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Filippos Vingopoulos,1,2 Megan Kasetty,1 Itika Garg,1,2 Rebecca F Silverman,1 Raviv Katz,1,2 Ryan A Vasan,3 Alice C Lorch,3 Zhonghui K Luo,3 John B Miller1,2 1Harvard Retinal Imaging Lab, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; 2Retina Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; 3Comprehensive Ophthalmology and Cataract Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USACorrespondence: John B Miller, Harvard Retinal Imaging Lab, Massachusetts Eye and Ear, Harvard Medical School, 243 Charles St, Boston, MA, USA, Tel +1 617 573-3750, Fax +1 617 573-3698, Email john_miller@meei.harvard.eduBackground: To characterize contrast sensitivity function (CSF) in cataractous and pseudophakic eyes compared to healthy control eyes using a novel quantitative CSF test with active learning algorithms.Methods: This is a prospective observational study at an academic medical center. CSF was measured in eyes with visually significant cataract, at least 2+ nuclear sclerosis (NS) and visual acuity (VA) ≥ 20/50, in pseudophakic eyes and in healthy controls with no more than 1+ NS and no visual complaints, using the Manifold Contrast Vision Meter. Outcomes included Area under the Log CSF (AULCSF) and CS thresholds at 1, 1.5, 3, 6, 12, and 18 cycles per degree (cpd). A subgroup analysis as performed on cataract eyes with VA ≥ 20/25.Results: A total of 167 eyes were included, 58 eyes in the cataract group, 77 controls, and 32 pseudophakic eyes with respective median AULCSF of 1.053 (0.352) vs 1.228 (0.318) vs 1.256 (0.360). In our multivariate regression model, cataract was associated with significantly reduced AULCSF (P= 0.04, β= − 0.11) and contrast threshold at 6 cpd (P= 0.01, β= − 0.16) compared to controls. Contrast threshold at 6 cpd was significantly reduced even in the subgroup of cataractous eyes with VA ≥ 20/25 (P=0.02, β=− 0.16).Conclusion: The novel qCSF test detected disproportionate significant contrast deficits at 6 cpd in cataract eyes; this remained significant even in the cataractous eyes with VA ≥ 20/25. CSF testing may enhance cataract evaluation and surgical decision-making, particularly in patients with subjective visual complaints despite good VA.Keywords: cataract, contrast sensitivity function, Contrast sensitivity, qCSF method

Bradley A Colarusso,1 Shannon M Bligdon,2 Allen Y Ganjei,3 Alan Kwok,4 Daniel Brocks,4 Zhonghui K Luo1 1Massachusetts Eye and Ear, Boston, MA, USA; 2Ajax Eye Care, Ajax, ON, Canada; 3Drexel University College of Medicine, Philadelphia, PA, USA; 4BostonSight, Needham, MA, USACorrespondence: Zhonghui K Luo, Massachusetts Eye and Ear, 800 Huntington Avenue, Boston, MA, 02115, USA, Tel +1-617-936-6092, Fax +1-617-936-6186, Email Zhonghui_luo@meei.harvard.eduPurpose: To understand the degree and explore the possible causes of ocular graft-versus-host disease (oGVHD) underdiagnosis in patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).Patients and Methods: A 15-question survey was emailed to 6032 subscribers to the Blood and Marrow Transplant Information Network. A total of 371 respondents confirmed the history of allo-HSCT, of which 335 were symptomatic. Their self-reported symptoms, onset, treatments tried, degree of symptom control and established diagnoses of systemic chronic graft-versus-host disease (cGVHD) and oGVHD were analyzed.Results: Among the 335 symptomatic survey respondents, 306 reported their ocular symptom onset was after allo-HSCT, with only 170 [55.6% (170/306)] ever receiving a diagnosis of oGVHD; 23 reported worsening pre-existing ocular symptoms after allo-HSCT, with only 5 [21.7% (5/23)] ever receiving a diagnosis of oGVHD; 6 reported stable symptoms before and after allo-HSCT, with 1 ever receiving a diagnosis of oGVHD. Of the 176 respondents carrying the diagnosis of oGVHD, 167 [94.9% (167/176)] also had the diagnosis of cGVHD. Logistic regression analysis showed that the diagnosis of oGVHD was highly correlated with the number of symptoms and treatments one reported. Furthermore, 35% of the respondents with new onset ocular symptoms reported onset within the first 6 months after allo-HSCT (previously reported), as well as 39% of the respondents with worsened existing symptoms.Conclusion: oGVHD underdiagnosis is likely associated with the previous diagnostic criteria, in which cGVHD of another organ system was required. The correct notion that oGVHD commonly causes severe dry eye disease has likely led to its underdiagnosis in patients with fewer number of symptoms and/or who tried fewer treatments.Keywords: oGVHD, cGVHD, dry eye, keratoconjunctivitis sicca, hematopoietic stem cell transplantation

