Werner Adler

Split Cornea Transplantation : Relationship between Storage Time of Split Donor Tissue and Outcome

PURPOSE To analyze the relationship between storage time of split donor tissue and outcomes after deep anterior lamellar keratoplasty (DALK) and Descemets membrane endothelial keratoplasty (DMEK). DESIGN Retrospective analysis of a nonrandomized, consecutive, interventional case series. PARTICIPANTS One hundred ten eyes with anterior stromal disease suitable for DALK and 110 eyes with endothelial disease suitable for DMEK underwent surgically successful split cornea transplantation combining both procedures within 7 days after splitting. METHODS Split donor storage times (splitting to grafting) and total storage times (death to grafting) were correlated with the 1-year functional and morphologic outcomes after DALK and DMEK surgery using a Spearman correlation coefficient and a Mann-Whitney U test. MAIN OUTCOME MEASURES Best spectacle-corrected visual acuity (BSCVA), endothelial cell density, and complication rates within 12 months of follow-up. RESULTS The mean split donor storage time was 35 ± 47 hours (range, 0-162 hours) after splitting for anterior donor grafts and 21 ± 40 hours (range, 0-158 hours) for posterior grafts. The mean total storage time was 352 ± 108 hours (range, 108-678 hours) for anterior lamellas and 339 ± 109 hours (range, 96-630 hours) for posterior lamellas. One year after DALK, the mean BSCVA was 20/30 (range, 20/50-20/20), endothelial cell loss was 8% (range, 2%-16%), and the complication rate (Descemets folds, epitheliopathy, loose sutures) was 18%. One year after DMEK, the mean BSCVA was 20/25 (range, 20/40-20/16), endothelial cell loss was 41% (range, 17%-63%), and the complication rate (partial graft detachment) was 62%. For DALK and DMEK, no significant association was observed between split donor storage time as well as total storage time and BSCVA (P ≥ 0.409), endothelial cell loss (P≥0.236), or complication rate (P ≥ 0.647) within 1 year of follow-up. CONCLUSIONS Anterior and posterior donor tissue may be stored safely for up to 1 week in organ culture before use in DALK and DMEK surgery. This simplifies the clinical feasibility of split cornea transplantation to reduce donor shortage and cost in corneal transplantation in the future. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Intraocular Tumor-Associated Lymphangiogenesis: A Novel Prognostic Factor for Ciliary Body Melanomas with Extraocular Extension?

PURPOSE To evaluate whether intraocular tumor-associated lymphangiogenesis contributes to prognosis of ciliary body melanomas with extraocular extension and to study its association with other tumor characteristics. DESIGN Nonrandomized, retrospective case series. PARTICIPANTS Twenty consecutive patients enucleated for a malignant melanoma of the ciliary body with extraocular extension. METHODS Lymphatic vessels were identified using lymphatic vascular endothelial-specific hyaluronic acid receptor-1 (LYVE-1) and podoplanin as specific immunohistochemical markers for lymphatic vascular endothelium. Baseline tumor characteristics included intra- and extraocular tumor size, 2009 tumor, node, metastasis (TNM) classification, route of extraocular spread, tumor cell type, mitotic rate, Ki-67 proliferation-index, microvascular patterns and density, tumor-infiltrating lymphocytes and macrophages, and expression of human leukocyte antigen (HLA) class I and insulin-like growth factor-1 receptor. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed. MAIN OUTCOME MEASURES Prevalence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels and association with intraocular tumor characteristics and metastasis-free survival. RESULTS Intraocular LYVE-1(+) and podoplanin(+) lymphatic vessels could be detected in 12 (60%) of 20 ciliary body melanomas with extraocular extension. Presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels was significantly associated with larger intra- (P = 0.002) and extraocular tumor size (P<0.001), higher TNM categories (P = 0.004), epithelioid cellularity (P = 0.016), higher mitotic rate (P = 0.003), higher Ki-67 proliferation-index (P = 0.049), microvascular networks (P = 0.005), higher microvascular density (P = 0.003), more tumor-infiltrating macrophages (P = 0.002), higher expression of HLA class I (P = 0.046), and insulin-like growth factor-1 receptor (P = 0.033), but not significantly with route of extraocular spread (P = 0.803), and tumor-infiltrating lymphocytes (P = 0.069). Melanoma-specific mortality rates increased significantly with the presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels (P = 0.008). By multivariate Cox regression, tumor size (hazard ratio, 14.40; P = 0.002), and presence of intraocular lymphatic vessels (hazard ratio, 8.09; P = 0.04) were strong prognostic predictors of mortality. CONCLUSIONS Intraocular peritumoral lymphangiogenesis seems to be associated with an increased mortality risk in patients with ciliary body melanomas and extraocular extension. This association may be primarily because of an association of intraocular lymphangiogenesis with greater tumor size and increased malignancy.

