Ablative Fractional Laser Enhances Artificial or Natural Daylight Photodynamic Therapy of Actinic Field Cancerization: A Randomized and Investigator-initiated Half-side Comparative Study.

Artificial daylight photodynamic therapy is a near-painless treatment for actinic keratoses, which can be performed indoors using a controlled light dose. Daylight photodynamic therapy is approved only for treatment of grade I-II actinic keratoses. The aim of this study was to evaluate whether fractional laser pre-treatment improves the outcomes of daylight photodynamic therapy for actinic keratoses of all grades. In addition, the study compared the outcomes of artificial and natural daylight photodynamic therapy. This randomized single-blinded split-side comparative study included 60 patients with ≥ 2 actinic keratoses of the head. Fractional laser pre-treatment was assigned randomly for actinic keratoses on 1 side of the head and, subsequently, the entire treatment area was treated with artificial or natural daylight photodynamic therapy. Fractional laser-mediated daylight photodynamic therapy achieved significantly higher complete clearance (50.0% vs 30.3%, p = 0.04), partial clearance (78.6% vs 50.0%, p < 0.01) and lesion-specific clearance (86.2% vs 70.2%, p < 0.01) than daylight photodynamic therapy alone at the 6-month follow-up. No significant differences were found in the outcomes of artificial vs natural daylight photodynamic therapy or grade I lesions vs grade II-III lesions. Thus, fractional laser pre-treatment appears to significantly increase the efficacy of artificial and natural daylight photodynamic therapy, and to be suitable for treatment of actinic keratoses of all grades.

Hyperspectral Imaging for Non-invasive Diagnostics of Melanocytic Lesions.

Malignant melanoma poses a clinical diagnostic problem, since a large number of benign lesions are excised to find a single melanoma. This study assessed the accuracy of a novel non-invasive diagnostic technology, hyperspectral imaging, for melanoma detection. Lesions were imaged prior to excision and histopathological analysis. A deep neural network algorithm was trained twice to distinguish between histopathologically verified malignant and benign melanocytic lesions and to classify the separate subgroups. Furthermore, 2 different approaches were used: a majority vote classification and a pixel-wise classification. The study included 325 lesions from 285 patients. Of these, 74 were invasive melanoma, 88 melanoma in situ, 115 dysplastic naevi, and 48 non-dysplastic naevi. The study included a training set of 358,800 pixels and a validation set of 7,313 pixels, which was then tested with a training set of 24,375 pixels. The majority vote classification achieved high overall sensitivity of 95% and a specificity of 92% (95% confidence interval (95% CI) 0.024-0.029) in differentiating malignant from benign lesions. In the pixel-wise classification, the overall sensitivity and specificity were both 82% (95% CI 0.005-0.005). When divided into 4 subgroups, the diagnostic accuracy was lower. Hyperspectral imaging provides high sensitivity and specificity in distinguishing between naevi and melanoma. This novel method still needs further validation.

Differentiating Malignant from Benign Pigmented or Non-Pigmented Skin Tumours-A Pilot Study on 3D Hyperspectral Imaging of Complex Skin Surfaces and Convolutional Neural Networks.

Several optical imaging techniques have been developed to ease the burden of skin cancer disease on our health care system. Hyperspectral images can be used to identify biological tissues by their diffuse reflected spectra. In this second part of a three-phase pilot study, we used a novel hand-held SICSURFIS Spectral Imager with an adaptable field of view and target-wise selectable wavelength channels to provide detailed spectral and spatial data for lesions on complex surfaces. The hyperspectral images (33 wavelengths, 477-891 nm) provided photometric data through individually controlled illumination modules, enabling convolutional networks to utilise spectral, spatial, and skin-surface models for the analyses. In total, 42 lesions were studied: 7 melanomas, 13 pigmented and 7 intradermal nevi, 10 basal cell carcinomas, and 5 squamous cell carcinomas. All lesions were excised for histological analyses. A pixel-wise analysis provided map-like images and classified pigmented lesions with a sensitivity of 87% and a specificity of 93%, and 79% and 91%, respectively, for non-pigmented lesions. A majority voting analysis, which provided the most probable lesion diagnosis, diagnosed 41 of 42 lesions correctly. This pilot study indicates that our non-invasive hyperspectral imaging system, which involves shape and depth data analysed by convolutional neural networks, is feasible for differentiating between malignant and benign pigmented and non-pigmented skin tumours, even on complex skin surfaces.

