Purpose: To assess quality of life over long-term follow-up in patients who received sutureless pars plana vitrectomy for symptomatic vitreous floaters, with short-term safety reexamined. Methods: A single-center, consecutive case series with retrospective analysis of clinical and surgical records preceding and following sutureless pars plana vitrectomy was conducted from May 2022 to December 2022. Descriptive statistics compared data preceding surgery to last clinic visit. A 10-item quality-of-life questionnaire was then distributed to patients 4 to 7 years following surgery, after institutional review board–approved consent was obtained via telephone. Results: A total of 142 eyes (117 patients) underwent sutureless 25- or 27-gauge pars plana vitrectomy for symptomatic vitreous floaters. Overall mean (± SD) best-available Snellen visual acuity was 20/30 (0.2 ± 0.2 logMAR) preoperatively, which improved to 20/25 (0.1 ± 0.2 logMAR) postoperatively ( P < .01). Early postoperative complications occurred in 7 (4.9%) of 142 eyes, of which 4 had transient cystoid macular edema, and 3 had a vitreous hemorrhage (1 of which had an additional surgery). Survey responses were collected on 71.1% of eyes, with 91.1% of patients rating the procedure a “complete or significant success,” and the same percentage recommending family members undergo the procedure. Floaters impacted quality of life moderately or severely before vitrectomy in 94.1% of patients. Recurrence of any floaters occurred in 31.7% of eyes, with 26.7% experiencing only mild symptoms, 3% having no symptoms at the time of survey, and 2% having significant floaters. No specific preoperative characteristics were found to be predictive of a dissatisfied patient or a significant recurrence of vitreous floaters. Conclusions: Long-term patient-reported outcomes of sutureless pars plana vitrectomy for symptomatic floaters demonstrated improvements in patient quality of life and visual outcomes, with a low rate of complications. Sutureless vitrectomy should be considered for symptomatic patients who report their subjective severity of daily symptoms as “moderate” or “severe” floaters.

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier stages of genetic evolution than larger tumors. Further, the 15-GEP support vector machine discriminant score predicts small tumors undergoing transformation from low-risk Class 1 to high-risk Class 2 profile. These results shed light on the early genetic evolution of UM and move us closer to a molecular definition of malignant transformation in this cancer type.

Purpose:This study aimed to assess long-term visual acuity outcomes and multiple secondary factors in fellow eyes of uveal melanoma patients treated with either iodine-125 (125I) plaque radiotherapy (PRT), transpupillary thermotherapy (TTT), or proton beam therapy (PBT). Material and methods:A retrospective chart review of 213 patients treated from 2000 to 2022 was performed, with baseline and post-treatment visual acuity data collected at follow-up time points up to 10 years, when available. Paired t-tests compared changes in visual acuity (VA) and intraocular pressure (IOP) over time for affected and fellow eyes. Spearman's rho test assessed correlations between melanoma thickness and VA over time, and repeated measures ANOVA determined interactions between time and comorbidities in VA. Results:Fellow eyes VA showed no significant change up to a decade post-treatment regardless of treatment modality, except for a likely false positive improvement at 2 years post-PRT. In contrast, affected eyes had significant VA decline post-PRT and PBT, while TTT used in affected eyes demonstrated no significant change. IOP did not show any significant changes in fellow eyes. Tumor thickness and the presence of diabetes, hypertension, or coronary artery disease, did not correlate with fellow eye VA outcomes. Conclusions:This study suggests that following uveal melanoma treatment with either 125I PRT, TTT, or PBT, fellow eyes remain stable regarding VA and other outcomes up to 10 years. This provides important information for treatment choice in patients with ocular melanoma, especially as VA can decline in affected eye post-treatment, leading to reliance on contralateral eye.