Prognostic Significance of Tumor-Associated Lymphangiogenesis in Malignant Melanomas of the Conjunctiva

PURPOSE To evaluate whether tumor-associated lymphangiogenesis contributes to prognosis of conjunctival malignant melanomas and to study its association with other tumor characteristics. DESIGN Nonrandomized, retrospective case series. PARTICIPANTS A total of 109 consecutive patients with primary conjunctival malignant melanoma. METHODS Proliferating lymphatic vessels were identified immunohistochemically using lymphatic vascular endothelial hyaluronan receptor-1 and podoplanin as specific lymphatic endothelial markers and Ki-67 as proliferation marker. Baseline tumor characteristics included tumor location, tumor thickness, tumor diameter, tumor origin, and tumor growth pattern. Kaplan-Meier and Cox regression analyses of the risk of local recurrence, lymphatic spread, distant metastasis, and melanoma-related death were performed. MAIN OUTCOME MEASURES Intratumoral lymphatic vascular density and its association with tumor characteristics and recurrence-free, lymphatic spread-free, distant metastasis-free, and melanoma-specific survival. RESULTS Intratumoral and peritumoral proliferating lymphatic vessels could be detected in all of the 109 conjunctival melanoma samples. High intratumoral lymphatic density was significantly associated with palpebral tumor location (P<0.001), greater tumor thickness (P<0.001), larger tumor diameter (P = 0.001), tumor origin de novo (P = 0.002), and nodular tumor growth pattern (P = 0.037). Patients with high intratumoral lymphatic density revealed significantly lower recurrence-free, lymphatic spread-free, distant metastasis-free, and melanoma-specific survival rates (P<0.001 for all). By multivariate Cox regression, factors predictive of local recurrence included palpebral tumor location (hazard ratio [HR] 2.66, P = 0.014), large tumor diameter (HR 5.48, P<0.001), and high intratumoral lymphatic density (HR 2.48, P = 0.043); factors predictive of lymphatic spread included palpebral tumor location (HR 4.13, P = 0.009), high tumor thickness (HR 12.17, P<0.001), and high intratumoral lymphatic density (HR 6.79, P = 0.019); factors predictive of distant metastasis included palpebral tumor location (HR 7.63, P<0.001), high tumor thickness (HR 8.60, P<0.001), large tumor diameter (HR 0.30, P = 0.029), and high intratumoral lymphatic density (HR 8.90, P = 0.047); and factors predictive of melanoma-related death included palpebral tumor location (HR 7.74, P<0.001), high tumor thickness (HR 10.88, P<0.001), large tumor diameter (HR 0.28, P = 0.018), and, with borderline significance, high intratumoral lymphatic density (HR 8.46, P = 0.052). CONCLUSIONS Tumor-associated lymphangiogenesis seems to be associated with an increased risk of local recurrence, lymphatic spread, distant metastasis, and melanoma-related death in patients with conjunctival malignant melanomas. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Tumor-associated lymphangiogenesis in the development of conjunctival melanoma.

