Reactive Species Risk Assessment Using Optimized HET-CAM Safety Evaluation of Feed Gas-Modified Gas Plasma Technology and Anticancer Drugs.

Clinical therapies, including dermatology and oncology, require safe application. In vitro experiments allow only limited conclusions about in vivo effects, while animal studies in, e.g., rodents have ethical constraints at a large scale. Chicken embryos lack pain reception until day 15 postfertilization, making the in ovo model a suitable alternative to in vivo safety assessment. In addition, the hen's egg test on chorioallantoic membrane assay allows irritation potential analysis for topical treatments, but standardized analysis has been limited so far. Medical gas plasma is a topical, routine, approved dermatology treatment. Recent work suggests the potential of this technology in oncology. Its main mode of action is the release of various reactive species simultaneously. Intriguingly, varying plasma feed gas compositions generates customized reactive species profiles previously shown to be optimized for specific applications, such as skin cancer treatment. To support clinical implications, we developed a novel chicken embryo CAM scoring and study scheme and employed the model to analyze 16 different plasma feed gas settings generated by the atmospheric pressure plasmajet kINPen, along with common anticancer drugs (e.g., cisplatin) and physiological mediators (e.g., VEGF). Extensive gas- and liquid-phase plasma reactive species profiling was done and was found to have a surprisingly low correlation with irritation potential parameters. Despite markedly different reactive species patterns, feed gas-modulated kINPen plasma was equally tolerated compared to standard argon plasma. CAM irritation with gas plasmas but not anticancer agents was reversed 48 h after treatment, underlining the only temporary tissue effects of medical gas plasma. Our results indicate a safe therapeutic application of reactive species.

Combined ultrasound and photoacoustic C-mode imaging system for skin lesion assessment.

Accurate assessment of the size and depth of infiltration is critical for effectively treating and removing skin cancer, especially melanoma. However, existing methods such as skin biopsy and histologic examination are invasive, time-consuming, and may not provide accurate depth results. We present a novel system for simultaneous and co-localized ultrasound and photoacoustic imaging, with the application for non-invasive skin lesion size and depth measurement. The developed system integrates an acoustical mirror that is placed on an ultrasound transducer, which can be translated within a flexible water tank. This allows for 3D (C-mode) imaging, which is useful for mapping the skin structure and determine the invasion size and depth of lesions including skin cancer. For efficient reconstruction of photoacoustic images, we applied the open-source MUST library. The acquisition time per 2D image is <1 s and the pulse energies are below the legal Maximum Permissible Exposure (MPE) on human skin. We present the depth and resolution capabilities of the setup on several self-designed agar phantoms and demonstrate in vivo imaging on human skin. The setup also features an unobstructed optical window from the top, allowing for simple integration with other optical modalities. The perspective towards clinical application is demonstrated.

Evaluation of Choroidal Melanoma Vascularization by Color Doppler Flow Imaging: An Option for Follow-Up Tumor Control Assessment after CyberKnife®?

Background and Objectives: Thus far, tumor control for choroidal melanoma after teletherapeutic radiation is clinically difficult. In contrast to brachytherapy, the tumor height does not necessarily have to shrink as a result of teletherapy. Therefore, the objective of this study was to evaluate tumor vascularization determined by color Doppler flow imaging (CDFI) as a possible approach for monitoring the therapy response after teletherapy of choroidal melanoma. Materials and Methods: A single-center retrospective pilot study of 24 patients was conducted, all of whom had been diagnosed with choroidal neoplasm, treated and followed up. Besides tumor vascularization, the following parameters were collected: age, gender, tumor entity, location, radiation dose, knowledge of relapse, tumor height, radiation-related complications, occurrence of metastases, visual acuity in logMAR. Results: The level of choroidal melanoma vascularization markedly decreased in all included subjects after treatment with the CyberKnife® technology. Initially, the level of vascularization was 2.1 (SD: 0.76 for n = 10); post-therapeutically, it averaged 0.14 (SD: 0.4). Regarding the tumor apex, CDFI sonography also demonstrated a significant tumor regression (mean value pre-therapeutically: 8.35 mm-SD: 3.92 for n = 10; mean value post-therapeutically: 4.86 mm-SD: 3.21). The level of choroidal melanoma vascularization declined in the patient collective treated with ruthenium-106 brachytherapy. The pre-therapeutic level of vascularization of 2 (SD: 0 for n = 2) decreased significantly to a level of 0 (mean: 0-SD: 0). The tumor height determined by CDFI did not allow any valid statement regarding local tumor control. In contrast to these findings, the patient population of the control group without any radiation therapy did not show any alterations in vascularization. Conclusions: Our data suggest that the determination of the tumor vascularization level using CDFI might be a useful and supplementary course parameter in the follow-up care of choroidal melanoma to monitor the success of treatment. This especially applies to robot-assisted radiotherapy using CyberKnife®. Further studies are necessary to validate the first results of this assessment.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Assessment of melanoma histotypes and associated patient related factors: basis for a predictive statistical model.