Pulsed Dye Laser-mediated Photodynamic Therapy is Less Effective than Conventional Photodynamic Therapy for Actinic Field Cancerization: A Randomized Half-side Comparative Study.

Previous research presents pulsed dye laser-mediated photodynamic therapy as a promising alternative to conventional red-light photodynamic therapy. In this study, 60 patients with 2 or more actinic keratoses randomly received either of these treatments on each side of the head. A physician blinded to the treatment evaluated treatment response at 6 months for each lesion, as completely, partially or not healed. Significantly lower complete clearance rates (10.3% vs 44.9%) and lesion-specific complete clearance rates were found for pulsed dye laser-mediated photodynamic therapy (47.9%) vs conventional red-light photodynamic therapy (73.4%). Significantly lower pain scores were found for pulsed dye laser-mediated photodynamic therapy, with a mean numerical rating of 2.3, compared with 4.1 for conventional red-light photodynamic therapy. The study population had a mean of 7.9 lesions, and 78% of patients had been treat-ed previously for actinic keratoses on the treatment area. To conclude, in a population with severe sun dam-age, pulsed dye laser-mediated photodynamic therapy seems less effective than conventional red-light photo-dynamic therapy. Pulsed dye laser-mediated photodynamic therapy may still be a treatment option for patients who are not compliant with conventional red-light photodynamic therapy.

Evaluating complications in below-knee skin cancer surgery after introduction of preoperative appointments: A 2-year retrospective cohort study.

Below-knee dermatological surgery has a high risk of complications such as wound infection, bleeding, and necrosis. In this study, we evaluated the impact of preoperative appointments on complication risks. We searched the medical records of the Helsinki University Central Hospital (HUS) Dermatosurgery unit for all below-knee surgeries during 2016, when no preoperative nurse appointments were carried out, and compared it with 2018, when preoperative appointments for risk patients were introduced. The study included 187 patients in 2016 and 179 patients in 2018, of whom 68 (about one third) attended preoperative appointments. At the appointments, risk factors were evaluated, and compression therapy was introduced when possible. The results show complication rates of 13.4% in 2016 vs 10.1% in 2018 (P = .33), despite significantly higher risks in the 2018 patient group. The odds ratio for complications in appointment attendees vs non-attendees was reduced after adjustments to 0.58; however, this was insignificant (P = .47). The odds of complications for skin grafts were considerably higher: 11.33 vs other surgery techniques (P = .00). In conclusion, the introduction of preoperative appointments appeared to reduce complications in below-knee surgery. For graft reconstructions, complication risk is high, even with carefully planned pre- and postoperative care. Further studies are needed to evaluate preventable risk factors of below-knee graft reconstructions.

Occurrence of newly discovered human polyomaviruses in skin of liver transplant recipients and their relation with squamous cell carcinoma in situ and actinic keratosis - a single-center cohort study.

