Differential effects of synthetic sphingosine derivatives on melanoma cell motility, growth, adhesion and invasion in vitro

Cancer cell surface glycosphingolipids are considered to play a critical role in tumor growth and metastasis. However, the implications of glycoconjugates in the control of cell motility, which is considered to be involved in tumor invasion, are not fully understood. In this study, the effects of a series of synthetic sphingosine derivatives, obtained by the chemical transformation of azidosphingosines, on directional migration of K1735-M2 melanoma cells grown on type I collagen-coated surfaces were investigated. Following the application of 60 µm (2R, 3S, 4E)-2,3-epimino-4-octadecen-3-ol (S4) the migration rate was 94 ± 10 m/day, compared with 377 ± 22 µm/day in the control experiment. Six other analogues were not as potent. S4 also considerably down-modulated melanoma single cell motility. Inhibition of motile activity was associated with changes in the actin filament organization as well as with changes in the number and distribution of vinculin plaques. Moreover, the compound reduced the attachment abilities of melanoma cells to basement membrane Matrigel. Tumor cell invasion, however, was less affected and proliferation remained unimpaired after treatment with S4. These data suggest at least one intracellular mode of action of this particular synthetic sphingosine derivative by modulation of cytoskeletal organization. Melanoma cell motility and growth may be controlled independently via glycosphingolipids.     

Recent trends in burn epidemiology worldwide: A systematic review

Burns have been more prevalent among low socioeconomic populations and in less developed regions. Incredible advances in burn care and social development over the recent decades, however, should have placed the incidence and severity of burns in a downwards trend. The aim of this review was to give an overview on current trends in burn epidemiology across the world. Also the socioeconomic development in countries that have published epidemiological data used in this study has been taken into account when comparing the results. There was a worldwide downwards trend of burn incidence, burn severity, length of hospital stay, and mortality rate. These findings were particularly pronounced in very highly developed countries. Data from highly and medium developed countries were more heterogeneous. No studies could be obtained from low and middle income countries. Comparisons between the different studies were compromised by the fact that studies emerged from specialized facilities on one hand and general hospitals on the other. Analyzed studies were also frequently focusing on limited patient populations such as “children” or “elderly”. Our findings indicate the need for an international burn database with a minimal data-set in order to obtain objective and comparable results in respect of burn epidemiology.     

Biological basis of metastasis formation]

Disseminated metastases are the most common cause of death in patients suffering from malignant disease. Tumor cell invasion and metastatic spread have often been considered to indicate an "undifferentiated" state of the tumor cells. In recent years, however, numerous studies point out, that invasiveness and the metastatic cascade are complex, highly differentiated processes based on manyfold interactions of the tumor cells and the surrounding stroma tissue. Changes of the cytoskeleton, adhesion molecules, motility, matrix-degrading enzyme activities, intercellular communication and intracellular signal transduction are considered to regulate the metastatic process. Thus basic research provides insight in pathogenetic mechanisms, which might represent targets for antimetastatic therapy in the future. This would be particularly mandatory in the case of malignant melanoma of the skin, where conventional cytotoxic chemotherapy has been rather disappointing.     

Correlation of image analysis features and visual morphology in melanocytic skin tumours using in vivo confocal laser scanning microscopy

Background/purpose: In vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the non-invasive examination of skin cancer morphology at a quasi histological resolution without biopsy. Previous studies dealt with the search for diagnostic, but subjective visual criteria. In this study we examined the correlation between objectively reproducible image-analysis features und visual morphology in melanocytic skin tumours using CLSM.
Methods: Eight hundred and fifty-seven CLSM tumour images including 408 benign nevi and 449 melanoma images were evaluated. Image analysis was based on features of the wavelet transform and classification tree analysis (CART) was used for classification purposes. In a second step, morphologic details of CLSM images, which have turned out to be of diagnostic significance by the classification algorithm were evaluated.
Results: CART analysis of the whole set of CLSM images correctly classified 97.55% of all melanoma images and 96.32% of all nevi images. Seven classification tree nodes seemed to indicate benign nevi, whereas six nodes were suggestive for melanoma morphology. The visual examination of selected nodes demonstrated that monomorphic melanocytic cells and melanocytic cell nests are characteristic for benign nevi whereas polymorphic melanocytic cells, disarray of melanocytic architecture and poorly defined or absent keratinocyte cell borders are characteristic for melanoma.
Conclusion: Well-known, but subjective CLSM criteria could be objectively reproduced by image analysis features and classification tree analysis. Moreover, features not accessible to the human eye seem to contribute to classification success.     

Differences in intraosseous and extraosseous post-chemotherapy regression of Ewing sarcomas and their influence on prognosis

BackgroundIn Ewing sarcomas (ES), histological response to polychemotherapy is the main prognostic factor. We aimed at evaluating the histological response separately for the extraosseous and intraosseous tumor compartment as well as its prognostic influence.MethodsThirty-one patients with ES and marked soft tissue expansion, treated at our department between January 2006 and December 2015, were retrospectively included. Data was taken from medical records. Original histologic specimens of the resected tumors were re-evaluated separately for intra- and extraosseous tumor regression according to Salzer-Kuntschik regression grading. Multivariate survival analysis with stepwise backward variable selection was calculated to determine the impact of extraosseous and intraosseous regression on prognosis.ResultsAll patients had received chemotherapy, 15 (48.4%) had been administered preoperative radiotherapy. Extraosseous tumor regression was significantly worse than intraosseous regression (Wilcoxon signed-rank test, p = 0.018). While neither intraosseous nor extraosseous tumor regression had an impact on overall survival, extraosseous complete remission had a beneficial impact on event-free-survival in the multivariate analysis (Cox-regression; hazard ratio: 0.148, 95% confidence interval 0.031-0.707, p = 0.017).ConclusionsOn average, regression of ES seems to be worse in the extraosseous tumor compartment following preoperative chemotherapy. Moreover, extraosseous tumor regression may have a stronger prognostic influence on event-free survival than intraosseous regression.     

