The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (T_FH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6^MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6^MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6^MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6^MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6^MUT lymphoma cells and in STAT6^MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6^MUT but not STAT6^WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6^MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6^MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6^MUT FL.

The aim of this study was to evaluate the long-time results of highly concentrated autologous platelet-rich plasma (PRP) used as an adjunct in lamellar macular hole (LMH) surgery. Nineteen eyes of nineteen patients with progressive LMH were enrolled in this interventional case series, on which 23/25-gauge pars plana vitrectomy was performed and 0.1 mL of highly concentrated autologous platelet-rich plasma was applied under air tamponade. Posterior vitreous detachment was induced, and the peeling of tractive epiretinal membranes, whenever present, was performed. In cases of phakic lens status, combined surgery was carried out. Postoperatively, all patients were instructed to remain in a supine position for the first two postoperative hours. Best-corrected visual acuity (BCVA) testing, microperimetry, and spectral domain optical coherence tomography (SD-OCT) were carried out preoperatively and at minimum 6 months (in median 12 months) postoperatively. Foveal configuration was postoperatively restored in 19 of 19 patients. Two patients who had not undergone ILM peeling showed a recurring defect at 6-month follow-up. Best-corrected visual acuity improved significantly from 0.29 ± 0.08 to 0.14 ± 0.13 logMAR (p = 0.028, Wilcoxon signed-rank test). Microperimetry remained unchanged (23.38 ± 2.53 preoperatively; 23.0 ± 2.49 dB postoperatively; p = 0.67). No patients experienced vision loss after surgery, and no significant intra- or postoperative complications were observed. Using PRP as an adjunct in macular hole surgery significantly improves morphological and functional outcomes. Additionally, it might be an effective prophylaxis to further progression and also the formation of a secondary full-thickness macular hole. The results of this study might contribute to a paradigm shift in macular hole surgery towards early intervention.

This prospective interventional case study aimed to describe the anatomical and functional outcomes of pars plana vitrectomy (PPV) with adjunct highly concentrated autologous platelet-rich plasma (PRP) in patients with symptomatic, progressive lamellar macular hole (LMH) over an extended follow-up period. 20 eyes of 20 patients were included with a minimum follow-up of 24 months (mean 40.2 ± 11.8 months) and a morphological diagnosis of LMH. 23-/25-gauge PPV was conducted with peeling of the internal limiting membrane (ILM) and epiretinal proliferation (ERP; if present) with intraoperative application of autologous PRP under air or gas tamponade. Combined phacovitrectomy was performed in phakic eyes. Foveal anatomy was restored in all cases at first follow-up. Best-corrected visual acuity (BCVA) significantly improved from 0.36 ± 0.16 logMAR to 0.19 ± 0.24 logMAR at final follow-up (mean 0.17 logMAR, p = 0.005). Central retinal thickness (CRT) increased significantly ( p < 0.001), indicating retinal restoration. Ellipsoid Zone (EZ) defects, initially present in 80% of patients, fully resolved in 62.5% with a significant reduction of defect width ( p = 0.005). Microperimetry was stable throughout the entire follow-up. Three patients developed recurrent defects possibly attributable to insufficient peeling or postoperative position. No other significant intra- or postoperative complications were recorded. Autologous PRP in LMH surgery is safe and might be an effective adjuvant, potentially offering long-term anatomical stability and functional recovery while reducing the risk of postoperative complications. Those observed effects are exploratory as the cohort size is small and a control group is missing. A main strength of our study is the extended follow-up period which is essential to capture all possible regeneration mechanism.