Long-term clinical outcomes of imiquimod 5% cream vs. diclofenac 3% gel for actinic keratosis on the face or scalp: a pooled analysis of two randomized controlled trials.

BACKGROUND: Actinic keratosis (AK) is an early in situ epidermal cancer which can progress to invasive squamous cell carcinoma (SCC). Imiquimod 5% cream (IMIQ) and diclofenac 3% gel (DIC) are frequently used to treat AK; however, their long-term effects following repeated treatment cycles have never been compared. OBJECTIVE: To compare IMIQ and DIC in the treatment of AK with respect to the risk of change to grade III AK or invasive SCC, after 3 years. METHODS: Data were pooled from two randomized, active-controlled, open-label, multicentre, multinational, phase IV studies (Clinicaltrials.gov NCT00777127/NCT01453179), with two parallel groups. Studies were conducted between 2008 and 2015 and were almost identical in design. Patients eligible for inclusion were immunocompetent adults with 5-10 visible AK lesions on the face/scalp and grade I/II AK. The primary endpoint was inhibition of histological change to grade III AK or invasive SCC in the study treatment area, observed until month 36. Patients applied either IMIQ or DIC for a maximum of six treatment cycles. RESULTS: In total, 479 patients (IMIQ 242; DIC 237) were included in the full analysis set. Histological change to grade III AK or invasive SCC was observed until month 36 in 13 (5.4%) patients treated with IMIQ, compared with 26 (11.0%) patients treated with DIC (absolute risk difference -5.6% [95% confidence interval -10.7%, -0.7%]). Time to histological change was greater in the IMIQ group than the DIC group (P = 0.0266). Frequency of progression to invasive SCC was lower with IMIQ than with DIC at all time points. Initial clearance rate was higher in the IMIQ group compared with the DIC group, while recurrence rate was lower. Both treatments were well tolerated. CONCLUSIONS: Over 3 years, IMIQ was superior to DIC in clearing AK lesions and preventing histological change to grade III AK or invasive SCC and recurrence.

Evidence and consensus-based (S3) guidelines for the treatment of actinic keratosis: International League of Dermatological Societies in cooperation with the European Dermatology Forum: short version

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).(AU)

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

A comparison of CT/CT angiography and MRI/MR angiography for imaging of vertebrobasilar dolichoectasia.

PURPOSE: Vertebrobasilar dolichoectasia (VBD) is a rare dilatative arteriopathy predominantly affecting the basilar artery (BA) and vertebral arteries. Until today, the value of computed tomography (CT)/CT angiography (CTA) compared with magnetic resonance imaging (MRI)/time-of-flight MR angiography (TOF-MRA) has not been studied systematically. METHODS: We (1) compare CTA and TOF-MRA according to the established criteria (diameter at the mid-pons level, height, and lateral position), (2) explore the value of further CTA- and TOF-MRA-derived measures (maximum transverse diameter and length), as well as (3) explore the value of further non-contrast-enhanced MRI sequences such as T1, fluid-attenuated inversion recovery, and T2* for a detailed characterization of VBD in a series of 18 patients. RESULTS: Comparison of CTA and TOF-MRA revealed very good consistency of the measured diameter (Pearson's r = 0.994, p = 0.01) and the noted height of the BA (Kendall's tau = 1.0, p = 0.001). The same held true for the maximum transverse diameter (Pearson's r = 0.988, p = 0.01) and length of the BA (Pearson's r = 0.986, p = 0.01). In contrast to this, there was a lower agreement concerning the lateral position (Kendall's tau = 0.866, p = 0.01). In comparison with the diameter at the mid-pons level, the maximum transverse diameter was significantly larger (p = 0.002). Luminal thrombus was detected equally well by CTA and TOF-MRA. CT was useful to detect small circumscribed calcifications, whereas MRI was advantageous to demonstrate perifocal brainstem edema. CONCLUSIONS: We could demonstrate a substantial comparability of CT/CTA and MRI/TOF-MRA in the diagnosis of VBD. The maximum transverse diameter and length may be useful when an endovascular treatment is considered. Taking into account the different informative value of both techniques, it may be worth to perform both imaging procedures.