AIMS/HYPOTHESIS:Within the small intestine, neutrophils play an integral role in preventing bacterial infection. Upon interaction with bacteria or bacteria-derived antigens, neutrophils initiate a multi-staged response of which the terminal stage is NETosis, formation of protease-decorated nuclear DNA into extracellular traps. NETosis has a great propensity to elicit ocular damage and has been associated with diabetic retinopathy and diabetic macular oedema (DME) progression. Here, we interrogate the relationship between gut barrier dysfunction, endotoxaemia and systemic and intestinal neutrophilia in diabetic retinopathy. METHODS:In a cohort of individuals with type 2 diabetes (n=58) with varying severity of diabetic retinopathy and DME, we characterised the abundance of circulating neutrophils by flow cytometry and markers of gut permeability and endotoxaemia by plasma ELISA. In a mouse model of type 2 diabetes, we examined the effects of diabetes on abundance and function of intestinal, blood and bone marrow neutrophils, gut barrier integrity, endotoxaemia and diabetic retinopathy severity. Pharmacological inhibition of NETosis was achieved by i.p. injection of the peptidyl arginine deiminase 4 inhibitor (PAD4i) GSK484 daily for 4 weeks between 6 and 7 months of type 2 diabetes. RESULTS:In human participants, neutrophilia was unique to individuals with type 2 diabetes with diabetic retinopathy and DME and was accompanied by heightened circulating markers of gut permeability. At late-stage diabetes, neutrophilia and gut barrier dysfunction were seen in db/db mice. The db/db mice exhibited an increase in stem-like pre-neutrophils in the intestine and bone marrow and a decrease in haematopoietic vascular reparative cells. In the db/db mouse intestine, enhanced loss of gut barrier integrity was associated with elevated intestinal NETosis. Inhibition of NETosis by the PAD4i GSK484 resulted in decreased abundance of premature neutrophils in the intestine and blood and resulted in neutrophil retention in the bone marrow compared with vehicle-treated db/db mice. Additionally, the PAD4i decreased senescence within the gut epithelium and yielded a slowing of diabetic retinopathy progression. CONCLUSIONS/INTERPRETATION:Severity of diabetic retinopathy and DME were associated with peripheral neutrophilia, gut barrier dysfunction and endotoxaemia in the human participants. db/db mice exhibited intestinal neutrophilia, specifically stem-like pre-neutrophils, which was associated with elevated NETosis and decreased levels of vascular reparative cells. Chronic inhibition of NETosis in db/db mice reduced intestinal senescence and NETs in the retina. These changes were associated with reduced endotoxaemia and an anti-inflammatory bone marrow milieu with retention of pre-neutrophils in the bone marrow and increased gut infiltration of myeloid angiogenic cells. Collectively, PAD-4i treatment decreased gut barrier dysfunction, restoring physiological haematopoiesis and levels of haematopoietic vascular reparative cells.

PURPOSE Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P = .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P < .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P = .0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P = .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.

Purpose: To report a case of painless posterior scleritis presenting as a choroidal nodule in a patient with history of a tumor being treated with pembrolizumab. Methods: A case and its findings were analyzed, and a relevant literature review was performed. Results: A 20-year-old woman with a history of ependymoma presented with painless blurred vision in the right eye after being started on pembrolizumab for a tumor recurrence. Fundoscopy showed a solitary amelanotic choroidal lesion with surrounding subretinal fluid in the affected eye. Ultrasonography showed moderate internal reflectivity and fluid in Tenon capsule consistent with nodular posterior scleritis. After a course of systemic steroids and discontinuation of the pembrolizumab, the choroidal lesion completely resolved. Conclusions: Clinicians should be aware of posterior scleritis as an ocular complication of this class of medications.

