An increase in regulatory T cells in peripheral blood correlates with an adverse prognosis for malignant melanoma patients - A study of T cells and natural killer cells.

Malignant melanoma is a highly immunogenic tumour, and the immune profile significantly influences cancer development and response to immunotherapy. The peripheral immune profile may identify high risk patients. The current study showed reduced levels of CD4+ T cells and increased levels of CD8+ T cells in peripheral blood from malignant melanoma patients compared with controls. Percentages of peripheral CD56dimCD16+ NK cells were reduced and CD56brightCD16-KIR3+ NK cells were increased in malignant melanoma patients. Late stage malignant melanoma was correlated with low levels of CD4+ T cells and high levels of CD56brightCD16-KIR3+ NK cells. Finally, high levels of Tregs in peripheral blood were correlated with poor overall survival and disease-free survival. The results indicate that changes in specific immune cell subsets in peripheral blood samples from patients at the time of diagnosis may be potential biomarkers for prognosis and survival. Further studies will enable clarification of independent roles in tumour pathogenesis.

Ocular Chronic Graft-versus-Host Disease and Its Relation to Other Organ Manifestations and Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Ocular chronic graft-versus-host disease (cGVHD) has been shown to significantly reduce quality of life after allogeneic hematopoietic stem cell transplantation (HSCT). To learn more about this bothersome complication, we investigated the relationship between ocular cGVHD and cGVHD in other organs. We also investigated the associations between ocular cGVHD and overall mortality, nonrelapse mortality, and relapse. In this single-center study, we retrospectively included 1221 consecutive adults who underwent allogeneic HSCT. Patients were examined by an ophthalmologist before HSCT and annually for 5 years after HSCT or more frequently if needed. Patients with dry eye disease before HSCT were excluded. The International Chronic Ocular GVHD Consensus Group criteria were used to diagnose ocular cGVHD. Nonocular cGVHD was diagnosed using the National Institute of Health criteria. Out of 601 patients who were diagnosed with systemic cGVHD during follow-up, 279 (46%) developed ocular cGVHD. Ocular cGVHD was more frequent in patients with extensive cGVHD compared to those with limited cGVHD (50% versus 29%; P < .0001) and was associated with cGVHD in skin (P < .0001), oral cavity (P = .0024), genitals (P = .0023), and nails (P = .031). The frequency of ocular cGVHD was higher in patients with skin cGVHD with sclerosis compared to those with skin cGVHD without sclerosis (70% versus 49%; P = .0003). In an adjusted time-dependent Cox model, ocular cGVHD was associated with increased nonrelapse mortality (adjusted hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.17 to 2.21; P = .003), whereas there was no support for an association with relapse (adjusted HR, .85; 95% CI, .53 to 1.36; P = .5). Special attention to eye problems after HSCT should be given to patients with extensive cGVHD and cGVHD in ectodermal-derived organs (skin, mouth, nails, and genitals). Furthermore, ocular cGVHD is a potential risk factor for nonrelapse mortality. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Ocular graft-versus-host disease and dry eye disease after paediatric haematopoietic stem cell transplantation - incidence and risk factors.

Ocular graft-versus-host disease (oGVHD) contributes substantially to morbidity after allogeneic haematopoietic stem cell transplantation (HSCT) but is sparsely investigated in children. We assessed incidence and risk factors for oGVHD and dry eye disease (DED) in a nationwide, single-centre study of 484 consecutive children receiving HSCT during the period 1980-2016. Ophthalmological examinations were performed before and annually at least until five years after HSCT. Twenty-five patients had DED before transplantation (5.6%). The cumulative incidence was 1.9% for acute oGVHD, 6.0% for chronic oGVHD, 8.7% for new onset DED, and 12.7% for new onset Corneal Fluorescein Staining (CFS). In adjusted Fine-Gray regression models, the use of Busulfan was a risk factor for developing acute oGVHD (HR 5.01, p = 0.03), and malignant disease was a risk factor for developing CFS (HR 2.00, p = 0.047). Younger recipient age was associated with reduced risk of DED when comparing children aged 0-4 years with 10-16 years (HR 0.33, p = 0.03). These data underscore the need of attention to DED and oGVHD in relation to HSCT leading to our recommendation of performing ophthalmic examinations in all children before HSCT, and after HSCT when needed, in order to secure diagnosis and treatment of these complications.