Value of diffusion-weighted imaging in central pontine and extrapontine myelinolysis.

INTRODUCTION: Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are rare neurological disorders characterized by demyelination in and/or outside the pons. Whether diffusion-weighted imaging (DWI) might facilitate an earlier diagnosis has not yet been studied systematically. METHODS: We describe demographics, clinical presentation, and early magnetic resonance imaging (MRI) findings with special emphasis on the relevance for diagnosis of CPM and/or EPM in eight patients. RESULTS: Of the analysed eight patients (aged 37-70 years; two men, six women), CPM was diagnosed in three, EPM in one, and a combination of CPM and EPM in four patients. Aetiology was rapid correction of sodium in two patients; a combination of hyponatremia, alcoholism and alcohol withdrawal in five patients and unclear in one patient. Seven patients suffered from chronic alcoholism and four from malnutrition. Demyelinating lesions were found in the pons, thalamus, caudate nucleus, putamen and midbrain. While the lesions could be clearly delineated on T2- and T1-weighted images, DWI demonstrated a strong signal in only six patients. Furthermore, DWI demonstrated lesions only to some extent in two patients and was completely negative in two patients on initial MRI. In none of the patients did the demonstration of hyperintense lesions on DWI precede detection on conventional MRI sequences. Apparent diffusion coefficient (ADC) values were heterogenous with a decrease in two cases and an increase in the remainder. CONCLUSIONS: We conclude that early DWI changes are a common finding in CPM/EPM but do not regularly precede tissue changes detectable on conventional MRI sequences. Heterogenous ADC values possibly represent different stages of disease.

Visualisation of the zona incerta for deep brain stimulation at 3.0 Tesla.

PURPOSE: Deep-brain stimulation (DBS) of the zona incerta (ZI) has shown promising results for medication-refractory neurological disorders including Parkinson's disease (PD) and essential tremor (ET). The success of the intervention is indispensably dependent on the reliable visualisation of the ZI. The aim of the study was to evaluate different promising new magnetic resonance imaging (MRI) methods at 3.0 Tesla for pre-stereotactic visualisation of the ZI using a standard installation the protocol. METHODS: MRI of nine healthy volunteers was acquired (T1-MPRAGE, T2-FLAIR, T2*-FLASH2D, T2-SPACE and susceptibility-weighted imaging (SWI). Image quality and visualisation of the ZI for each sequence were analysed independently by two neuroradiologists using a 6-point scale. For T2*-FLASH2D the axial, coronal and sagittal planes were compared. The delineation of the ZI versus the internal capsule, the subthalamic nucleus and the pallidofugal fibres was evaluated in all sequences and compared to T2-FLAIR using a paired t-test. Inter-rater reliability, contrast-to-noise ratios (CNR), and signal-to-noise ratios (SNR) for the ZI were computed. For illustration, coronal T2*-FLASH2D images were co-registered with the corresponding section schema of the Schaltenbrand-Wahren stereotactic atlas. RESULTS: Only the rostral part of the ZI (rZI) could be identified. The rZI was best and reliably visualised in T2*-FLASH2D (particularly coronal orientation; p < 0.05). No major artifacts in the rZI were observed in any of the sequences. SWI, T2-SPACE, and T2*-FLASH imaging offered significant higher CNR values for the rZI compared to T2-FLAIR imaging using standard parameters. The co-registration of the coronal T2*-FLASH2D images projected the ZI clearly into the boundaries of the anatomical sections. CONCLUSIONS: The delineation of the rZI is best possible in T2*-FLASH2D (particularly coronal view) using a standard installation protocol at 3.0 T. The caudal ZI could not be discerned in any of the sequences.

Endovascular repositioning of a pipeline embolization device dislocated from the vertebral into the basilar artery using a stent-in-stent technique. Practical and technical considerations.