Shannon M Bligdon,1 Bradley A Colarusso,2 Allen Y Ganjei,3 Alan Kwok,4 Zhonghui Katie Luo,2 Daniel Brocks4 1Ajax Eye Care, Ajax, ON, Canada; 2Massachusetts Eye and Ear, Boston, MA, USA; 3Drexel University College of Medicine, Philadelphia, PA, USA; 4BostonSight, Needham, MA, USACorrespondence: Alan KwokBostonSight, 464 Hillside Ave, Unit 205, Needham, MA, 02494, USATel +1 781 726 7337Fax +1 781 726 7310Email akwok@bostonsight.orgPurpose: To evaluate the utilization of scleral lenses and prosthetic replacement of the ocular surface ecosystem devices (SL/PDs) in the management of ocular graft-versus-host disease (oGVHD).Patients and Methods: A survey of 15 questions was sent via email to 6032 subjects registered with the Blood and Marrow Transplant Information Network. The survey reviewed transplant history, graft-versus-host disease history, as well as oGVHD symptoms and onset. Additional questions surveyed treatments used for oGVHD, as well as the degree of ocular symptom control and experience with SL/PDs. A total of 306 respondents met the eligibility requirements to be part of the analyzed cohort.Results: The mean number of symptoms reported from the analyzed cohort was 4.79 ± 2.44, median (IQR) of 5.0 (3.0 to 7.0), with the most common symptom being gritty, dry eyes (87%). The mean number of treatments utilized across the analyzed cohort was 3.21 ± 2.55, median (IQR) of 2.5 (1.0 to 5.0), with the most common treatment being artificial tears (86%). Wearing scleral lenses resulted in a mean of 5.42 ± 1.86, median (IQR) of 6.0 (4.0 to 7.0) symptoms improving, with improved dryness/grittiness of the eyes (94%), improved eye pain (92%) and improved quality of life (89%) being the most commonly improved symptoms. Fifty-six percent of those wearing scleral lenses wished the lenses had been recommended sooner. The most common reason patients cited for not wearing scleral lenses was that they had never heard of them (63%).Conclusion: SL/PDs help to control the symptoms of oGVHD. With their use, clinicians are able to improve the quality of life of this patient population. Despite the known benefits, SL/PDs still remain underutilized in oGVHD care. A majority of current SL/PD wearers wish that they had been recommended sooner as a treatment option. SL/PDs should be considered a component of comprehensive oGVHD management.Keywords: GVHD, oGVHD, dry eye, keratoconjunctivitis sicca, QOL, HSCT, allo-HSCT

Purpose: Ocular graft-versus-host disease (oGVHD) affects more than half of the patients following allogeneic hematopoietic stem cell transplantation (HSCT). The disease onset and the pathogenesis of oGVHD are not well understood. We hope to identify the triggers and explore the clinical signs and symptoms of oGVHD development at the early stages., Methods: The records of post-HSCT patients seen consecutively in a 1-year span in a single provider's clinic were reviewed. The history, symptoms, and clinical findings of the patients with erosive tarsal conjunctival lesions (ETCLs) were analyzed., Results: Out of the 228 patients screened, 19 had clinically witnessed ETCL in at least one eye during the period. Twelve (63%) patients had a never-before-described nodular erosion on the subtarsal conjunctiva; seven (37%) had previously described pseudomembranous erosions. The ocular symptom onset was within 1 month after immunosuppression (IS) taper, vaccination, or donor lymphocyte infusion (DLI) in 16 of the 19 patients. While 16 (84%) patients reported painless mucous discharge, only 9 (47%) reported dryness as the initial symptom. Within 6 months, only 4 (21%) had discharge but 15 (82%) patients endorsed dryness. Subepithelial conjunctival fibrosis followed ETCL immediately in situ. Corneal punctate staining increased with time, while aqueous tear production decreased., Conclusions: The ETCL described is likely one of the earliest detectable findings of oGVHD and triggered by certain immunogenic events. The ocular symptoms of wet mucous discharge should be considered a warning sign for oGVHD onset, particularly when it occurs shortly after prominently immunogenic events.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts., (© 2024. The Author(s).)