Introduction Online teaching has rapidly emerged as a viable alternative to traditional face-to-face education. How to teach surgical skills in the online environment, however, has not yet been fully established nor evaluated. Methods An international 1-day online surgical skills course consisting of lectures, pre-recorded virtual workshops, live demonstrations and along with surgical skills teaching in breakout rooms was organised. Based on existing learning theories, new methods were developed to deliver skills teaching online. Simultaneously, traditional in-person surgical skills teaching was also conducted and used as a benchmark. Skills development was assessed by trained demonstrators and self-reported competency scores were compared between the online and face-to-face event. Results 553 delegates from 20 different countries attended the online course. Of these, 64 were trained in breakout rooms with a 1:5 demonstrator-to-delegate ratio whilst the remaining 489 delegates participated in didactic skills development sessions. In a separate face-to-face course, 20 delegates were trained with traditional methods. Demonstrators rated the competency of delegates for suturing, tendon repair and vascular anastomosis. There was no significant difference in the competency ratings of delegates receiving online teaching or face-to-face teaching ( p = 0.253, p = 0.084, p = 1.00, respectively). The development of the same skills to “articulation” were not different between formats ( p = 0.841, p = 0.792, p = 1.00, respectively). Post course self-rated competency scores improved for all technical skills ( p < 0.001). Small group sessions, both online and face-to-face, received higher satisfaction ratings compared to large group sessions in terms of clarity of instructions, answers to questions and demonstrator feedback. Overall feedback on teaching quality, however, was equivalent across both groups. Discussion Online teaching of surgical skills for early training years is an appropriate alternative to face-to-face teaching.

Background The prognosis for patients with macula-off rhegmatogenous retinal detachment (RRD) and concomitant age-related macular degeneration (AMD) is not well known. The purpose of this study is to compare visual outcomes in macula-off RRD in eyes with AMD versus a group of comparison eyes without AMD. Methods This was a retrospective chart review of 1149 patients. A total of 191 eyes met study criteria, 162 non-AMD eyes (controls), and 29 AMD eyes. The main outcome measure was postoperative visual acuity following pars plana vitrectomy (PPV), scleral buckle (SB), or combined PPV/SB in control eyes versus AMD eyes. This was compared using Fisher’s exact test. Results There was a statistically significant difference in postoperative visual acuity by AMD status, with those without AMD having a worse visual outcome overall ( p = 0.0048). A similar percentage of AMD versus non-AMD eyes achieved vision better than 20/40. More patients in the non-AMD group achieved a final visual acuity between 20/40 and 20/200. Of patients with AMD, more had vision worse than 20/200 though 58% maintained functional vision (better than 20/200). Those without AMD had a higher frequency of Count Fingers (CF), Hand Motion (HM), Light Perception (LP), or No Light Perception (NLP) vision ( p = 0.023). Conclusions Though postoperative visual acuity was worse overall in the non-AMD group with a higher frequency of patients having final vision of CF, HM, LP, or NLP, this is likely a function of the difference in sample size and composition between the two groups. Importantly, this study suggests AMD patients can expect similar outcomes to non-AMD patients after RRD repair. We conclude that AMD patients can achieve functional vision after RRD surgery, similar to those without AMD.

