidime (1 mg in 0.1-mL solution) at the time of cataract surgery had no significant effect on ECD and CPT postoperatively.

Intravitreal dexamethasone for diabetic macular edema: a pilot study.

BACKGROUND AND OBJECTIVE: To determine the response and safety profile of intravitreal dexamethasone in treating diabetic macular edema. PATIENTS AND METHODS: In this prospective pilot study, 12 eyes of 12 patients with diabetic macular edema were randomized to receive a single injection of 0.4 mg (n = 6) or 0.8 mg (n = 6) of intravitreal dexamethasone. The outcome measures were changes in best-corrected visual acuity and central foveal thickness on optical coherence tomography. Side effects were monitored. RESULTS: The 3-month results were reported. In both dosage groups, there were transient improvements in best-corrected visual acuity and central foveal thickness, but the changes were not significant at any time point (best-corrected visual acuity: P > or = 0.14; central foveal thickness: P > or = .08). No significant side effects were observed, except one eye developed a peak intraocular pressure of greater than 21 mm Hg. CONCLUSION: A single injection of intravitreal dexamethasone (0.4 or 0.8 mg) did not have significant beneficial effects on diabetic macular edema within 3 months from injection in this small pilot study.

Factors associated with variability in response of diabetic macular oedema after intravitreal triamcinolone.

PURPOSE: To identify factors associated with variability in anatomical and functional response of diabetic macular oedema (DMO) after 4 mg of intravitreal triamcinolone acetonide (ivTA), and for recurrence of macular oedema. DESIGN: Pooled analysis of individual data from two randomized controlled trials. METHODS: This was a multicentre study involving 107 eyes with DMO administered 4 mg ivTA. Predictive factors for response to treatment were evaluated with linear regression analysis. Factors associated with time to recurrence of oedema were studied with Cox proportional hazards modelling. Main outcome measures were maximum improvement in optical coherence tomography (OCT)-measured central foveal thickness (CFT) and best-corrected visual acuity (BCVA), final CFT and BCVA at 12 months and time to oedema recurrence. RESULTS: Greater reduction of retinal thickening occurred in eyes with worse baseline thickening (P < 0.001). There was also greater improvement of visual acuity in eyes with poorer preoperative BCVA levels (P < 0.001). Age, duration of oedema and previous macular laser treatment had no significant effect on maximal BCVA or CFT improvement. Eyes given 4 mg triamcinolone alone were more likely to develop recurrence of oedema at 12 months than those given a combination of 4 mg triamcinolone plus sequential laser (hazard ratio 2.60 [95% confidence interval: 1.45-4.67]). CONCLUSION: Baseline OCT-measured retinal thickening and BCVA are important predictors of maximal anatomical and functional response of DMO to ivTA, respectively. Combination treatment strategy using sequential laser therapy may have a role in delaying recurrence of oedema after triamcinolone.

Efficacy of 1.25 MG versus 2.5 MG intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial.

PURPOSE: To evaluate the efficacy of intravitreal injections of two different dosages of bevacizumab (Avastin) for treating diffuse diabetic macular edema. METHODS: Fifty-two eyes of 52 patients with diabetic macular edema were randomized to receive three monthly intravitreal injections of 1.25 mg or 2.5 mg bevacizumab. Patients were observed for 6 months and optical coherence tomography central foveal thickness, logMAR best-corrected visual acuity (BCVA), and adverse events were assessed. RESULTS: Forty-eight eyes of 48 patients completed the 6-month follow-up and were analyzed. Significant mean central foveal thickness reductions were observed in both groups at all follow-up visits (P < 0.013). Significant improvements between baseline and 6-month mean logMAR BCVAs were seen, with the mean logMAR BCVA improved from 0.63 to 0.52 in the 1.25 mg group and 0.60 to 0.47 in the 2.5 mg group. No significant difference in BCVA was observed between the two groups at any time point (P > 0.56). Subgroup analysis showed that intravitreal bevacizumab seemed to be more effective in eyes without any previous diabetic macular edema treatment. CONCLUSIONS: Three monthly intravitreal bevacizumab injections resulted in significant reduction in central foveal thickness and improvements in BCVA in diabetic macular edema patients. Both 1.25 mg and 2.5 mg seemed to have similar treatment efficacy.

Central serous chorioretinopathy after sequential argon-neodymium: YAG laser iridotomies.

