Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

Evolutionary distinct roles of γ-secretase subunit nicastrin in zebrafish and humans.

BACKGROUND: Mutations in the genes that encode the human γ-secretase subunits Presenilin-1, Presenilin Enhancer Protein 2, and Nicastrin (NCSTN) are associated with familial hidradenitis suppurativa (HS); and, regarding Presenilin Enhancer Protein 2, also with comorbidity for the hereditary pigmentation disorder Dowling-Degos disease. OBJECTIVE: Here, the consequences of targeted inactivation of ncstn, the zebrafish homologue of human NCSTN, were studied. METHODS: After morpholino (MO)-mediated ncstn-knockdown, the possibilities of phenotype rescue through co-injection of ncstn-MO with wildtype zebrafish ncstn or human NCSTN mRNA were investigated. Further, the effects of the co-injection of a human missense, nonsense, splice-site, and frameshift mutation were studied. RESULTS: MO-mediated ncstn-knockdown resulted in a significant reduction in melanophore morphology, size and number; and alterations in their patterns of migration and distribution. This phenotype was rescued by co-injection of zebrafish ncstn RNA, human NCSTN RNA, or a construct encoding the human NCSTN missense mutation p.P211R. CONCLUSION: Human NCSTN mutations encoding null alleles confer loss-of-function regarding pigmentation homeostasis in zebrafisch. In contrast, the human missense mutation p.P211R was less harmful, asserting sufficient residual ncstn activity to maintain pigmentation in zebrafish. Since fish lack the anatomical structures affected by HS, our data suggest that the zebrafish ncstn gene and the human NCSTN gene have probably acquired different functions during evolution. In fish, one major role of ncstn is the maintenance of pigmentation homeostasis. In contrast, one of the roles of NCSTN in humans is the prevention of inflammatory processes in the adnexal structures of the skin, as seen in familial HS.

NF-кB c-Rel modulates pre-fibrotic changes in human fibroblasts.

Skin fibrosis is one central hallmark of the heterogeneous autoimmune disease systemic sclerosis. So far, there are hardly any standardized and effective treatment options. Pathogenic mechanisms underlying fibrosis comprise excessive and uncontrolled myofibroblast differentiation, increased extracellular matrix protein (ECM) synthesis and an intensification of the forces exerted by the cytoskeleton. A deeper understanding of fibroblast transformation could help to prevent or reverse fibrosis by specifically interfering with abnormally regulated signaling pathways. The transcription factor NF-κB has been implicated in the progression of fibrotic processes. However, the cellular processes regulated by NF-κB in fibrosis as well as the NF-κB isoforms preferentially involved are still completely unknown. In an in vitro model of fibrosis, we consistently observed the induction of the c-Rel subunit of NF-κB. Functional abrogation of c-Rel by siRNA resulted in diminished cell contractility of dermal fibroblasts in relaxed, but not in stressed 3D collagen matrices. Furthermore, directed migration was reduced after c-Rel silencing and total N-cadherin expression level was diminished, possibly mediating the observed cellular defects. Therefore, NF-кB c-Rel impacts central cellular adhesion markers and processes which negatively regulate fibrotic progression in SSc pathophysiology.

Topical scabies therapy with permethrin is effective and well tolerated in infants younger than two months.

BACKGROUND AND OBJECTIVES: Proper management of infantile scabies is indispensable in order to prevent prolonged duration and spread of the disease. Data are still lacking that support topical treatment with permethrin 5 % cream in infants under two months of age, and application remains off-label for this age group. PATIENTS AND METHODS: We identified infants younger than two months who suffered from scabies in order to evaluate the safety and efficacy of topical treatment with permethrin cream in this age group. Diagnosis of scabies was based on the typical symptoms and pathognomonic features as determined with dermoscopy. We analyzed the efficacy and safety of the therapies that were applied. RESULTS: Seven scabies patients under two months of age were treated with permethrin 5 % cream. Topical therapy was repeated up to three times in four patients due to incomplete resolution or recurrence of skin lesions. CONCLUSIONS: Permethrin therapy was well tolerated in all seven infants, even when conducted several times. Our results confirm that the use of permethrin 5 % cream in children younger than two months of age is safe.

Pre-Existing Chronic Pain Influences the Severity of Acute Herpes Zoster Pain-A Prospective Observational Cohort Study.