Ocular graft-versus-host disease (oGVHD) remains a challenging and potentially devastating complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although oGVHD significantly impacts the quality of life of affected survivors, it often goes unrecognized, particularly in the early stages. Targeting all providers in the HSCT community who see patients regularly and frequently for their post-allo-HSCT care, this review and opinion piece introduces the basic concepts of ocular surface pathophysiology, dissects the different stages of clinical presentation of oGVHD, explains why the current diagnostic criteria tend to capture the late disease stages, and highlights the warning signs of early disease development to facilitate prompt referral of oGVHD suspects for ocular specialist care. Along with introducing a comprehensive list of treatment options, this review emphasizes basic therapeutic strategy and options that can be safely and effectively initiated by any care provider. We believe in empowering patients as well as care providers beyond disciplinary boundaries to provide the most cohesive and integrated care in a multidisciplinary approach., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Non-anatomical factors significantly affect treatment guidance and prognostic prediction in nasopharyngeal carcinoma (NPC) patients. Here, we developed a novel survival model by combining conventional TNM staging and serological indicators., Methods: We retrospectively enrolled 10,914 eligible patients with nonmetastatic NPC over 2009-2017 and randomly divided them into training (n = 7672) and validation (n = 3242) cohorts. The new staging system was constructed based on T category, N category, and pretreatment serological markers by using recursive partitioning analysis (RPA)., Results: In multivariate Cox analysis, pretreatment cell-free Epstein-Barr virus (cfEBV) DNA levels of >2000 copies/mL [HR OS (95 % CI) = 1.78 (1.57-2.02)], elevated lactate dehydrogenase (LDH) levels [HR OS (95 % CI) = 1.64 (1.41-1.92)], and C-reactive protein-to-albumin ratio (CAR) of >0.04 [HR OS (95 % CI) = 1.20 (1.07-1.34)] were associated with negative prognosis (all P < 0.05). Through RPA, we stratified patients into four risk groups: RPA I (n = 3209), RPA II (n = 2063), RPA III (n = 1263), and RPA IV (n = 1137), with 5-year overall survival (OS) rates of 93.2 %, 86.0 %, 80.6 %, and 71.9 % (all P < 0.001), respectively. Compared with the TNM staging system (eighth edition), RPA risk grouping demonstrated higher prognostic prediction efficacy in the training [area under the curve (AUC) = 0.661 vs. 0.631, P < 0.001] and validation (AUC = 0.687 vs. 0.654, P = 0.001) cohorts. Furthermore, our model could distinguish sensitive patients suitable for induction chemotherapy well., Conclusion: Our novel RPA staging model outperformed the current TNM staging system in prognostic prediction and clinical decision-making. We recommend incorporating cfEBV DNA, LDH, and CAR into the TNM staging system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To analyze the recurrence pattern of rectal cancer patients with radical surgery after neoadjuvant chemoradiotherapy. Methods: The clinicopathological characteristics and follow-up information of rectal cancer patients with radical surgery after neoadjuvant chemoradiotherapy in the Cancer Hospital of the Chinese Academy of Medical Sciences from June 2004 to December 2017 were retrospectively collected. The recurrence pattern including the time and site was investigated. Results: The age of 537 patients was (55.5±11.7) years, of whom 361 were male (67.2%). The median follow-up time [ M ( Q 1 , Q 3 )] was 77.9 (64.5, 95.6) months. Moreover, 30.7% (165/537) of patients had distant metastasis or local recurrence; 26.8% (144/537) of patients had distant metastasis; 5.6% (30/537) of patients had local recurrence; 1.7% (9/537) of patients had both distant metastasis and local recurrence. In all the recurrent patients, 23.6% (39/165) were in the first year after surgery, followed by 27.3% (45/165) in the second year, 17.0% (28/165) in the third year, and 15.8% (26/165) after five years. According to the risk curve drawn by the life table, the highest metastasis risk of patients occurred in the second year after surgery, and the metastasis risk peak occurred again after more than five years. The lung was the most common metastatic organ, accounting for 47.9% (69/144), followed by the liver (18.8%, 27/144). The ratios of the recurrent patients in each ypTNM stage were 9.5% (8/84), 12.0% (12/100), 26.5% (41/155), 52.5% (104/198), respectively. The proportion of recurrent patients in tumor regression grade (TRG) 1-2 and TRG 3-5 patients were 19.2% (38/198) and 37.5% (127/339), respectively. Conclusions: The recurrence pattern of patients undergoing radical surgery after neoadjuvant chemoradiotherapy is mainly distant metastasis. The lung is the primary metastatic organ. The risk of distant metastasis and local recurrence is high in the first three years after surgery, and there is still high risk of recurrence after five years. For patients with ypTNM stage 2, 3 and TRG3-5, the postoperative adjuvant chemotherapy and long-term follow-up should be strengthened.

Background: The conversion of phytosterols to steroid synthons by engineered Mycolicibacteria comprises one of the core steps in the commercial production of steroid hormones. This is a complex oxidative catabolic process, and taking the production of androstenones as example, it requires about 10 equivalent flavin adenine dinucleotide (FAD). As the high demand for FAD, the insufficient supply of FAD may be a common issue limiting the conversion process., Results: We substantiated, using the production of 9α-hydroxy-4-androstene-3,17-dione (9-OHAD) as a model, that increasing intracellular FAD supply could effectively increase the conversion of phytosterols into 9-OHAD. Overexpressing ribB and ribC, two key genes involving in FAD synthesis, could significantly enhance the amount of intracellular FAD by 167.4% and the production of 9-OHAD by 25.6%. Subsequently, styrene monooxygenase NfStyA2B from Nocardia farcinica was employed to promote the cyclic regeneration of FAD by coupling the oxidation of nicotinamide adenine dinucleotide (NADH) to NAD + , and the production of 9-OHAD was further enhanced by 9.4%. However, the viable cell numbers decreased by 20.1%, which was attributed to sharply increased levels of H 2 O 2 because of the regeneration of FAD from FADH 2 . Thus, we tried to resolve the conflict between FAD regeneration and cell growth by the overexpression of catalase and promotor replacement. Finally, a robust strain NF-P2 was obtained, which could produce 9.02 g/L 9-OHAD after adding 15 g/L phytosterols with productivity of 0.075 g/(L h), which was 66.7% higher than that produced by the original strain., Conclusions: This study highlighted that the cofactor engineering, including the supply and recycling of FAD and NAD + in Mycolicibacterium, should be adopted as a parallel strategy with pathway engineering to improve the productivity of the industrial strains in the conversion of phytosterols into steroid synthons., (© 2023. The Author(s).)