PURPOSE: Stent dislocation is a rarely encountered problem in interventional neuroradiology. This article describes the repositioning of a pipeline embolization device (PED) dislocated from the vertebral artery (VA) into the basilar artery (BA) using a stent-in-stent technique. Based on this case additional in vitro measurements were performed. METHODS: In a patient, a larger PED (4.0 × 20 mm) was partially opened in a PED (3.0 × 20 mm) floating freely within the distal BA. The microcatheter with the partially opened stent was pulled back hereby pulling back the stent-in-stent construct into the VA. In vitro the maximum tensile force that could be applied to a 3.5 mm and a 4.5 mm PED before dislodgement out of a 3.0 mm PED was determined. Videomorphometric analyses of the stent-in-stent construct were performed while applying traction to the construct. RESULTS: Repositioning of a dislocated PED is feasible using a stent-in-stent technique. Higher dislodgement forces can be applied using a larger PED (4.5 mm, 0.36 N) whereas dislodgement occurred faster using a smaller PED (3.5 mm, 0.26 N). Before dislodgement occurs, elongation and tapering of both stents can be seen. Finally, it was found that incidental extraction of the 4.5 mm PED out of the delivering microcatheter during traction is possible. CONCLUSIONS: Repositioning of a lost PED is feasible using a stent-in-stent technique. Principally, dislodgement force is higher using a larger PED, while in this case care has to be taken to avoid incidental extraction of the second PED out of the microcatheter.

Arterial spin labeling at 3.0 Tesla in subacute ischemia: comparison to dynamic susceptibility perfusion.

PURPOSE: Arterial spin labeling (ASL) is a promising but clinically not established non-invasive method to assess cerebral perfusion. The purpose of this study was to compare perfusion imaging with pulsed ASL (pASL) to conventional dynamic susceptibility contrast (DSC) perfusion-weighted imaging (PWL) using commercially available equipment and postprocessing (3.0 Tesla, 32-channel head coil) in patients with subacute ischemia. METHODS: The pASL and DSC-PWI techniques were compared in 15 patients with subacute ischemia (age 49-88 years, 6 females and 9 males, time from onset to scan 4-161 h). Image inhomogeneity was assessed with the non-uniformity index. Image quality, delineation of hypoperfusion and degree of hypoperfusion were rated by two readers using a 5-scale grading system. The volume of hypoperfusion was quantified planimetrically. RESULTS: Image quality and image inhomogeneity were superior in DSC time-to-peak (TTP) compared to pASL cerebral brain flow (CBF; both p < 0.05). The delineation of hypoperfusion was better in DSC-TTP (p < 0.05) and the hypoperfusion was graded as more severe in DSC-TTP (p < 0.05). The volume of hypoperfusion did not differ between pASL-CBF and DSC-TTP, however, in pASL-CBF five cases with small infarctions (lacunar and pontine) were false negative compared to DSC-relative CBF. The mismatch frequency was lower in pASL (13%) than in DSC-rCBF (20%) and DSC-TTP (47%). CONCLUSIONS: Using a commercially available sequence and a 32-channel head coil at 3.0 Tesla pASL-CBF is feasible but limited compared to DSC-PWI in the assessment of ischemic stroke. In its present form pASL has a reserve role in clinical practice for situations when gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) is contraindicated.

Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results.

BACKGROUND: Actinic keratoses (AKs) arise after chronic sun exposure. Because long-term ultraviolet (UV) damage may induce proliferation of atypical keratinocytes, treatment of AKs is recommended. OBJECTIVES: To compare 5-fluorouracil 0·5%/salicylic acid 10·0% [low-dose 5-FU/SA (Actikerall®)] with diclofenac 3% in hyaluronic acid (diclofenac HA) and vehicle for the treatment of AKs. METHODS: This was a randomized, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical low-dose 5-FU/SA once daily, its vehicle or diclofenac HA twice daily for a maximum of 12 weeks. The final evaluation was at week 20. The primary objectives were to demonstrate the histological clearance rate of one predefined lesion. The secondary objectives were the improvement of treated lesions, tolerability and safety. RESULTS: There were 470 patients with 4-10 AK lesions each (grade I or II) on the face/forehead or bald scalp included in the study. Low-dose 5-FU/SA was superior to diclofenac HA (P < 0·01) and vehicle (P < 0·0001) for histological clearance of one representative lesion 8 weeks post-treatment. In 72·0%, 59·1% and 44·8% of patients in the low-dose 5-FU/SA, diclofenac HA and vehicle groups, respectively, the week-20 biopsy revealed no AKs. Significantly more lesions were cleared with low-dose 5-FU/SA (74·5%) compared with diclofenac HA (54·6%; P < 0·001) or vehicle (35·5%; P< 0·001). Low-dose 5-FU/SA was superior in terms of complete clinical clearance: 55·4%, vs. diclofenac HA (32·0%, P < 0·001) and vehicle (15·1%P < 0·001). Application-site disorders (mainly burning and inflammation) were more frequent with low-dose 5-FU/SA but mainly of mild to moderate intensity. CONCLUSIONS: Topical low-dose 5-FU/SA demonstrated higher histological and clinical clearance rates vs. diclofenac HA or vehicle. Low-dose 5-FU/SA is an effective lesion-directed treatment for AKs.