OBJECTIVE: Pre-existing chronic pain has been associated with severe postoperative pain. To analyze the impact of chronic pain on non-surgical acute pain, a cohort of patients with acute herpes zoster was studied. METHODS: Consecutive patients, who needed hospitalization because of an acute zoster infection, were characterized and compared according to their pain history. Pain intensity, pain-related function, analgesic consumption, and psychological and physiological characteristics were assessed as baseline parameters on the day of hospitalization. Pain intensity and functional restrictions were evaluated on day 1, 4, 7, and on the day of discharge. The analgesic consumption was recorded and scored for each of these days. A multivariate analysis was performed for individual predictors. RESULTS: 59 patients were included; 25 patients (42.4%) had pre-existing chronic pain. These patients had more severe acute zoster pain on all assessment days and were more restricted in function, such as sleep quality and mobilization. There were, however, no differences in analgesic consumption. In patients without chronic pain, only the amount of analgesic consumption was associated with the severity of zoster pain. In contrast, in patients with chronic pain, the severity of the chronic pain, physical health, and the extent of neuropathic pain characteristics were associated with the intensity of zoster-related acute pain, while analgesic consumption was not. CONCLUSIONS: Patients with chronic pain had higher intensity of zoster-related acute pain. Furthermore, they showed more pain-related dysfunction and needed longer hospitalization than patients without chronic pain. These results go along with findings for acute postoperative pain.

Nodal Basin Recurrence After Sentinel Lymph Node Biopsy for Melanoma: A Retrospective Multicenter Study in 2653 Patients.

UNLABELLED: The objective of this study was to analyze different types of nodal basin recurrence after sentinel lymph node biopsy (SLNB) for melanoma. PATIENTS AND METHODS: Kaplan-Meier estimates and the Cox proportional hazards model were used to study 2653 patients from 3 German melanoma centers retrospectively.The estimated 5-year negative predictive value of SLNB was 96.4%. The estimated false-negative (FN) rates after 1, 2, 3, 5, and 10 years were 2.5%, 4.6%, 6.4%, 8.7%, and 12.6%, respectively. Independent factors associated with false negativity were older age, fewer SLNs excised, and head or neck location of the primary tumor. Compared with SLN-positive patients, the FNs had a significantly lower survival. In SLN-positive patients undergoing completion lymphadenectomy (CLND), the 5-year nodal basin recurrence rate was 18.3%. The recurrence rates for axilla, groin, and neck were 17.2%, 15.5%, and 44.1%, respectively. Significant factors predicting local relapse after CLND were older age, head, or neck location of the primary tumor, ulceration, deeper penetration of the metastasis into the SLN, tumor-positive CLND, and >2 lymph node metastases. All kinds of nodal relapse were associated with a higher prevalence of in-transit metastases.The FN rate after SLNB steadily increases over the observation period and should, therefore, be estimated by the Kaplan-Meier method. False-negativity is associated with fewer SLNs excised. The beneficial effect of CLND on nodal basin disease control varies considerably across different risk groups. This should be kept in mind about SLN-positive patients when individual decisions on prophylactic CLND are taken.

The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas.

PURPOSE: To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. METHODS: Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN-negative, SLN micrometastases or macrometastases. RESULTS: In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46% in SLN-negative patients, 57% in SLN positive patients, and 69% in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4%, 11.7% and 0.0 %, respectively (P = 0.002). CONCLUSION: In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted hotspots.

Sentinel node biopsy improves prognostic stratification in patients with thin (pT1) melanomas and an additional risk factor.

BACKGROUND: Sentinel lymph node (SLN) biopsy (SLNB) for pT1 melanomas is not generally recognized as a clinical standard. We studied the value of SLNB for pT1 melanoma patients having at least one additional risk factor. PATIENTS: Among 931 patients with SLNB, 210 had pT1 melanomas. All of the latter showed at least one of the following risk factors: ulceration (4 %) Clark level IV (44 %), nodular growth pattern (11 %), mitoses (59 %), regression (38 %) or age ≤ 40 years (27 %). RESULTS: In this selected pT1 population, we observed a surprisingly high SLN positivity rate of 18 %. The melanoma-specific overall survival significantly depended on SLN status. Compared with Clark IV, a lower invasion level (Clark II/III) was associated with a higher proportion of positive SLNs (25 vs. 10 %; p < 0.01). There was a trend towards a higher SLN positivity rate in younger patients (p = 0.06). Breslow, ulceration, mitoses, nodular growth pattern, and sex did not reach significance. Regression was significantly more frequently found in very thin melanomas (≤ 0.75 mm) and tended to be significant in this subgroup (p = 0.075). CONCLUSIONS: SLNB improves prognostic stratification in patients with thin melanomas having an additional risk factor. Clark level IV most likely does not belong to these risk factors. The impact of regression deserves further consideration. Our data suggest that SLNB should be offered to patients with thin melanomas, if ulceration, nodular growth pattern, mitoses, or regression are present, or if the patient is younger than 40 years of age.

