Corneal melting after collagen cross-linking for keratoconus: a case report

<p>Abstract</p> <p>Introduction</p> <p>Corneal collagen cross-linking is a rather new technique that uses riboflavin and ultraviolet A light for collagen fiber stabilization in keratoconus corneas. Other than reversible side effects, the preliminary results of corneal collagen cross-linking studies suggest that it is a rather safe technique. In this report, we demonstrate a case of corneal melting after corneal collagen cross-linking for keratoconus corneas associated with an acute inflammatory response.</p> <p>Case presentation</p> <p>A 23-year-old Caucasian man with keratoconus cornea stage 1 to 2 underwent uneventful corneal collagen cross-linking treatment according to the Dresden protocol. The next day the patient had intense photophobia, watering and redness of the eye, and his visual acuity was limited to counting fingers. Slit lamp biomicroscopy revealed severe corneal haze accompanied by non-specific endothelial precipitates following an acute inflammatory response. Mild inflammation could be detected in the anterior chamber. Moreover, the re-epithelialization process could barely be detected. His corneal state gradually deteriorated, resulting in descemetocele and finally perforation.</p> <p>Conclusion</p> <p>In this report, we present a case of a patient with corneal melting after standard corneal collagen cross-linking treatment for keratoconus corneas following an acute inflammatory response. Despite modifying postoperative treatment, elaboration of all apparent associated causes by the treating physicians and undergoing extensive laboratory testing, the patient developed descemetocele, which led to perforation. Our report suggests that further research is necessary regarding the safety of corneal collagen cross-linking in keratoconus corneas.</p

The meaning of the demarcation line after riboflavin-UVA corneal collagen crosslinking

Introduction: The demarcation line (DL) observed since the pioneering crosslink (CLX) protocol at the posterior edge of the cross-linked stroma has been universally accepted as a therapeutic milestone of treatment. Numerous laboratory and clinical CXL studies demonstrate that a deeper DL is associated with a higher amount and saturation level of crosslinks, a more pronounced stiffening effect, and a more durable ectasia stability. Areas covered: A critical revision of laboratory, clinical, and analytical studies on the DL depth supports the significance of the DL as an evaluator of the performance of CLX procedures in terms of biomechanical efficacy and safety avoiding extensive experiments. A mechanical approach based on experimental data shows that the DL depth obtained with different CXL protocols relates with an asymptotic non-linear increasing function to the modified biomechanical corneal stiffness (elastic modulus). Expert opinion: The strong connection between the depth of the DL and the increase of the biomechanical efficacy can be explained by means of UV cross-linking chemical investigations demonstrating that only a limited amount of free reactive collagen residues is involved in the short-wave UV-mediated CXL. Thus, the CXL density can rise only up to an upper boundary value, i.e. the saturation value

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed

Prognostic Relevance of Type 2 Diabetes and Metformin Treatment in Head and Neck Melanoma: Results from a Population-Based Cohort Study

Background: Type 2 Diabetes (DM2) and the consecutively daily use of antidiabetic medication are characterized by a frequent prevalence worldwide and were shown to impact the initiation and progression of malignant diseases. While these effects were observed in a variety of malignancies, comprehensive data about the role of DM2 and antidiabetic drugs in the outcome of head and neck melanoma (HNM) patients are missing. Methods: This retrospective population-based cohort study included 382 HNM patients from Eastern Bavaria having received tumor resection to negative margins between 2010 and 2017. Recurrence-free survival (RFS) was evaluated with regard to DM2 and routine metformin intake. Statistical analysis was performed by uni- and multivariate analyses. The median follow-up time was 5.6 years. Results: DM2 was diagnosed in 68 patients (17.8%), routine metformin intake was found in 39 cases (10.2%). The univariate survival analysis revealed impaired 5-year RFS in HNM patients with DM2 compared to non-diabetic controls (p = 0.016; 64.0% and 74.5%, respectively). The multivariate Cox regression substantiated this effect (HR = 1.980, 95% CI = 1.108–3.538, p = 0.021). In detail, the cumulative locoregional recurrence rate displayed the most far-reaching negative effect on the RFS of diabetic HNM patients (HR = 4.173, 95% CI = 1.628–10.697, p = 0.003). For metformin intake, a profound positive effect on the RFS in multivariate statistics was observed, both in the complete cohort (HR = 0.396, 95% CI = 0.177–0.884, p = 0.024) as well as in the cohort of diabetic HNM patients (HR = 0.352, 95% CI = 0.135–0.913, p = 0.032). Conclusions: This study emphasizes that DM2 is a relevant comorbid condition in HNM patients, impairing patient survival. Metformin intake was associated with a favorable outcome in HNM patients, providing possible therapeutic implications for future adjuvant treatment regimes

TIGIT Expression on Intratumoral Lymphocytes Correlates with Improved Prognosis in Oral Squamous Cell Carcinoma

Background: T-cell immunoglobulin and ITIM domain (TIGIT) is a potential immunotherapeutic target in a variety of malignant entities, and antibody-based treatments are currently under investigation in clinical trials. While promising results were observed in patients with lung cancer, the role of TIGIT in oral squamous cell carcinoma (OSCC) as a biomarker as well as a therapeutic target remains elusive. Therefore, we evaluated the role of TIGIT as a prognostic factor in OSCC. Methods: Here, we describe the results of a retrospective tissue microarray (TMA) OSCC cohort. Using immunohistochemistry, TIGIT expression was correlated with overall and recurrence-free survival (OAS and RFS, respectively). Additionally, in silico analysis was performed based on the TCGA Head and Neck Squamous Cell Carcinoma (HNSCC) cohort in order to correlate patients’ survival with TIGIT and CD274 (encoding for PD-L1) gene expression levels. Results: Database analysis revealed a beneficial outcome in OAS for tumor patients with high intraepithelial CD3-TIGIT-expression (n = 327). Hereby, OAS was 53.9 months vs. 30.1 months for patients with lower TIGIT gene expression levels (p = 0.033). In our retrospective OSCC-TMA cohort, elevated TIGIT levels on CD3+ cells correlated significantly with improved OAS (p = 0.025) as well as distant RFS (p = 0.026). Conclusions: This study introduces TIGIT as a novel prognostic factor in OSCC, indicating the improved outcome of OSCC patients relative to their increased TIGIT expression. TIGIT might provide therapeutic implications for future immunotherapy in advanced-stage OSCC patients

