[New optical examination procedures for the diagnosis of skin diseases]. / Neue optische Untersuchungsverfahren für die Diagnostik von Hautkrankheiten.

BACKGROUND: Since the establishment of dermoscopy as a routine examination procedure in dermatology, the spectrum of noninvasive, optical devices has further expanded. In difficult-to-diagnose clinical cases, these systems may support dermatologists to arrive at a correct diagnosis without the need for a surgical biopsy. OBJECTIVE: To give an overview about technical background, indications and diagnostic performance regarding four new optical procedures: reflectance confocal microscopy, in vivo multiphoton tomography, dermatofluoroscopy, and systems based on image analysis by artificial intelligence (AI). MATERIALS AND METHODS: This article is based on a selective review of the literature, as well as the authors' personal experience from clinical studies relevant for market approval of the devices. RESULTS: In contrast to standard histopathological slides with vertical cross sections, reflectance confocal microscopy and in vivo multiphoton tomography allow for "optical biopsies" with horizontal cross sections. Dermatofluoroscopy and AI-based image analyzers provide a numerical score, which helps to correctly classify a skin lesion. The presented new optical procedures may be applied for the diagnosis of skin cancer as well as inflammatory skin diseases. CONCLUSION: The presented optical procedures provide valuable additional information that supports dermatologists in making the correct diagnosis. However, a surgical biopsy followed by dermatohistopathological examination remains the diagnostic gold standard in dermatology.

Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

Epidermal changes during UVB phototherapy assessed by multiphoton laser tomography.

BACKGROUND: Multiphoton laser tomography (MPT) is a non-invasive technique that allows imaging of skin in vivo with very high spatial resolution and contrast. Previous work of our group has demonstrated that known morphological changes due to erythematogenic ultraviolet B (UVB) irradiation may be imaged in vivo by MPT. The present work investigated if morphological skin changes known from experimental erythematogenic UVB irradiation are also demonstrable in the course of a standard phototherapy regime that implies suberythematogenic doses of narrow band UVB. METHODS: Sixteen patients with psoriasis vulgaris receiving a narrow band phototherapy were included. A test field and a light-protected control field were measured with the multiphoton tomograph DermaInspect® at four time points: at baseline, the next day, after 3 days and at the day of the last exposure. RESULTS: In the course of the UVB phototherapy, spongiosis and pleomorphy as parameters of inflammation and cellular damage did not show significant changes. By contrast, an adaptive skin reaction with significant changes of keratosis and pigmentation was observed. CONCLUSION: MPT is a suitable technique for the investigation of qualitative and quantitative skin changes after UVB irradiation. After suberythematogenic UVB irradiation, photoadaptive skin changes, but no cellular damage can be observed with MPT.

[Multiphoton tomography]. / Multiphotonentomographie.

In recent years, multiphoton tomography (MPT) and multiphoton microscopy have gained increasing importance as noninvasive examination techniques in dermatology. MPT imaging is based on the specific stimulation of biogenic fluorophores. The induction of second harmonic generation is also used for imaging of particular molecules. Additional fluorescence staining or fluorescence markers are not necessary-an important advantage for the in vivo examination of human skin. Multiphoton techniques are not only appropriate for clinical diagnostics but also for biomedical research. MPT provides an optical biopsy depth up to 200 µm with subcellular resolution depicting cellular and extracellular structures. In combination with fluorescence lifetime imaging, additional information about the microenvironment, the energetic state and the cellular metabolism can be obtained. This review presents recent developments of MPT for the in vivo evaluation of physiological and pathological changes of skin and diagnostics of dermal diseases.

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.

BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography.