Objective: To analyze the clinicopathological factors affecting long-term disease-free survival and the characteristics of local recurrence or distance metastasis of rectal cancer patients with complete pathological response after neoadjuvant chemoradiotherapy. Methods: The clinicopathological data and follow-up information of patients with a complete pathological response of rectal cancer after neoadjuvant chemoradiotherapy in the Cancer Hospital of Chinese Academy of Medical Sciences from June 2004 to December 2019 were retrospectively collected. The clinicopathological factors affecting the long-term disease-free survival of patients were analyzed to build a prediction model of local recurrence and distant metastasis and to evaluate the benefits of postoperative chemotherapy. Results: The age of 108 patients was(56.3±11.6) years, of which 68 were males (63.0%); The median follow-up time was 79.9 (61.8, 112.6) months. There were 12 patients (11.1%) who had a local recurrence or distant metastasis. The 5-year disease-free survival rate was 91.1% with 9 patients who experienced recurrence. Multivariate Cox proportional hazards regression analysis showed that the maximum diameter of the residual tumor or scar ( HR =8.41, 95% CI : 1.08-65.22, P =0.042) and the distance from the lower edge of the tumor to the anal margin before treatment ( HR =4.54, 95% CI : 1.23-16.81, P =0.023) were independent risk factors affecting the prognosis. The prognosis of patients was stratified based on relevant factors. The 5-year cumulative disease-free survival rate of those patients receiving postoperative standardized chemotherapy was 92.0%, while for patients who did not receive or complete standardized chemotherapy, the 5-year cumulative disease-free survival rate was 82.3%. Conclusions: The maximum diameter of the residual tumor or scar and the distance from the lower edge of the tumor to the anal margin before treatment were independent risk factors affecting the prognosis of patients with a complete pathological response. Patients with independent risk factors could benefit from the standardized postoperative chemotherapy.

Objective: The purpose of this study was to retrospectively assess the efficacy and safety of percutaneous nephrolithotomy (PCNL) for upper urinary stones using upper pole access (UPA) and other (low or middle) pole access (OPA)., Materials and Methods: A comprehensive literature review of articles investigating the clinical efficacy and safety of UPA and OPA was performed. The relevant literature was obtained from PubMed, EMBASE, Science Direct, Google Scholar and the Cochrane Library. The primary outcomes, including the stone-free rate, were evaluated using Review Manager 5.4 software. The secondary outcomes (peri- and postoperative complications and operative date) were also compared and analyzed., Results: Ten comparative studies involving 5,290 patients were included in the analysis. The pooled data showed that the UPA group had a stone-free rate (SFR) similar to that of the OPA group [odds ratio (OR) 1.38, 95% confidence interval (CI): 0.94 to 2.03; p=0.22] but a higher incidence of blood transfusion [OR: 1.50; 95% CI: (1.03, 2.19), p=0.04]. There was no statistically significant difference in operative time [mean difference (MD): -7.27; 95% CI: (-25.18, 10.65), p=0.43] or hospital stay [MD: -0.13; 95% CI: (-0.64, 0.37), p=0.60] between the two groups. In addition, the results support that UPA causes fewer complications than OPA., Conclusions: Our findings suggest that UPA and OPA are both effective treatments for the management of upper urinary stones. Compared to OPA, UPA is associated with less need for blood transfusion and fewer complications. Nevertheless, the findings should be further confirmed by well-designed prospective randomized controlled trials (RCTs) with large samples and strict standards.