Asymptomatic primary malignant melanoma of the esophagus

BACKGROUND: Primary malignant melanoma of the esophagus is an exceedingly rare disease. This tumor is typically aggressive and disseminates early via the lymphatics and the bloodstream with a mean survival time between 10 and 15 months after radical surgical resection. The role of chemotherapy and immunotherapy is unclear. No treatment plan for the disease has yet been established. CASE REPORT: A 78-year-old man came for a checkup with a medical history of reflux esophagitis and chronic gastritis. Esophagogastroscopy showed a bluishgray tumor of the esophagus, and histology revealed features consistent with malignant melanoma. The patient underwent total transhiatal esophagectomy with curative intention, and esophagogastric anastomosis was performed. Immunohistochemistry revealed tumor cells strongly positive for the melanoma-specific antigen HMB45 and protein S-100, and negative for cytokeratin. A proposed postoperative chemotherapy was declined by the patient. Nine months after surgery, the patient's condition deteriorated, and a mediastinal lymph node conglomerate was found. Two months later, he died of bleeding into the cervical soft tissue. CONCLUSION: Up to date, radical surgical resection is the main treatment. Very little is known about the benefits of chemotherapy and immunotherapy. However, these therapeutic modalities may play an important role in the future.     

Evaluating the British sarcoma referral form

IntroductionThis study investigated the accuracy of general practitioner (GP) referrals under the two-week wait pathway for soft tissue sarcomas and whether the current National Institute for Health and Care Excellence criteria should be refined.MethodsAll patients referred under the two-week wait system to one centre over the course of one year were reviewed. Comparison was made between the criteria identified by the GP and those confirmed by the centre to assess the accuracy of the referrals, and to identify what criteria predicted malignancy.ResultsOverall, 135 patients were referred to our unit with a mean age of 56.4 years. Of these, 45 (33%) were found to have a malignant tumour. Factors identified by the GP were accurate in 74% of cases. The best predictor of malignancy was ‘size >5cm’ (76% sensitivity) while ‘pain’ was the least useful (27% sensitivity). Lowering the threshold for concern to a size of >4cm increased sensitivity to 89%. Although 106 patients had undergone some form of imaging prior to referral, this did not increase the likelihood of malignancy being detected. The combination of factors most likely to predict malignancy was a size of >5cm, increase in size, deep location and no pain (10 out of 13 referrals, 77% accuracy).ConclusionsBased on the results of this study, we recommend an adaption of the existing features for concern. The new feature for concern should be ‘size >4cm’ and the factor ‘pain’ should be removed from the urgent referral form.     

Non-invasive imaging of tissue PO2 in malignant melanoma of the skin

In various tumor systems, decreased PO2 values have been demonstrated by various methods. This study addresses the question of whether tumor hypoxia can be found in cutaneous melanoma using lifetime imaging of non-invasive sensors showing phosphorescence quenched by oxygen. Twenty-three cases of cutaneous malignant melanoma (average tumor thickness 1.25 mm, range 0.5-8 mm) were examined using the SkinCam lifetime imaging system for the assessment of cutaneous PO2 levels within the tumors and in adjacent clinically normal skin. For comparison, 30 non-melanoma skin tumors were evaluated. In 15 exploitable melanoma cases, the average hypoxic difference of the lesion compared with the surrounding skin was -10 mmHg, typically associated with an inhomogeneous distribution. Only 10% of the non-melanoma lesions showed a similar hypoxia (false positives). The SkinCam equipment uses a non-invasive imaging method and provides further diagnostic hints in the assessment of benign and malignant skin tumors.     

Calculated tumour volume as a prognostic parameter for survival in choroidal melanomas

PURPOSE: Tumour diameter, tumour height, and tumour volume are considered important prognostic indicators of survival in choroidal melanomas. In this study, we investigated the prognostic impact on survival of the easily calculated volume estimate based on the assumption of a half-rotation ellipsoid. METHODS: The largest tumour diameter and tumour height were measured by ultrasound A- and B-scan in 93 patients with choroidal melanoma. Tumour volume was calculated by the half volume of a rotation ellipsoid formula, rotated around the y-axis, and compared to tumour diameter and tumour height. All parameters were correlated to the clinical outcome of the patients. RESULTS: At the time of diagnosis, the mean diameter was 10.4 mm (range 4.1-18.9 mm), and the mean height was 5.7 mm (range 1.74-14.9 mm). The range of the calculated tumour volume was between 11 and 628 mm(3) (mean volume 190 mm(3)). Among all patients, distant metastases occurred in 10 patients (10.8%). In a univariate approach using Mantel-Haenszel log-rank test, the calculated tumour volume at the time of diagnosis was the best prognostic indicator of survival followed by tumour diameter and tumour height (P=0.028). When tumour volume, horizontal and vertical tumour diameter, age, sex, and primary tumour therapy were considered in a multivariate approach using Cox proportional Hazard model, only tumour volume turned out as a significant prognostic parameter (P=0.001). CONCLUSIONS: Calculated tumour volume is a better prognostic indicator of survival of patients with choroidal melanomas than the largest tumour diameter and tumour height, and might be established in daily routine.