BACKGROUND: Multiphoton tomography (MPT) is a novel non-invasive imaging method in dermatology allowing the depiction of the epidermis with sub-cellular resolution. Here, we present a descriptive characterization of unaffected human epidermis, morphometric data on human keratinocytes and some epidermal parameters in vivo and a morphological characterization of keratinocyte changes in actinic keratoses. METHODS: In a clinical setting, 57 volunteers of different age groups were examined using MPT. RESULTS: The morphological appearance of keratinocytes showed polygonal cells in the horny layer, a granular cytoplasm in the stratum granulosum, smaller prickle cells in the stratum spinosum and hyperpigmented small round basal cells. Actinic keratoses presented remarkable differences including widened inter-cellular spaces, heterogeneity in cellular fluorescence and shape as well as an increased ratio of nuclear to cellular size. Finally, the thickness of the epidermis was significantly increased in actinic keratoses compared with the control. CONCLUSION: In vivo MPT provides high-resolution images allowing the identification and quantification of cellular morphometric parameters. First observations of morphology and morphometry of actinic keratoses are reported.

Actinic damage and its treatments.

Over the last decades, there has been a dramatic increase of skin tumour incidence that results from actinic damage. This increase is mainly due to the current demographic development, but also due to a change in spare time habits. Thus, the treatment and prevention of light induced skin tumours is gaining interest, but also the treatment of photoaged skin. This review will focus on 1) the basic principles of actinic damage including carcinogenesis; 2) treatment options for photoaged skin and 3) an overview of current therapy concepts of light induced skin tumours.

[Multiphoton microscopy and in vivo tomography in dermatologic imaging]. / Multiphotonenmikroskopie und In-vivo-Multiphotonentomographie in der dermatologischen Bildgebung.

Multiphoton microscopy (MPM) and in vivo multiphoton tomography (MPT) are non-invasive examination techniques that allow for the evaluation of cellular as well as extra-cellular structures by working at a subcellular resolution level. These techniques are thus appropriate not only for clinical diagnostics but also for scientific issues in basic and applied research. MPM and MPT are based on the stimulation of biogenic fluorophores by two or more long-wave, low-energy photons and the evocation of second harmonic generation (SHG). Thus, the evaluation quality of cell clusters and tissues is similar to histological sections. At the same time the dermal fiber network can be assessed. MPT was developed further for the application in non-invasive in vivo diagnostics of skin diseases. This review presents the capabilities of multiphoton-based diagnostics in the evaluation of transcutaneous metabolism. In addition, the multiphoton techniques employed for the evaluation of physiologic and pathologic changes of the dermal fiber network as well as in the diagnosis of dermal and epidermal disorders by visual biopsy. Besides the morphological classification of benign and malignant skin tumors or allergic or inflammatory skin lesions, the techniques also allow for recording metabolic processes.

Induction of benign symmetric lipomatosis (Launois-Bensaude syndrome) in a female patient after liver transplantation.

Benign symmetric lipomatosis, also known as Madelung's disease or Launois-Bensaude syndrome, is a rare disease, the etiology of which is still unknown. The presence of multiple, symmetric, nonencapsulated lipomatous masses in the face, neck, upper arms and upper trunk is typical. Until now many causes have been discussed among which liver dysfunctions are described frequently. In up to 90% of patients, alcoholism is observed. In our case the Launois-Bensaude syndrome developed after liver transplantation in a 49-year-old female patient suffering from decompensated cirrhosis (Child-Pugh C score: 12 points). Shortly after the transplantation a slow progress in tissue-building appeared on both upper arms, cervical areas as well as in the face. During postsurgical prednisolone therapy, a massive increase in fluid in the tissue developed, which led to a discontinuation of this therapy regimen. In the further course there was an increase in weight of 20 kg. As far as we know, this case is the first description of the induction of a Launois-Bensaude syndrome following liver transplantation.

Clinical two-photon microendoscopy.

Two-photon medical imaging has found its way into dermatology as an excellent method for noninvasive skin cancer detection without need of contrast agents as well as for in situ drug screening of topically-applied cosmetical and pharmaceutical components. There is an increasing demand to apply the multiphoton technology also for deep-tissue skin imaging as well as for intracorporal imaging. We report on the first clinical use of multiphoton endoscopes, in particular of a miniaturized rigid two-photon GRIN lens endoscope. The microendoscope was attached to the multiphoton tomograph DermaInspect and employed to detect the extracellular matrix proteins collagen and elastin in the human dermis of volunteers and patients with ulcera by in vivo second harmonic generation and in vivo two-photon autofluorescence.