To date 14 human polyomaviruses (HPyVs) have been identified. The newly found HPyVs have not been examined with regard to post-transplant skin carcinogenesis. To determine the occurrences in skin and possible pathological associations of the HPyVs, we studied their genoprevalences in squamous cell carcinoma (SCC) in situ or actinic keratosis and benign skin in liver transplant recipients (LiTRs); and of healthy skin in immunocompetent adults. We used highly sensitive and specific HPyV PCRs of two types. Overall, Merkel cell polyomavirus (MCPyV), human polyomavirus 6 (HPyV6), human polyomavirus 7 (HPyV7), trichodysplasia spinulosa polyomavirus (TSPyV), and Lyon IARC polyomavirus (LIPyV) were found in 58/221 (26.2%) skin biopsies. MCPyV DNA was detected in 5/14 (35.7%) premalignant vs. 32/127 (25.2%) benign skin of LiTRs, and in 12/80 (15%) healthy skin of immunocompetent adults, with no statistically significant difference in viral DNA prevalence or load. TSPyV DNA was found in a single skin lesion. LIPyV, HPyV6 and HPyV7 DNAs occurred exclusively in benign skin. Overall, the viral findings in premalignant versus benign skin were alike. The occurrences of HPyVs in skin of LiTRs and immunocompetent individuals speak against a role for any of the 14 HPyVs in SCC development.

Cutavirus DNA in Malignant and Nonmalignant Skin of Cutaneous T-Cell Lymphoma and Organ Transplant Patients but Not of Healthy Adults.

BACKGROUND: Three new parvoviruses of Protoparvovirus genus, bufavirus (BuV), tusavirus (TuV), and cutavirus (CuV), have recently been discovered in diarrheal stools. CuV was further detected in a proportion of cutaneous T-cell lymphoma (CTCL)/mycosis fungoides skin samples and in one melanoma. PATIENTS AND METHODS: With novel multiplex quantitative polymerase chain reaction and antibody assays, we studied 3 patient groups for BuV, TuV, and CuV DNA and immunoglobulin G (IgG): CTCL patients, immunosuppressed solid-organ transplant recipients, and immunocompetent healthy adults. RESULTS: CuV DNA was detected in skin biopsies of 4/25 (16.0%) CTCL and 4/136 (2.9%) transplant patients but not in any of 159 skin samples of 98 healthy adults. The dermal CuV-DNA prevalence was significantly higher in CTCL patients than in the other subjects. CuV DNA was further detected in healthy skin of 4 organ transplant recipients, 2 of whom also had CuV-positive skin carcinomas. One CTCL patient harbored CuV DNA in both malignant (CTCL, melanoma) and nonmalignant skin and sentinel lymph nodes but not in his prostate. The CuV IgG seroprevalences were among CTCL patients 9.5% (4/42), transplant recipients 6.5% (8/124), and healthy adults 3.8% (3/78). BuV and TuV DNAs were absent and antibodies infrequent in all cohorts. Parvoviral antibodies were shown to persist for ≥20 years and dermal CuV DNA for 4 years. All 3 CuV-DNA-positive patients, with both biopsies and sera available, were CuV-IgG positive. CONCLUSION: Our results suggest that dermal CuV DNA carriage is associated with CTCL. Any putative roles of CuV in the carcinogenesis must be determined in forthcoming studies.

Sensitivity of Above-Ground Biomass Estimates to Height-Diameter Modelling in Mixed-Species West African Woodlands.

It has been suggested that above-ground biomass (AGB) inventories should include tree height (H), in addition to diameter (D). As H is a difficult variable to measure, H-D models are commonly used to predict H. We tested a number of approaches for H-D modelling, including additive terms which increased the complexity of the model, and observed how differences in tree-level predictions of H propagated to plot-level AGB estimations. We were especially interested in detecting whether the choice of method can lead to bias. The compared approaches listed in the order of increasing complexity were: (B0) AGB estimations from D-only; (B1) involving also H obtained from a fixed-effects H-D model; (B2) involving also species; (B3) including also between-plot variability as random effects; and (B4) involving multilevel nested random effects for grouping plots in clusters. In light of the results, the modelling approach affected the AGB estimation significantly in some cases, although differences were negligible for some of the alternatives. The most important differences were found between including H or not in the AGB estimation. We observed that AGB predictions without H information were very sensitive to the environmental stress parameter (E), which can induce a critical bias. Regarding the H-D modelling, the most relevant effect was found when species was included as an additive term. We presented a two-step methodology, which succeeded in identifying the species for which the general H-D relation was relevant to modify. Based on the results, our final choice was the single-level mixed-effects model (B3), which accounts for the species but also for the plot random effects reflecting site-specific factors such as soil properties and degree of disturbance.