PURPOSE To analyze whether tumor-associated lymphangiogenesis is concurrent with the progression of premalignant conjunctival melanocytic intraepithelial neoplasia (C-MIN) into invasive conjunctival melanoma (CM) and to study its association with prognosis. METHODS Twenty patients with CM were closely matched with 20 patients with C-MIN with atypia and 20 with C-MIN without atypia regarding tumor size, tumor location, tumor extension, and patients age. All conjunctival specimens were analyzed for the immunohistochemical presence of proliferating lymphatic vessels, with LYVE-1 and podoplanin used as specific lymphatic endothelial markers and Ki-67 as a proliferation marker. Lymphatic vascular density was measured within the mass (intratumoral) and within an area ≤ 500 μm from the tumor border (peritumoral) and was correlated with recurrence, metastasis, and survival rates. RESULTS Intratumoral and peritumoral proliferating lymphatic vessels were detected in none of the C-MINs without atypia, in 10 of the 20 C-MINs with atypia, and in all 20 CMs. Invasive CM showed a significantly higher intra- and peritumoral density of proliferating lymphatics than did C-MIN with atypia (P ≤ 0.001). Patients with high intratumoral lymphatic density revealed significantly lower recurrence-free survival rates (P = 0.041) in C-MIN with atypia and significantly lower recurrence-free (P = 0.006), lymphatic-spread-free (P = 0.041), distant-metastasis-free (P = 0.029), and melanoma-specific survival rates (P = 0.029) in CM. CONCLUSIONS Development of CM from premalignant precursors is concurrent with the outgrowth of lymphatic vessels. This active lymphangiogenesis seems to be associated with an increased risk of local recurrence in patients with C-MIN with atypia and with an increased risk of local recurrence, lymphatic spread, distant metastasis, and tumor-related death in patients with invasive CM.

Is there a need for autogenous blood donation in orthognathic surgery

Background: The present study sought to determine the frequency of blood transfusion and to evaluate the need for autogenous blood donations in patients undergoing bimaxillary orthognathic surgery. Methods: According to an inclusion and exclusion protocol, 65 patients were selected for further analysis. Twenty-six patients donated a total of 45 units of autogenous blood; the remaining 39 patients did not. Medical records were reviewed retrospectively. Results: Donors tended to have lower preoperative, intraoperative, and postoperative hemoglobin values, as well as lower hematocrit and leukocyte counts. Only the difference in mean preoperative leukocyte count, however, was statistically significant (donor: 6500/&mgr;l versus nondonor: 7400/&mgr;l; p = 0.021). The rate of transfusion was 2.5 percent for nondonors and 13 percent for donors of autogenous blood. Six donors had to be transfused a total of 8 units of autogenous blood, whereas only one of 39 nondonors received an allogenic blood transfusion. This difference turned out to be significant according to Fishers exact test (p = 0.013). None of the donors received allogenic blood transfusion. Conclusions: In the authors’ analysis, preoperative autogenous blood donation appears to be effective in reducing exposure to allogenic blood. Donors of autogenous blood, however, were transfused significantly more often than nondonors were. Neither intraoperative blood loss nor hematological values justify a preoperative donation of autogenous blood on a regular basis.

Optical nerve detection by diffuse reflectance spectroscopy for feedback controlled oral and maxillofacial laser surgery.

BackgroundLaser surgery lacks haptic feedback, which is accompanied by the risk of iatrogenic nerve damage. It was the aim of this study to investigate diffuse reflectance spectroscopy for tissue differentiation as the base of a feedback control system to enhance nerve preservation in oral and maxillofacial laser surgery.MethodsDiffuse reflectance spectra of nerve tissue, salivary gland and bone (8640 spectra) of the mid-facial region of ex vivo domestic pigs were acquired in the wavelength range of 350-650 nm. Tissue differentiation was performed using principal component (PC) analysis followed by linear discriminant analysis (LDA). Specificity and sensitivity were calculated using receiver operating characteristic (ROC) analysis and the area under curve (AUC).ResultsFive PCs were found to be adequate for tissue differentiation with diffuse reflectance spectra using LDA. Nerve tissue could be differed from bone as well as from salivary gland with AUC results of greater than 88%, sensitivity of greater than 83% and specificity in excess of 78%.ConclusionsDiffuse reflectance spectroscopy is an adequate technique for nerve identification in the vicinity of bone and salivary gland. The results set the basis for a feedback system to prevent iatrogenic nerve damage when performing oral and maxillofacial laser surgery.

Bootstrap estimated true and false positive rates and ROC curve

Diagnostic studies and new biomarkers are assessed by the estimated true and false positive rates of the classification rule. One diagnostic rule is considered for high-dimensional predictor data. Cross-validation and the leave-one-out bootstrap are discussed to estimate true and false positive rates of classifiers by the machine learning methods Adaboost, Bagging, Random Forest, (penalized) logistic regression and support vector machines. The .632+ bootstrap estimation of the misclassification error has been previously proposed to adjust the overfitting of the apparent error. This idea is generalized to the estimation of true and false positive rates. Tree-based simulation models with 8 and 50 binary non-informative variables are analysed to examine the properties of the estimators. Finally, a bootstrap estimation of receiver operating characteristic (ROC) curves is suggested and a .632+ bootstrap estimation of ROC curves is discussed. This approach is applied to high-dimensional gene expression data of leukemia and predictors of image data for glaucoma diagnosis.