Individualized surgery: gamma-probe-guided lymphadenectomy in patients with clinically enlarged lymph node metastases from melanomas.

BACKGROUND: The value of a preoperative lymphoscintigraphy in melanoma patients with clinically evident regional lymph node metastases has not been studied. Therapeutic lymph node dissection (TLND) is regarded as the clinical standard, but the appropriate extent of TLND is controversial in all lymphatic basins. PATIENTS AND METHODS: Of the 115 consecutive patients with surgery on palpable lymph node metastases, 34 received a pre-operative lymphoscintigraphy. Lymphatic drainage to a second nodal basin outside the clinically involved basin was found in 15 cases. In 13 patients, the ectopic tumor-draining lymph nodes were excised as in a sentinel node biopsy. The lymph nodes from the TLND specimens were postoperatively separated and classified as either radioactive or non-radioactive. RESULTS: A total of 493 lymph nodes were examined pathologically. The largest macrometastasis maintained the ability to take up radiotracer in 77% of cases. Radioactively labeled lymph nodes carried a higher risk of being involved with metastasis. The proportions of tumor involvement for radioactive and non-radioactive lymph nodes were 44.5 and 16.9%, respectively (P=0.00002). Of the 13 ectopic nodal basins surgically explored, six harbored clinically occult metastases. CONCLUSION: In patients undergoing TLND for palpable metastases, tumor-draining lymph nodes in a second, ectopic nodal basin should be excised, because they could be affected by occult metastasis. With respect to radioactive lymph nodes situated within the nodal basin of the macrometastasis but beyond the borders of a less-radical lymphadenectomy, further studies are needed.

Solitary cutaneous nodule of blastic plasmacytoid dendritic cell neoplasm progressing to overt leukemia cutis after chemotherapy: immunohistology and FISH analysis confirmed the diagnosis.

Blastic plasmacytoid dendritic cell (BPDC) neoplasm, formerly called blastic natural killer cell lymphoma or CD4+/CD56+ hematodermic neoplasm, is a rare tumor entity, now regarded to be derived from the plasmacytoid dendritic cell (PDC) lineage. Because over 90% of patients present with skin lesions usually early in their disease, dermatologists have to be familiar with the specific diagnostic features and the clinical course of this devastating disease. We present a woman with a long standing solitary skin tumor of BPDC neoplasm, who experienced a deleterious clinical course, which is typical for this disease. Phenotypic and karyotypic characteristics distinguishing this tumor from myelomonocytic leukemia with skin involvement are presented.

Treatment of scalp angiosarcoma by controlled perfusion of A. carotis externa with pegylated liposomal doxorubicin and intralesional application of pegylated interferon alfa.

BACKGROUND: Angiosarcoma of the scalp is a rare but highly aggressive malignant tumor that differentiates toward vascular endothelial cells and shows a tendency for diffuse, often clinically occult spread. OBSERVATIONS: A 65-year-old Caucasian man presented with multiple erythematous skin lesions at the right scalp hemisphere and a prominent forehead edema that had developed during a period of 2 months. The clinical diagnosis of angiosarcoma was confirmed by histopathology. Because of the advanced local progression of the tumor and the unilateral localization on the right side of the scalp, we initiated an intra-arterial chemotherapy using pegylated liposomal doxorubicin (Caelyx) (8 mg/cycle every 4 weeks by an A. carotis externa port system). In addition, the patient received pegylated interferon alfa (50 microg/wk) by a percutaneous intralesional injection route. After 2 months, the tumor showed a marked regression; after 4 months, only one nodule located at the margins of the area perfused by the A. carotis externa persisted but regressed after focal irradiation. At 30 months after diagnosis, the patient shows no recurrence of tumor growth. CONCLUSIONS: In combination with intralesional interferon alfa, intra-arterial doxorubicin may be a promising innovative therapeutic option for localized scalp angiosarcoma, a hitherto poorly manageable and aggressive malignant tumor.