A Retrospective Study of Treatment of Squamous Cell Carcinoma In situ.

Squamous cell carcinoma in situ is an intra-epidermal malignancy of the skin with potential to progress to invasive carcinoma. Commonly used treatments are surgical excision, cryotherapy, photodynamic therapy, laser ablation, curettage with cautery, radiotherapy, topical 5-fluorouracil, and topical imiquimod. The efficacies of these different treatment modalities are compared in this retrospective study of 239 patients with squamous cell carcinoma in situ diagnosed and treated at our hospital during a period of one year. A total of 263 histologically confirmed in situ lesions were followed up for approximately 8 years. The overall recurrence rate was 6.5%. Surgical excision had the lowest recurrence rate, at 0.8%. Recurrence rates with the less-invasive treatment modalities were markedly higher; cryotherapy 4.7% and photodynamic therapy 18%. Of all recurrences, 65% were carcinoma in situ and 35% squamous cell carcinomas. Twenty-three patients had actinic keratosis in the area treated, but these were not counted as recurrences. In conclusion, excisional surgery is the gold standard treatment for squamous cell carcinoma in situ, although it has limitations. Less invasive methods may sometimes be preferred.

[Diagnosis and treatment of actinic keratosis]. / Aktiinisen keratoosin diagnostiikka ja hoito.

Actinic keratoses are premalignant skin lesions with the risk of converting into squamous cell carcinoma, and therefore they should be treated. Treatment modalities include cryotherapy, photodynamic therapy, carbon dioxide laser and also topical treatments such as imiquimode, ingenol mebutate, 5-fluorouracil and diclophenac. In the future, the treatment of actinic keratosis can be more often done in primary health care. The most favorable treatment modality depends on patient age, general health, and the thickness, size and localization of the lesion.

[Basal cell carcinoma, squamous cell carcinoma and premalignant skin lesions--how to treat?]. / Basalioomat, okasolusyöpä ja sen esiasteet, miten hoidan?

Increasing exposure to UV radiation is considered the most important etiologic factor of nonmelanoma skin cancers. Consequently, exposed areas such as the scalp and face, are the primary areas for developing non-melanoma skin cancers. Once a patient has presented with one tumor, additional lesions are common. The diagnosis is based on typical clinical picture and biopsy or excision for histopathological analysis. Various non-surgical treatment options have been established. Superficial basal cell carcinoma, superficial carcinoma in situ and all actinic keratoses are preferentially treated non-surgically. Most other basal cell and squamous cell carcinomas should be surgically removed.

Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. METHODOLOGY/PRINCIPAL FINDINGS: We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. CONCLUSIONS/SIGNIFICANCE: Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.

Current strategies for the treatment of hereditary tyrosinemia type I.

Hereditary tyrosinemia type I (HT-I) is the most common of the three known diseases caused by defects in tyrosine metabolism. This type of tyrosinemia is caused by a mutation in the gene coding for fumarylacetoacetate hydrolase; several mutations in this gene have been identified. The main clinical features of HT-I are caused by hepatic involvement and renal tubular dysfunction. Dietary intervention with restriction of phenylalanine and tyrosine together with supportive measures can ameliorate the symptoms, but given the high risk for hepatocellular carcinoma, a cure for these patients has so far been possible only with liver transplantation. Pharmacologic treatment with nitisinone, a peroral inhibitor of the tyrosine catabolic pathway, offers an improved means of treatment for patients with HT-I. However, longer follow-up periods are needed to establish the role of this drug in ultimately protecting patients from end-stage organ involvement and hepatocellular carcinoma. Experimental work in mice has provided some promise for the future management of tyrosinemia with gene therapy.