Abstract Introduction Post-transplant lymphoproliferative disease (PTLD) is a rare and life-threatening complication of solid organ transplantation (SOT). Most are of B-cell origin and treated with rituximab with or without chemotherapy. Patients achieving a complete response (CR) to rituximab have good outcomes and can avoid the excess toxicity of chemotherapy. The prospective PTLD-1 trial reported a CR rate of 25% with rituximab. We postulated adding ibrutinib to rituximab may increase CR rates, avoid chemotherapy for more patients and improve outcomes overall. Methods TIDaL is a prospective, single-arm, phase II trial evaluating the activity of ibrutinib in combination with rituximab (IR), with chemotherapy added using a risk-stratified sequential treatment strategy. Eligible patients had treatment naïve, CD20-positive PTLD of any histologic subtype arising after SOT. Patients required measurable disease and adequate organ function. All patients received ibrutinib 560 mg daily with 4 doses of rituximab 375 mg/m 2 on days 1, 8, 15 and 22. Interim response to IR was assessed by CT scan between days 42-49. Risk stratification for subsequent therapy was based on baseline and interim CT response. Patients were assigned to the low risk arm if they achieved a CR on interim CT (irrespective of IPI) or a partial response (PR) with an IPI of 0-1. They continued with IR receiving 4 further 3-weekly doses of rituximab, ibrutinib continued until 3 weeks after the last dose of rituximab. All other patients were assigned to the high risk arm and received 4 cycles of R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone in 21-day cycles). Ibrutinib continued until 3 weeks after the last cycle of R-CHOP for all , . Prophylaxis against Pneumocystis pneumonia was mandated, as was granulocyte colony stimulating factor for all high risk patients. The primary outcome was CR assessed by interim CT. A CR rate of ≥40% was considered to be of interest, with an unacceptable CR rate set at ≤25%. Following a Simon's 2 stage design, 38 evaluable patients would need to be recruited, with at least 12 achieving CR to indicate further investigation is warranted. Secondary outcomes included allocation to the low risk arm, progression free survival (PFS), post-IR PFS (excluding disease progression events during initial IR treatment), overall survival (OS), and treatment tolerability. Results Between January 2017 and March 2020, 39 patients were recruited from 17 sites; 22 male, median age 59 years (range 23 to 76), 28% with IPI 3-5. Transplanted organs were kidney (n=20), liver (n=13), heart (n=4) and lung (n=2). Primary outcome analysis was based on the first 38 patients recruited. After initial IR treatment, 11 patients (29%, 95% confidence interval 15% to 46%) achieved a CR, not reaching the pre-specified threshold. All other analyses were based on the full set of 39 evaluable patients. An overall response (OR) by 7 weeks was seen in 25 patients , comprising 12 CR and 13 PR. Sixteen patients (41%) were subsequently allocated to the low risk arm, 23 (59%) to high risk. , 26 patients (67%, 50% to 81%) achieved an OR (22 CR, 4 PR). After a median follow up of 24 months, 1 year and 2 year outcomes are: PFS 63% (50% to 81%) and 56% (42% to 75%); post-IR PFS 72% (59% to 89%) and 65% (51% to 84%); OS 83% (72% to 96%) and 75% (62% to 92%). Serious adverse events were most commonly infective (38%), and during IR-CHOP therapy (56%). Other common SAEs were gastrointestinal (31%) and haematological (9%). Two patient deaths due to sepsis and Pneumocystis pneumonia were related to treatment, 6 of the 7 further deaths were due to lymphoma. Conclusions Adding ibrutinib to rituximab for the initial treatment of PTLD did not result in a sufficiently high CR rate to warrant further investigation. Survival outcomes (PFS and OS) in our study are similar to those reported previously for rituximab with or without CHOP chemotherapy using a sequential risk stratified treatment approach. Of interest, in comparison to previous reports, a greater proportion of patients (41%) were allocated to low risk and continued IR therapy, thus avoiding cytotoxic chemotherapy. Therefore, the incorporation of novel agents in PTLD management merits further investigation to reduce treatment-related toxicity and improve survival. Figure 1 Figure 1. Disclosures Chaganti: Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel to scientific conferences; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences; Janssen: Honoraria, Other: Travel to scientific conferences; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paneesha: Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celgene: Honoraria. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Davies: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Menne: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. OffLabel Disclosure: Ibrutinib for PTLD.