[A child's birthday with consequences]. / Ein Kindergeburtstag mit folgen.

Foreign body ingestion is a common pediatric emergency and if the foreign body cannot be detected radiologically or endoscopically further investigations are required. In this article the case of a radiolucent, ingested foreign body (mini-candleholder of a birthday cake) is presented. The foreign body could not initially be identified via X-ray and endoscopy due to its parapharyngeal localization but was finally visualized by magnetic resonance imaging (MRI) which additionally uncovered the co-existence of acute mediastinal inflammation.

Treatment with 311-nm ultraviolet B accelerates and improves the clearance of psoriatic lesions in patients treated with etanercept.

BACKGROUND: Some patients with plaque-type psoriasis respond slowly to treatment with etanercept. In such cases combining etanercept with conventional treatments might be helpful. OBJECTIVES: To investigate whether treatment with 311-nm ultraviolet (UV) B can improve the therapeutic response in patients treated with etanercept. METHODS: Four women and one man (mean age 57 years, range 48-66) with moderate to severe plaque-type psoriasis who had received standard treatment with etanercept 50 mg twice weekly for 6 weeks without Psoriasis Area and Severity Index (PASI) reduction of 75% or greater (of initial mean PASI of 16.0, range 15.4-20.4) were enrolled in the study. Starting at 6 weeks, 311-nm UVB treatment was given to a randomly selected body half (left or right, excluding the head) for another 6 weeks, while all patients continued receiving etanercept. The patients were monitored by half-body PASI at weekly intervals. RESULTS: During the 6-week irradiation regimen, 311-nm UVB significantly bolstered the therapeutic response in the patients on etanercept treatment. After 6 weeks of 311-nm UVB, the patients had a mean PASI on their UV-irradiated body halves of 1.6 (range 0.6-3.3) vs. 4.7 (range 1.4-8.6) on nonirradiated body halves (P = 0.0192, paired two-tailed t-test), compared with 10.7 (range 6-16.4) and 10.5 (range 5.2-16.4) at start of 311-nm UVB treatment. The overall mean PASI reduction from baseline (i.e. at etanercept start) was 89% vs. 68%, respectively (P = 0.0009 and P = 0.0088). CONCLUSIONS: Treatment with 311-nm UVB significantly accelerates and improves the clearance of psoriatic lesions in patients responding slowly to etanercept monotherapy.

The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality.

BACKGROUND: The influence of phenotype and detection of clonality on prognosis in early mycosis fungoides has never been addressed in large studies. OBJECTIVES: To correlate immunophenotype and detection of clonality with clinical outcome. METHODS: We analysed 73 biopsy specimens from 68 patients with early mycosis fungoides (stage Ia or Ib) and at least 10 years of follow up (or dead of disease). RESULTS: Four phenotypic groups could be identified: group A (alpha/beta+ CD4+ CD8- TIA1-), 51 patients; median survival time 160 months; group B (alpha/beta+ CD4- CD8+ TIA1+), 10 patients; median survival time 195 months; group C (alpha/beta- CD4- CD8+/- TIA1+), five patients; median survival time 165 months; and group D (alpha/beta+ CD4- CD8- TIA1-), two patients; median survival time 130 months. Survival curves did not show statistical differences among the groups. Monoclonality was detected in 36 of 67 tested biopsies (54%), and statistical analyses did not show prognostic differences between the clonal and nonclonal cases. CONCLUSIONS: We conclude that cytotoxic phenotype and detection of monoclonal T-cell receptor-gamma gene rearrangement in early lesions of mycosis fungoides do not have any prognostic significance.