Head and neck melanoma: outcome and predictors in a population-based cohort study

Background To evaluate predictive clinico-pathological characteristics on outcome in head and neck melanoma (HNM) in a population-based study with particular emphasis on the prognostic effect of sentinel lymph node biopsy (SLNB), Charlson comorbidity index (CCI) and distinct tumor localisations. Methods Here we primarily describe a retrospective multicenter population-based cohort study with 402 patients having undergone resection with curative intent of HNM between 2010 and 2017. SLNB was used in the diagnosis of 79 HNM patients. Outcome was analyzed, focusing on SLNB, CCI as well as tumor localisation. Overall survival (OAS) und recurrence free survival (RFS) was examined by uni- and multivariate analysis. Results Histopathologically verified lymph node metastasis according to SLNB was associated with impaired RFS in HNM patients (p = 0.004). Especially in higher tumor stages, the sole implementation of SLNB improved survival significantly in the present cohort (p = 0.042). With most of the HNM being located in the face, melanoma of the scalp and neck could be linked to deteriorated patient’s outcome in uni- as well as multivariate analysis (p = 0.021, p = 0.004). Conclusions SLNB is a useful tool in predicting development of distant metastasis after HNM resection with curative intent. Especially in higher tumor stages, performing a SLNB ameliorated survival of HNM patients. Additionally, CCI as well as a distinct tumor localisations in HNM were identified as important risk factors in our population-based cohort study

Riboflavin/UVA Collagen Cross-Linking-Induced Changes in Normal and Keratoconus Corneal Stroma

Purpose To determine the effect of Ultraviolet-A collagen cross-linking with hypo-osmolar and iso-osmolar riboflavin solutions on stromal collagen ultrastructure in normal and keratoconus ex vivo human corneas. Methods Using small-angle X-ray scattering, measurements of collagen D-periodicity, fibril diameter and interfibrillar spacing were made at 1 mm intervals across six normal post-mortem corneas (two above physiological hydration (swollen) and four below (unswollen)) and two post-transplant keratoconus corneal buttons (one swollen; one unswollen), before and after hypo-osmolar cross-linking. The same parameters were measured in three other unswollen normal corneas before and after iso-osmolar cross-linking and in three pairs of swollen normal corneas, in which only the left was cross-linked (with iso-osmolar riboflavin). Results Hypo-osmolar cross-linking resulted in an increase in corneal hydration in all corneas. In the keratoconus corneas and unswollen normal corneas, this was accompanied by an increase in collagen interfibrillar spacing (p<0.001); an increase in fibril diameter was also seen in two out of four unswollen normal corneas and one unswollen keratoconus cornea (p<0.001). Iso-osmolar cross-linking resulted in a decrease in tissue hydration in the swollen normal corneas only. Although there was no consistent treatment-induced change in hydration in the unswollen normal samples, iso-osmolar cross-linking of these corneas did result in a compaction of collagen fibrils and a reduced fibril diameter (p<0.001); these changes were not seen in the swollen normal corneas. Collagen D-periodicity was not affected by either treatment. Conclusion The observed structural changes following Ultraviolet-A cross-linking with hypo-osmolar or iso-osmolar riboflavin solutions are more likely a consequence of treatment-induced changes in tissue hydration rather than cross-linking

A20 as a Potential New Tool in Predicting Recurrence and Patient’s Survival in Oral Squamous Cell Carcinoma

A20, known as a potent inhibitor of NF-κB signaling, has been characterized in numerous clinical as well as preclinical studies. Recently, especially in various malignant diseases, the prognostic and therapeutic relevance of A20 was investigated. In oral squamous cell carcinoma (OSCC) however, the characterization of A20 is uncharted territory. We analyzed a tissue microarray (TMA) of 229 surgically-treated OSCC patients (2003–2013). Immunohistochemical (IHC) stainings were performed for A20 and CD3; additionally, standard haematoxylin-eosin staining was applied. IHC findings were correlated with a comprehensive dataset, comprising clinical and pathohistological information. A20 expression was analyzed in tumor cells as well as in tumor infiltrating lymphocytes (TILs) and correlated with the overall survival (OS) and recurrence-free survival (RFS) using uni- and multivariable Cox regression. The median follow-up time was 10.9 years and the A20 expression was significantly decreased in CD3+ TILs compared to mucosa-infiltrating lymphocytes (MILs). In the Kaplan–Meier analyses, higher A20 expression in TILs was correlated with better OS (p = 0.017) and RFS (p = 0.020). In the multivariable survival analysis, A20 overexpression correlated with improved OS (HR: 0.582; 95% CI 0.388–0.873, p = 0.009) and RFS (HR 0.605; 95% CI 0.411–0.889, p = 0.011). Our results indicate a novel prognostic role for A20 in OSCC. Due to its elevated expression in TILs, further research is highly desirable, which therefore could offer new therapeutic opportunities for patients suffering from OSCC