Abstract Allogeneic stem-cell transplantation is an important curative strategy in acute myeloid leukaemia (AML) consequent upon the development of a graft-versus-leukaemia (GVL) effect. Disease relapse is the major cause of transplant failure and novel therapeutic strategies are required in patients with measurable residual disease (MRD) post-transplant. Recognizing that full donor T cell chimerism serves as a biomarker of GVL and that mixed donor T cell chimerism reflects the presence of bi-directional tolerance, we report the first prospective correlation of the impact of post-transplant T cell chimerism and MRD in patients allografted for AML/MDS. Methods: 186 patients from FIGARO, a prospective randomized trial of reduced intensity conditioning regimens in AML/MDS, were alive and relapse free, at the first MRD timepoint and provided post-transplant bone marrow samples for flow cytometric MRD monitoring (day+42, month+3/+6/+9/+12) and peripheral blood samples for T cell chimerism analysis (3-monthly during the first year). Results were not available to clinicians. Flow cytometric MRD incorporating an unsupervised immunophenotypic analysis approach was used on 778 sequential samples. The prognostic significance of post-transplant MRD from each sampling timepoint was assessed by landmark analysis. Results: 29 (15.6%) patients were MRD+ at one or more timepoints in the first year after transplant. The presence of post-transplant MRD was associated with reduced OS (HR:2.19, p=0.0026) and RFS (HR:5.36, p<0.0001), when analyzed as a time varying Cox variable. We, and others, have shown that pre-transplant MRD status is an important determinant of post-transplant survival. We therefore performed a multivariate analysis of factors that may determine the prognoses of patients with pre-transplant MRD+ disease. This demonstrated that the presence of detectable post-transplant MRD was the only independent determinant of RFS in this group of patients (HR 9.05 (95%CI:1.70-48.2), p=0.0099), even when adjusted for cytogenetics, FLT3-ITD and GVHD. The highest frequency of post-transplant MRD positivity occurred at day+42/month+3. The 2yr OS of day+42 MRD+ patients (n=13/158) was 30.8% (95%CI 9.5-55.4) compared to 67.1% (95%CI 58.5-74.2) in MRD negative patients (p<0.001); and 2yr CIR in day+42 MRD+ patients was 92.3% (95% CI:35.8-99.4) versus 22.8%% (95%CI:16.3-29.9) when MRD negative (p<0.001). Day+42 MRD was associated with more rapid relapse kinetics (median RFS of 2 months) compared to when MRD was first detected at later timepoints. Next, we examined the impact of T-cell chimerism, and post-transplant MRD on outcomes. In patients with mixed-donor T-cell chimerism (MDTC) at month+3 or +6, the presence of post-transplant MRD (preceding or at time of first MDTC) was associated with decreased OS (p=0.001) and RFS. Specifically, 2yr RFS in MRD+ patients was 23.1% (95%CI:5.6-47.5), compared to 63.6% (95%CI:44.9-77.5) in patients who were MRD negative (p=0.004) (Figure). In contrast, in 48 patients with full donor T-cell chimerism (FDTC) at months 3 and 6, only 5 patients were MRD+ post-transplant and their outcomes were equivalent to patients who were MRD negative (FDTC/MRD negative 2yr RFS: 80.9% (95% CI:65.3-90.0)). Downregulation of HLA class II molecules on AML blasts after transplant may result in immune evasion from GVL: we examined whether this had an additional impact on outcome in post-transplant MRD+ patients. Both RFS and OS were significantly lower in MRD+ patients when MRD+ blasts had down-regulated HLA-DR expression. In MRD+ patients, 2yr OS was 20.0% (95%CI:3.1-47.5) in those with HLA-DR down-regulation, versus 57.9% (95%CI 33.2-76.3) in those without (p=0.001). Conclusion We demonstrate that dynamic assessment of post-transplant MRD is an important predictor of outcome in patients allografted for AML/MDS, with additional prognostic value to pre-transplant MRD assessment. Post-transplant MRD and T-cell chimerism results are most informative when combined, underlining the importance of a GVL effect in AML/MDS. This suggests post-transplant strategies which result in FDTC may improve outcomes in patients allografted for AML/MDS. Our data also supports the clinical relevance of monitoring for leukemic immune escape as HLA-DR down-regulation identifies a post-transplant MRD positive subgroup at risk of almost inevitable relapse. Figure 1 Figure 1. Disclosures Loke: Novartis: Other: Travel; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Daichi Sankyo: Other: Travel. Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Jazz: Other: Education events; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Objective:This study investigates undiagnosed depression and anxiety related to diabetes in patients with diabetic retinopathy and identifies commonly feared complications that these patients experience.Methods:The 74 consecutive individuals with diabetes were recruited for this investigation from the office of a retina specialist, and data were obtained from the participants through a self-report survey given to the patients before their appointment.Results:The most feared complication reported by patients surveyed was blindness (38.36%). When asked about depression and anxiety related to their diabetes, 20.27% of patients stated they have depression related to their diabetes, whereas 18.92% had anxiety related to their diabetes. Only 17.57% of the patients said they were being treated for their depression and/or anxiety at the time of the survey.Conclusions:This study demonstrates that many patients with diabetic retinopathy have coexisting fears and mental health concerns. Because most retina specialists treat a high number of patients with diabetes, it is crucial to understand the barriers and comorbidities related to this patient population. Retina specialists may play a role in identifying the hidden and underlying fears, depression, and anxieties in patients with diabetes so that these patients can get the necessary help and counseling they need.