Distinct signatures of B-cell homeostatic and activation-dependent chemokine receptors in the development and progression of extragastric MALT lymphomas.

Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Recent studies have revealed important contributions of chemokine receptors to the development, progression, and dissemination of haematopoietic neoplasms. Because the chemokine receptor expression profile in extragastric MALT lymphoma is unknown, we performed a comprehensive study on tissue samples of parotid glands, parotid glands affected by Sjögren syndrome, extragastric MALT lymphoma, and extranodal diffuse large B-cell lymphoma (eDLBCL) originating from MALT lymphoma (transformed MALT lymphoma). By investigating the expression of 19 chemokine receptors by real-time PCR using a semi-quantitative approach and of four chemokine receptors (CCR1, CCR5, CXCR6, and XCR1) by immunohistochemistry, we show that the chemokine receptor expression profiles of extragastric MALT lymphomas differ substantially from those of extranodal DBLCL, with lower expression of CCR1, CCR8, and CXCR3, and the absence of expression of CX3CR1 and XCR1 in eDLBCL. Expression of CCR6, CCR7, CXCR3, CXCR4, and CXCR5, responsible for B-cell homing to secondary lymphoid tissue, was detected in both B-cell malignancies. Expression of CCR4 was just detected in trisomy 3-positive MALT lymphoma cases. Comparing gastric with extragastric MALT lymphomas, up-regulation of CXCR1 and CXCR2 accompanied by down-regulation of CCR8 and CX3CR1 and loss of XCR1 expression in extragastric MALT lymphomas appear to be key determinants for the site of origin of MALT lymphomagenesis. Our results support a model of stepwise progression of extragastric MALT lymphoma from a non-neoplastic event to Sjögren syndrome, to MALT lymphoma, and finally to overt eDLBCL, guided by differentially expressed B-cell homeostatic and activation-dependent chemokine receptors and their ligands.

Pathology and pathobiology of actinic (solar) keratosis - an update.

Actinic keratosis is a UV light-induced lesion and develops mostly in fair-skinned patients being susceptible to solar damage. The term actinic keratosis (AK) describes clinically ill-defined reddish to reddish-brown scaly lesions on erythematous base in areas damaged severely by sunlight. The term does not imply anything about the biology or histopathology. Actinic keratoses (AKs) have been recognized as precursor of cancer or of precancerous lesions in the past but today they are considered as an early in situ squamous cell carcinoma (1,2) and are categorized in several classifications with subdivisions into three grades depending on the amount of atypical keratinocytes in the epidermis.(3-6) The incidence of development of AK in caucasians increases with age, proximity to the equator and outdoor occupation. Australia has the highest skin cancer rate in the world. AKs are discovered in up to 40-50% of the Australian population older than 40 years.(7) AKs are the most common malignant lesion of the skin.(8-12).

Epidemiology and aetiology of basal cell carcinoma.

Basal cell carcinoma (BCC) is a malignant epithelial neoplasm of the skin preferentially affecting male caucasians and is rarely observed in patients with more intense skin pigmentation. A characteristic feature of BCCs are their extremely low risk to metastasize. Epidemiological data indicate that the overall incidence is increasing worldwide significantly by about 3-10% per annum.(1-3) Based on the increasing incidence of this usually not life-threatening tumour BCC appears to develop into a growing public health problem. This review elucidates the risk factors for the development and for the progression of BCC leading to an improved understanding of this tumour.

[Dermatopathology in German-speaking Europe. Developments and perspectives]. / Dermatopathologie im deutschen Sprachraum. Entwicklungen und Perspektiven.

Dermatopathology is defined as the combination of macroscopic pathology of the skin as part of the clinical diagnosis and microscopic pathology of the skin. Investigative pathology of skin diseases should be integrated into the academic practice of dermatopathology. There is no question that dermatopathology is the most important tool in dermatology for providing a specific diagnosis of skin diseases. Thus it is important to develop and support an approach to insure the highest standards for the practice of dermatopathology.