Diffuse reflectance spectroscopy for optical soft tissue differentiation as remote feedback control for tissue-specific laser surgery.

Laser surgery does not provide haptic feedback for operating layer‐by‐layer and thereby preserving vulnerable anatomical structures like nerve tissue or blood vessels. Diffuse reflectance spectra can facilitate remote optical tissue differentiation. It is the aim of the study to use this technique on soft tissue samples, to set a technological basis for a remote optical feedback system for tissue‐specific laser surgery.

In vivo optical tissue differentiation by diffuse reflectance spectroscopy: preliminary results for tissue-specific laser surgery.

Objectives. Laser surgery requires feedback to avoid the accidental destruction of critically important tissues. It was the aim of the authors to identify different tissue types in vivo by diffuse reflectance spectroscopy to set the basis for tissue-specific control of laser surgery. Methods. Tissue differentiation was performed on in vivo tissue of rats (skin, fat, muscle, and nerve) by diffuse reflectance spectroscopy between 350 and 650 nm. Data analysis was done using principal components analysis, followed by linear discriminant analysis (LDA). The differentiation performance was evaluated by receiver operating characteristic (ROC) analysis. Results. ROC analysis showed a tissue differentiation of 100%, with a high sensitivity of more than 99%. Only the tissue pair skin/fat showed a reduced differentiation performance and specificity. Conclusion. The results show the general viability of in vivo optical tissue differentiation and create a basis for the further development of a control system for tissue-specific laser surgery.

Corneal nerve alterations in different stages of Fuchs’ endothelial corneal dystrophy: an in vivo confocal microscopy study

PurposeTo analyze potential alterations in corneal nerve morphology and function in different stages of Fuchs’ endothelial corneal dystrophy (FECD).MethodsThirty eyes with FECD underwent in vivo confocal microscopy using the Heidelberg Retina Tomograph II (HRT II; Heidelberg Engineering, Heidelberg, Germany) and the Rostock Cornea Module (RCM) to quantify the morphology of the central subbasal corneal nerve plexus (total nerve length, total nerve number, number of main nerve trunks, number of nerve branches) as well as esthesiometry (using the Cochet-Bonnet esthesiometer) of the central cornea to determine central corneal sensation as a measure of nerve function. Findings were correlated with an age-matched control group of 30 healthy individuals. Comparisons to biomicroscopical stage of FECD, visual acuity and central corneal thickness were performed using Spearman correlation.ResultsDepending on slit-lamp examination, all 30 eyes were classified into FECD stage 1–4 (stage 1: six eyes; stage 2: 15 eyes; stage 3: six eyes; stage 4: three eyes). Total nerve length (ρ = −0.8, p < 0.001), total nerve number (ρ = −0.7, p < 0.001), number of main nerve trunks (ρ = −0.6, p < 0.001), and number of nerve branches (ρ = −0.7, p < 0.001) decreased significantly with increasing FECD stages. Comparing to the visual acuity, significant positive correlations were found for total nerve length (ρ = 0.5, p = 0.012), total nerve number (ρ = 0.5, p = 0.005), number of main nerve trunks (ρ = 0.4, p = 0.017), and number of nerve branches (ρ = 0.5, p = 0.009). With central corneal thickness, there were significant inverse correlations for total nerve length (ρ = −0.6, p = 0.001), total nerve number (ρ = −0.5, p = 0.012), number of main nerve trunks (ρ = −0.4, p = 0.015), and number of nerve branches (ρ = −0.4, p = 0.017). Central corneal sensation was full in all FECD stage 1, stage 2 and stage 3 eyes, but mildly reduced in FECD stage 4 eyes.ConclusionsIncreasing severity of Fuchs’ endothelial corneal dystrophy (FECD) is concurrent with marked attenuation of the density, as well as mild diminishment of the function, of the subbasal corneal nerve plexus in late stage of the disease.