INTRODUCTION: Allogeneic stem cell transplantation (allo-SCT) is an important curative strategy in adults with high risk acute myeloid leukemia (AML) and myelodysplasia (MDS). Disease relapse represents the major cause of treatment failure and whilst retrospective analyses have identified that pre-transplant measurable residual disease (MRD) is an important predictor of transplant outcome this has never been examined prospectively. The advent of reduced intensity conditioning (RIC) regimens has substantially increased the number of older adults eligible for allo-SCT but the optimal RIC regimen in high risk AML remains unknown. Registry data have demonstrated improved outcomes using a sequential transplant regimen utilizing cytosine arabinoside (araC)/amsacrine (AMSA) cytoreduction followed by a fludarabine (Flu)/busulfan (Bu) based RIC regimen (FLAMSA-Bu). However, although the FLAMSA-Bu regimen is now widely used in adults with high risk AML and MDS its benefit has not been evaluated in a randomized trial. We report the results of a randomized trial evaluating the FLAMSA-Bu regimen compared with standard RIC regimens which also represents the first prospective evaluation of the impact of pre-transplant MRD levels on transplant outcome. PATIENTS AND METHODS: 244 patients (median age 59 yrs) with high risk AML (n=164) or high risk myelodysplasia (n=80) were randomized 1:1 to a control arm determined by investigator's choice of either Flu/B2/ATG (Flu, Bu 3.2 mg/kg x 2 days, ATG 2.5 mg/kg x 2 days); Flu/Mel/Alemtuzumab (A) (Flu, Mel 140 mg/m2, A 50 mg) or Flu/Bu2/A (Flu, Bu 3.2 mg/kg x 2 days, A 50 mg) versus an experimental arm of FLAMSA-Bu (Flu, araC 2g/m2 x 4 days, AMSA 100mg/m2 x 4 days, Bu -total dose 11.2 mg/kg). Patients over the age of 60 received an adjusted FLAMSA-Bu regimen utilising a reduced dose of araC (1mg/m2 x 4 days) and a total Bu dose of 6.4 mg/kg. Patients were transplanted using either an HLA identical sibling (n=49) or matched (10/10 or 9/10) unrelated donor (n=195). All patients received cyclosporine GVHD prophylaxis. 155 patients with AML were in CR1 or CR2 at the time of transplant and 9 had primary refractory disease. MRD was monitored by flow cytometry (applying different-from-normal analysis when no diagnostic/relapse leukemic aberrant immunophenotype was available). Pre-transplant MRD levels were measured up to four weeks prior to transplantation in 201 patients (MRD positive = 80 (40%), MRD negative = 94 (47%), inadequate sample = 27 (13%)). MRD results were not reported to clinicians. The primary outcome was overall survival. RESULTS: Baseline characteristics including CR1/CR2 status, adverse cytogenetics and MRD levels were similar between regimens. Median follow up was 35 months. Transplant outcomes were comparable between patients allografted in the control and FLAMSA-Bu arms. 2 yr overall survival (OS) and cumulative incidence of relapse (CIR) were 61% and 30% respectively in the control arm vs 62% and 26% for the FLAMSA-Bu arm. Transplant related mortality at 100 days was 3.0% in patients allografted using the control regimen vs 14% in patients allografted using the FLAMSA-Bu regimen and 17% vs 21% at 1 year. In the study cohort pre-transplant MRD positivity was associated with both an increased CIR compared to patients testing MRD negative (2 yr CIR 42% vs 19%, p=0.009) and decreased OS (2 yr OS 52% vs 71%, p=0.048). The FLAMSA-Bu regimen failed to improve OS or reduce CIR in either MRD positive or MRD negative patients. CONCLUSIONS: This trial, the largest randomized trial of RIC regimens in AML to date, did not detect any benefit of intensification of the conditioning regimen in adults with high risk AML or MDS. Specifically, the FLAMSA-Bu regimen was not associated with improved transplant outcome in patients who were MRD positive pre-transplant. These data include the first demonstration in a prospective analysis that the presence of pre-transplant MRD measured in real time is associated with reduced OS consequent upon an increased risk of disease relapse. Further randomized studies of novel conditioning regimens in adult AML, crucially with integrated MRD studies, are now required but these results support exploration of alternative strategies, such as pre or post-transplant pharmacological intervention, as the most promising strategy to reduce the risk of disease relapse post allograft. Disclosures Russell: Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Freeman:Jazz Pharmaceuticals: Speakers Bureau. OffLabel Disclosure: We report data using the combination of fludarabine, busulphan, amsacrine and cytosine arabinsoide as a conditioning regimen in patients allografted for high risk acute myeloid leukemia