Objective: To evaluate the impact of number-indexes of lymph nodes for prognostic stratification in stage N1c colorectal cancer (CRC) patients. Methods: The clinicopathologic data of CRC patients with stage pTxN1cM0 who initially underwent radical surgery in Cancer Hospital, Chinese Academy of Medical Sciences and the Surveillance, Epidemiology and End Results (SEER) database from January 2010 to December 2015 were retrospectively analyzed. A total of 1 165 patients with stage N1c were included in this study. Among them, 85 patients (including 54 males and 31 females) were from Cancer Hospital, Chinese Academy of Medical Sciences and their median age was 58 (range: 32-80) years; 1 080 patients (including 566 males and 514 females) were from the SEER database and their median age was 66 (range: 24-98) years. The prognostic significance of total number of lymph node (TLN), number of negative lymph node (NLN), and log odds of positive lymph nodes (LODDS) in stage N1c CRC patients were explored. Results: The optimal cut-off value of TLN or NLN was 13, and the optimal cut-off value of LODDS was -1.43. Among the 85 patients of Cancer Hospital, Chinese Academy of Medical Sciences, the 5-year overall survival (OS) rates of stage N1c1 (TLN or NLN≥13, 69 cases) and group LODDS1 patients (LODDS≤-1.43, 69 cases) were both 80.9%, which higher than that of stage N1c2 (TLN or NLN<13, 16 cases) and group LODDS2 (LODDS>-1.43, 16 cases) patients (both 53.3%, P =0.002); In the SEER cohort, the 5-year OS rates of stage N1c1 (837 cases) and group LODDS1 patients (LODDS≤-1.43, 837 cases) were both 64.7%, which higher than that of stage N1c2 (243 cases) and group LODDS2 (LODDS>-1.43, 243 cases) patients (both 52.2%, P <0.001). Both in the NCC cohort and SEER cohort, the results of Cox multivariate analysis all demonstrated that TLN or NLN<13 was the risk factor of OS of CRC patients with stage N1c ( HR =3.794, 95% CI : 1.539-9.349, P =0.004; and HR =1.588, 95% CI :1.232-2.048, P <0.001; respectively); LODDS≤-1.43 was the independent protective factor of OS of stage N1c CRC patients ( HR =0.264, 95% CI : 0.107-0.650; and HR =0.630, 95% CI : 0.488-0.812; respectively). Conclusions: TLN or NLN and LODDS were all independent prognostic factors of CRC patients with stage N1c. The clinicians could use TLN or NLN and LODDS for prognostic stratification and make the different adjuvant therapeutic schemes for CRC patients with stage N1c.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Objectives: To evaluate a novel approach to determine the refractive target for patients undergoing cataract surgery who are dependent on therapeutic scleral lenses, to avoid the need for postoperative scleral lens replacement., Methods: Retrospective single-surgeon case series. The target refraction for intraocular lens selection was determined by considering the effective scleral lens system power. This was calculated by adding the known scleral lens spherical power to the difference between the scleral lens base curve and the average keratometry value., Results: Six eyes from three patients with moderate myopia or emmetropia with ocular graft versus host disease dependent on therapeutic scleral lenses underwent cataract surgery with intraocular lens selection based on this method. All six eyes had corrected visual acuities of 20/30 or better while wearing their previous scleral lenses at the postoperative week 1 visit. All six eyes resumed full-time scleral lens use 1 week after phacoemulsification and did not require scleral lens replacement., Conclusions: Using this method, patients requiring therapeutic scleral lenses can quickly experience optimal vision, comfort, and ocular surface protection 1 week after cataract surgery. These patients can continue to use their existing scleral lenses and avoid the costs and burdens associated with lens replacement., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Contact Lens Association of Opthalmologists.)

There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to report outcomes of type I Boston keratoprosthesis (KPro) as primary corneal surgery in nonautoimmune corneal disorders., Methods: In this retrospective, observational, large single-center case series of 43 eyes (37 patients) that were followed for an average of 39 months (1-6 years), primary implantation of the type I Boston KPro was performed in all patients. Visual acuity at year 1, visual acuity at last follow-up, and postoperative complication rates were examined for all eyes., Results: Preoperative best-corrected visual acuity ranged from 20/60 to light perception, with vision of 20/200 or worse in 88%. Vision was ≥20/200 at 1 year in 77% of eyes (P < 0.0001). Complications included retroprosthetic membrane formation (51%), glaucoma progression (47%), corneal melt (19%), and sterile vitritis (14%)., Conclusions: In a large series with long follow-up, primary Boston KPro effectively restored vision. Close follow-up is needed to manage the known complications after Boston KPro.