Laser peripheral iridotomy is the standard treatment for acute angle-closure glaucoma. A patient with acute angle-closure glaucoma who developed central serous chorioretinopathy after uneventful laser iridotomies is described. Central serous chorioretinopathy occurring after sequential argon-neodymium:YAG laser peripheral iridotomy is a novel complication in the English literature and is related to the stress induced by both the initial disease and the subsequent procedure, particularly in psychologically susceptible individuals.

Central retinal vein occlusion associated with clomiphene-induced ovulation.

OBJECTIVE: To report a case of central retinal vein occlusion associated with clomiphene citrate (CC). DESIGN: Case study. SETTING: Ophthalmology clinic of an academic hospital. PATIENT(S): A 36-year-old woman referred from the infertility clinic for blurred vision. INTERVENTION(S): Ophthalmic examination after CC therapy. MAIN OUTCOME MEASURE(S): Central retinal vein occlusion after ovulation induction with CC. RESULT(S): A 36-year-old Chinese woman developed central retinal vein occlusion after eight courses of CC. A search of the literature on the thromboembolic complications of CC does not include this severe ophthalmic complication, although mild visual disturbance after CC intake is not uncommon. CONCLUSION(S): This is the first reported case of central retinal vein occlusion after treatment with CC. Extra caution is warranted in treating infertility patients with CC, and patients should be well informed of this side effect before commencement of therapy.

Retrocapsular lens matter in uneventful phacoemulsification: does it really exist?

PURPOSE: To have the first cytopathological evaluation of any lens matter fragments within retrocapsular anterior vitreous in those patients undergone uneventful phacoemulsification in Prince of Wales Hospital, Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong. METHODS: Thirty patients with cataracts and various vitreoretinal conditions that required combined surgery were recruited. After the uneventful clear corneal phacoemulsification, three sclerotomies including infusion port were created with cautions against any inadvertent leakage of vitreal content. The anterior vitreous at retrocapsular space was harvested by a special 'round-the-clock' dry vitrectomy into a special specimen reservoir hub and syringe. The aspirate was immediately fixed in 50% ethanol and together with a masked positive control sent for cytocentrifugation processing. The microscope slides of the anterior vitreal content and control were stained with haematoxylin and eosin and papanicolaou. Positive controls were collected from the effluent fluid of the phaco cassettes right after the phacoemulsification. The samples were masked and examined by an experienced pathologist for any cytopathological evidence of lens matter. RESULTS: Out of 30 patients, three suspicious cases of retrocapsular lens fragment were noted by retroillumination on the operating table. However, all the anterior vitreous specimens were negative for lens matter whereas all the controls were positive after cytopathological verification. CONCLUSIONS: This is the first cytopathological study objectively indicating low likelihood of the postulation that retrocapsular lens matter occurred after uneventful phacoemulsification.

Combined photodynamic therapy and intravitreal triamcinolone for choroidal neovascularization secondary to punctate inner choroidopathy or of idiopathic origin: one-year results of a prospective series.

PURPOSE: To evaluate the efficacy and safety of combined intravitreal triamcinolone (IVTA) and photodynamic therapy (PDT) with verteporfin in the treatment of subfoveal choroidal neovascularization (CNV) due to punctate inner choroidopathy (PIC) or of idiopathic cause. METHODS: Consecutive patients with subfoveal idiopathic and PIC CNV were prospectively recruited and received combined PDT and 4 mg IVTA injection. Patients were observed every 3 months for 1 year and retreatment was performed in the presence of angiographic leakage. Outcome measures included changes in the mean best-corrected visual acuity (BCVA), the proportion of patients who had stable or improved vision, and the mean number of treatments required during the 1-year period. RESULTS: Fourteen patients (14 eyes) were recruited and all completed the 1-year follow-up. The mean age of the patients was 34.7 years. The mean logMAR BCVA improved significantly from 0.52 at baseline to 0.20 at 1 year (Wilcoxon signed-ranks test, P = 0.003). For the entire group, 13 (92.9%) eyes had stable or improved vision with a mean improvement of 3.2 lines (range, -3-7 lines). The mean number of treatments during the 1-year study period was 1.1 sessions. No serious ocular or systemic complications were encountered. CONCLUSIONS: Combined PDT with IVTA seems to be a promising treatment strategy in the treatment of idiopathic CNV and CNV secondary to PIC as it resulted in fewer treatment sessions and superior visual improvement. Further study to assess its long-term safety and efficacy as the first line treatment is warranted.