Aim: The Clinical Application of DecisionDx-UM Gene Expression Assay Results study aimed to evaluate the clinical utility of the prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) patients in a large, prospective multicenter cohort. Patients & methods: Nine centers prospectively enrolled 138 UM patients clinically tested with the 15-GEP. Physician-recommended specialty referrals and metastatic surveillance regimens were collected. Results: A total of 93% of high-risk class 2 patients were referred to medical oncology for follow-up, compared with 51% of class 1 patients. A majority (62%) of class 2 patients were recommended overall high-intensity metastatic surveillance, while 85% of class 1 patients were recommended low-intensity metastatic surveillance. Conclusion: Treatment plan recommendations for UM patients are aligned with GEP-informed metastatic risk, consistent with prior studies.

PURPOSE: The main purpose of this paper was to describe the unique accumulation of cases of uveal melanoma (UM). All patients were white and did not have known occupational risk factors. From the authors' standpoint, there were no lifestyle factors in common in the reported cases. Results of more extensive analyses, including geospatial analysis, are currently being conducted and will be presented in a separate paper. DESIGN: Observational case series. METHODS: Descriptive data from medical records, patient interviews, and questionnaires were obtained from 5 patients from North Carolina, 6 patients from Alabama, and 14 patients from New York. Standard incidence ratio (SIR) calculations were provided by the respective states' cancer registries. UM is the most common primary malignant eye tumor in adults, although it is rare, with 2,500 cases diagnosed annually in the United States. Despite a growing understanding of the molecular characteristics, there remains uncertainty regarding epidemiologic trends and environmental risk factors. This study identified 3 geographic accumulations of UM: 1) Huntersville, NC; 2) Auburn, AL; and 3) Broome and Tioga Counties, New York. Investigation of these groups will guide ongoing efforts to discover potential risk factor and assist with future treatment and prevention. RESULTS: In North Carolina, 5 females who were identified as living in Huntersville, NC, were diagnosed with UM at ages 20, 22, 24, 30, and 31. The SIR calculations considering the observed and expected incidence ratios was 0.7 (95% confidence interval [CI], 0.5-0.9) in Mecklenburg County. In Alabama, 6 individuals who were identified as either attending Auburn University or employed there from 1989 to 1993 had diagnoses of UM. Initial SIR calculations for white females of all ages was 1.15 (95% CI, 0.989-1.328). In New York, SIR for Broome and Tioga counties were 0.93 and not significant. However, in Tioga county, for males and females and females alone, SIRs were 2.00 (P = .04) and 3.33 (P = .006). CONCLUSIONS: Although most of the conclusions that the SIR does not meet statistical criteria that defines these accumulations as true "cancer clusters,'' considering the incidence and demographics of UM, these accumulations of cases is unexpected and worth additional exploration. Further investigation into these cases with additional geospatial analyses and blood and tumor testing is ongoing. Information learned from the study of these unique populations may inform a better understanding of the pathogenesis of UM. ((C) 2020 Elsevier Inc. All rights reserved.)