BACKGROUND: Certain melanoma histotypes carry a worse prognosis than others. We aimed to identify patient related factors associated with specific melanoma histotypes. PATIENTS AND METHODS: Single center study including 347 melanoma patients, prospectively assessed for 22 variables leading to a database of more than 7,600 features. RESULTS: Melanomas were histologically categorized as superficial spreading (SSM, 70.6%), nodular (NM; 12.7%), acrolentiginous (ALM; 4.0%), lentigo maligna (LMM; 3.8%), or unclassified melanoma (UCM; 8.9%). Well recognized melanoma risk indicators (i. e. many atypical nevi, freckles, previous melanoma), were significantly associated with SSM and LMM histotypes. NM and ALM patients carried significantly less common and/or atypical nevi. NM were mostly self-detected or detected by relatives. In contrast, SSM, LMM, and ALM were most frequently detected by dermatologists. NM and UCM were preferentially located on poorly observable sites, SSM on the lower limbs, ALM on plantar sites, and LMM on the head and neck. ALM and LMM patients were significantly older than other patients. A multinomial logistic model was designed to predict a certain melanoma histotype (overall accuracy 81%), which could be helpful to focus the attention of clinicians or may be integrated into fully automated diagnostic algorithms. CONCLUSIONS: Melanoma histotypes show significant differences regarding patients' characteristics.

Selection of patients for long-term surveillance with digital dermoscopy by assessment of melanoma risk factors.

OBJECTIVE: To identify patients at increased melanoma risk who benefit from long-term surveillance with digital dermoscopy. DESIGN: Prospective, nonrandomized, observational study. SETTING: University-based surveillance program. PARTICIPANTS: Six hundred eighty-eight patients prospectively categorized into defined melanoma risk groups and followed up (mean, 44.3 months) by clinical examinations, dermoscopy, and, for atypical nevi, sequential digital dermoscopy. MAIN OUTCOME MEASURE: Association between patient risk factors and detection of melanomas. RESULTS: Odds ratios from a multivariate logistic regression analysis indicated a highly increased melanoma risk for patients with familial atypical mole and multiple melanoma (FAMMM) syndrome, atypical mole syndrome (AMS), or previous melanoma. Each digitally documented atypical lesion (range, 1-17 lesions per patient) denoted a significant 10% increase in melanoma risk. Patients with higher melanoma risk (1) showed a higher percentage of melanomas detected by digital dermoscopy (FAMMM syndrome group, 50%; AMS group, 22%), (2) more often developed multiple melanomas within shorter intervals, and (3) showed a ratio of melanoma to benign results for lesions excised because of dynamic changes of 1:15 (AMS group) or 1:4 (FAMMM syndrome group). Melanomas detected by digital dermoscopy were significantly thinner (0.41 mm in mean Breslow thickness) compared with melanomas detected by other means (0.62 mm; P = .04). CONCLUSIONS: We suggest an individualized surveillance plan, with digital dermoscopy performed at follow-up intervals of 3 months for patients with FAMMM syndrome and 6 to 12 months (depending on additional risk factors) for those with AMS. Patients with multiple common nevi and no additional risk factors had no benefit from sequential digital dermoscopy.

Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case-control study.

Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma. We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area. We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28). The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.