Chronic ocular graft-versus-host disease after allogeneic haematopoietic stem cell transplantation in Denmark - factors associated with risks and rates in adults according to conditioning regimen.

We investigated risks and hazard rates of developing chronic ocular graft-versus-host disease (oGVHD) in a large nationwide, single centre study by using the criteria proposed by "The International Chronic oGVHD Consensus Group". This retrospective study included 1407 consecutive adults who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Patients were examined by an ophthalmologist according to the hospital's guidelines: baseline examination before HSCT, annually up to 5 years after HSCT. The 186 (13%) had dry eye disease before HSCT. The 5-year cumulative incidence of oGVHD was 18% (95% CI: 15-21) after myeloablative (MA) and 35% (95% CI: 30-39) after non-myeloablative conditioning (NMA). Factors associated with the rate of oGVHD were assessed separately according to conditioning regimen by using multiple Cox regression analyses. Factors that increased the rate in the MA group: Malignant disease, Schirmer's test≤10 mm/5 min before transplantation, use of female donor, matched unrelated donor, peripheral blood as stem cell source, and grade III-IV acute GVHD. Factors that increased the rate in the NMA group: Schirmer's test≤10 mm/5 min before transplantation and higher recipient age. We recommend a baseline ophthalmological examination before HSCT since many of the patients have signs of dry eyes before transplantation which increased the risk and rate of developing oGVHD.

Characterization of HLA-G Regulation and HLA Expression in Breast Cancer and Malignant Melanoma Cell Lines upon IFN-γ Stimulation and Inhibition of DNA Methylation.

The potential role of human leukocyte antigen (HLA)-G as a target for new cancer immunotherapy drugs has increased the interest in the analysis of mechanisms by which HLA-G expression is regulated, and how the expression can be manipulated. We characterized HLA expression in breast cancer and malignant melanoma cell lines and investigated the induction of HLA-G expression by two distinct mechanisms: stimulation with interferon (IFN)-γ or inhibition of methylation by treatment with 5-aza-2'-deoxycytidine (5-aza-dC). The effect of IFN-γ and 5-aza-dC on HLA expression was dependent on the cancer cell lines studied. However, in general, surface expression of HLA class Ia was induced on all cell lines. Surface expression of HLA-G was inconclusive but induction of HLA-G mRNA was prevalent upon treatment with 5-aza-dC and a combination of IFN-γ and 5-aza-dC. IFN-γ alone failed to induce HLA-G expression in the HLA-G-negative cell lines. The results support that HLA-G expression is regulated partly by DNA methylation. Furthermore, IFN-γ may play a role in the maintenance of HLA-G expression rather than inducing expression. The study demonstrates the feasibility of manipulating HLA expression and contributes to the exploration of mechanisms that can be potential targets for immunotherapy in breast cancer and malignant melanoma.

Corneal endothelial morphology and central thickness in patients with type II diabetes mellitus.

PURPOSE: To investigate corneal endothelial cell density and morphology in type II diabetic and non-diabetic patients and to relate potential differences to the glycaemic status. METHODS: A prospective clinical study including 107 patients with type II diabetes and 128 non-diabetic patients. Sample size was based on a power calculation (power = 0.90; p = 0.05). The diabetic patients had on average more than four HbA1c tests performed (mean 4.1; range 2-14) with intervals of at least 3 months as a reflection of the long-term glycaemic status. The controls had no diabetes confirmed by two causal blood tests. The endothelial cell density, the variation in endothelial cell size (CV), the percentage of hexagonal cells, and the central corneal thickness (CCT) were recorded. RESULTS: Type II diabetic subjects did not differ from the non-diabetic control subjects with regards to endothelial cell density, hexagonality or variation in CV, but showed a significant increase in CCT (538 versus 546 µm, p < 0.05). In the diabetic group, lower cell counts were associated with higher HbA1c values (p < 0.05). The HbA1c did not, however, have any impact on the CCT. CONCLUSION: Type II diabetes has no impact on corneal cell density or morphology in subjects with good glycaemic status. However, higher HbA1c was associated with lower endothelial cell density. CCT was significantly increased in the diabetic group.