Cutaneous Langerhans cell histiocytosis with subsequent development of haematological malignancies. Report of two cases.

Adult cutaneous Langerhans cell histiocytosis (LCH) is a rare disease. We report two cases illustrating the variability of the clinical presentation and the response to treatment. In both cases a remission was achieved: in one case a partial remission with psoralen plus UVA irradiation (PUVA) and methotrexate plus topical corticosteroid ointment; in the other case by treatment with thalidomide. Despite a therapeutic response, both patients later developed haematological malignancies: a chronic myelo-monocytic leukaemia and an acute lymphatic leukaemia. In conclusion, patients with adult cutaneous LCH should be monitored carefully so that a secondary malignancy is not overlooked.

Microtubules regulate expression of ICAM-1 in epidermoid cells (KB cells).

The intercellular adhesion molecule-1/CD54 (ICAM-1) functions as a counterreceptor for other adhesion molecules (e.g. the lymphocyte function-associated antigen-1/CD11a/CD18) required for the interaction of a large variety of cells with leucocytes. Constitutive expression of ICAM-1 in human epidermoid cells (KB cells) is low, but inducible by interferon-gamma (IFN-gamma). Treatment of KB cells with microtubule-disrupting agents, like colchicine, nocodazole and vinblastine, potentiated the constitutive and cytokine-induced ICAM-1 expression on the cell surface. Actinomycin D inhibited microtubule-disrupting agent-induced ICAM-1 surface expression. Increased steady-state levels of ICAM-1 transcripts were found after treatment of KB cells with microtubule-disrupting agents. However, microtubule-disrupting agents neither altered the glyceraldehyde-3-phosphate dehydrogenase mRNA levels nor the amount of expressed alpha(2)-, alpha(3)-and beta(1)-integrins at the cell surface. In addition, they did not change the ICAM-1 mRNA half-life. These studies indicate a control function of the microtubule network on the expression of ICAM-1.

Vulvar dermatoses--irritant and allergic contact dermatitis of the vulva.

Irritant and allergic contact dermatitis are commonly seen in patients complaining about itching, burning and irritation in the vulvar area. Irritation often precedes allergic sensitization. Clinically, irritant and allergic contact dermatitis can be difficult to distinguish. Diagnosis is made by history, clinical investigation and patch testing. Recommended patch test series are the standard series, a medicament series, the patient's own topical medicaments, popular remedies and other suspected products. A skin biopsy may be useful to establish the diagnosis of contact dermatitis, but it is usually not helpful for the differential diagnosis between irritant and allergic dermatitis.

Clinical phase II study of pegylated liposomal doxorubicin as second-line treatment in disseminated melanoma.

BACKGROUND: Stage IV melanoma has a poor prognosis with a median survival of 3-11 months from diagnosis of distant metastases. Response rates in first-line regimens range around 15-20%. Non-responders have a median survival around 6 months. Currently, no second-line treatment in advanced melanoma has been established. PATIENTS AND METHODS: In a clinical phase II study we evaluated the efficacy of liposomal doxorubicin (Caelyx) in 30 patients (17 m, 13 f) with progressing metastatic melanoma who had failed a previous chemotherapy. Liposomal doxorubicin was given in an outpatient setting at a dose of 50 mg/m2 i.v. on d1, d22, d43 and d64, subsequently at 40 mg/m2 at d85 before first staging and in 4-week intervals thereafter. Treatment was very well tolerated with 100 cycles given in total. Response rate, survival time, time-to-progression and toxicity were assessed. RESULTS: Erythrodysesthesia was the most severe toxicity in 6% at CTC grade 3. Liposomal doxorubicin was of limited clinical efficacy with 21 patients progressing within the first 12 weeks. However, 7 patients were treated 3-9 months and were stable for >90 days, achieving 5 SD, 1 PR and 1 CR. Median survival after initiation of second-line treatment was 214 days (95% CI: 151-304 days) with 7 patients surviving >300 and 5 patients >400 days. CONCLUSIONS: Liposomal doxorubin as monotherapy is well tolerated but of limited clinical efficacy. Whether the survival benefit of a significant proportion of patients (20%) holds true in larger cohorts and whether the efficacy of liposomal doxorubicin can be improved by combinations without compromising the low toxicity profile needs further studies.

Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide.

Langerhans cell histiocytosis (LCH) represents a group of rare histiocytic syndromes characterized by tissue infiltration with dendritic cells. The management of LCH is difficult as these disorders respond inconsistently to immunosuppressive and chemotherapeutic strategies. Thalidomide (N-phtalimidoglutarimide), initially used as a tranquilizer, has recently been used in the management of several inflammatory skin diseases. We describe the case of a 38-year-old male with mucocutaneous LCH. A treatment course with 6 cycles of 2-chlorodeoxyadenosin (cladribine) was initiated. This was well tolerated but withdrawn after 6 months to prevent secondary malignancy. A partial remission was seen. Subsequently, a treatment course with thalidomide 200 mg daily was started. This therapy resulted in a significant improvement of the mucocutaneous lesions within 4 weeks and complete healing was achieved after 3 months. Treatment was then successfully continued with daily doses of 100 mg to prevent relapse. In conclusion, thalidomide monotherapy represents an effective, safe and well-tolerated treatment option that should be considered as first-line therapy for mucocutaneous LCH.

Erythema induratum of Bazin and Poncet's disease -- successful treatment with antitubercular drugs.

Erythema induratum of Bazin (EIB) is considered a tuberculide reaction and consists of recurrent painful nodules predominantly on the calves. Clinically it has common features with diseases like nodular vasculitis, perniosis, polyarteritis nodosa and erythema nodosum. Poncet's disease is a reactive arthritis that may accompany tuberculosis. We report a case of a young woman in which the simultaneous occurrence of erythema induratum of Bazin and Poncet's disease led to a clinical picture very similar to Löfgren's syndrome. The final diagnosis was obtained by polymerase chain reaction detection of mycobacterial DNA in a skin biopsy. A systemic therapy with tuberculostatic drugs led to the disappearance of symptoms. The presented case shows the usefulness of polymerase chain reaction diagnostics in EIB patients without other clinical signs of tuberculosis and a confusing combination of symptoms, and further confirms the presence of mycobacterial DNA in EIB lesions.

[Subungual chondroma, a case report]. / Subunguales Chondrom, ein Fallbericht.

Subungual chondroma is a rare occurrence of periosteal chondroma, which mainly affects short tubular bones of the hands and feet. Transformation towards malignancy has been described in a small number of cases; however histologic diagnosis can prove to be difficult, especially with regard to well differentiated chondrosarcoma. We report the case of a 14 year old girl with a one year history of subungual chondroma of the fourth toe with good clinical response to surgical removal.

Serum matrix metalloproteinase-2 in patients with malignant melanoma.

PURPOSE: Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases that are able to degrade extracellular matrix components. MMPs play a role in tumor invasion and tumor metastasis. MMP-2 (also known as gelatinase A) is expressed in human melanoma cells. METHODS: In this study, we measured MMP-2 in 337 serum probes of 166 melanoma patients with a recently developed enzyme immunoassay and compared these data with the tumor stage, presence of metastases, and the levels of S100beta and soluble intracellular adhesion molecule-1 (sICAM-1) in serum. RESULTS: The mean levels were (189.2 +/- 50.8) ng/ml for MMP-2, (263.2 +/- 74.1) ng/ml for sICAM-1, and (0.424 +/- 1.568) U/ml for S100beta. There was a statistical significant correlation of MMP-2 with sICAM-1 (P=0.05) and Sl00beta (P=0.01). The mean MMP-2 levels (in ng/ml) in patients with metastatic melanoma were 196.4 +/- 54.0 versus 182.6 +/- 46.9 in non-metastasizing melanoma (P=0.037). However, there was no significant difference in MMP-2 levels between the different tumor stages. CONCLUSION: Determination of MMP-2 serum levels is of limited value as a tumor marker in melanoma, though there are higher levels in the more advanced disease.