The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin

The imidazole derivative liarozole is a potent inhibitor of cytochrome P450-dependent 4-hydroxyla-tion of endogenous all- trans retinoic acid, thereby increasing the levels of all- trans retinoic acid in both plasma and skin. As part of a large, double-blind, randomized clinical study, we investigated the cell biological alterations in uninvolved and lesional skin of 20 patients with severe plaque psoriasis, who were treated with either liarozole or acitretin. The extent and severity of the skin lesions, as recorded by the Psoriasis Area and Severity Index score, was significantly reduced ( P 005) after 12 weeks of treatment in both the acitretin- and the liarozole-treated group. A significant decrease in the markers for inflammation (neutrophils), epidermal proliferation (Ki-67-positive cells), normal differentiation (transglutaminase) and abnormal differentiation [cytokeratin 16 and skin-derived antileucoproteinase (SKALP), also known as elafin] was seen in both groups. No significant differences were noted in clinical scores or cell biological scores between the liarozole- and acitretin-treated group. None of the markers returned to the levels seen in uninvolved skin or in normal human skin. The expression of epidermal fatty acid binding protein (E-FABP) was only minimally decreased after 12 weeks of treatment, a substantial part of the stratum spinosum remaining positive. SKALP levels in serum fell in both groups with similar kinetics and showed a statistically significant correlation with clinical scores. A remarkable finding in the uninvolved skin of patients treated with liarozole or acitretin was the distinct focal expression of SKALP in the granular layer and the expression of E-FABP in the spinous layers, which is not found in normal human skin. Although the mechanism of action differs fundamentally, liarozole and acitretin show similar effects with respect to clinical effects and cell biological changes in the lesional and non-lesional skin.     

Optimizing the association between disability and biological markers in MS

OBJECTIVE: Axonal damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain volume measurement on MRI can be used as an overall marker of tissue damage and axonal loss. The authors studied the relation of brain volume measurements with the MS Functional Composite (MSFC) in an attempt to improve the clinico-radiologic association. METHODS: In 137 patients with MS (80 relapsing-remitting [RR], 36 secondary progressive [SP], and 21 primary progressive [PP]) and 12 healthy controls, a brain MRI scan was obtained. Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments. MRI analysis included determination of hypointense T1- and hyperintense T2-weighted lesion load, and two brain volume measurements: 1) the parenchymal fraction (PF): whole brain parenchyma/intracranial volume; and 2) the ventricular fraction (VF): ventricular volume/whole brain parenchyma. RESULTS: The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01). For the patient population, moderate correlations were found between brain volume measurements and MSFC (0.36 for PF and -0.40 for VF). Patients with short disease duration showed a correlation of MSFC with both brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with brain volume measurements. CONCLUSION: Brain volume measurements are correlated with disability as assessed by the MSFC. Although in the early phase of the disease the amount of focal demyelination is important, the residual brain volume seems to be more relevant in determining disability in later phases of the disease.     

Modes of resistance to anti-angiogenic therapy

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.     

Life events, emotional eating and change in body mass index

The results are reported of a longitudinal study on effects of negative life events on change in body mass index (BMI; weight/height2 (kg/m2)) in men and women classified as either low or high emotional eaters. It was predicted that emotional eating and negative life events would have an interaction effect on change in BMI. Low emotional eaters would gain less weight and high emotional eaters would gain more weight after experiencing negative life events, than those who had not experienced such events. For men, emotional eating and negative life events were found to have a significant interaction effect on change in BMI 6 months after the assessment of life events on the first, but not on the second assessment date in the same study. Data on the long-term effects of negative life events indicate that the significant interaction effect found was not an artefact. For women, no such interaction effects were found. Thus, it is concluded that the hypothesis was confirmed to some extent in the men, but not in the women.     

Confirmation of raised phospholipase A2 activity in the uninvolved skin of psoriasis

Phospholipase A₂ has been measured in the lesions and the ‘uninvolved’ skin of patiens with psoriasis. We confirm a previous report that there is a generalized increase in the activity of this enzyme in psoriatic skin.     

TNF-α and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway

Keratinocytes of inflamed epidermis (psoriasis, wound healing) are hyperproliferative and display an abnormal differentiation programme. This regenerative differentiation pathway is characterized by the induction of genes that are not expressed by keratinocytes in normal skin, such as the cytokeratins CK6, CK16, CK17, and the proteinase inhibitor SKALP/elafin. In the study reported here we investigated the induction and regulation of SKALP expression as a marker for regenerative differentiation in epidermal keratinocytes. Various cytokines and growth factors known to be present in psoriatic epidermis were examined for their ability to induce SKALP gene expression in cultured human keratinocytes. Tumour necrosis factor-alpha (TNF-alpha) and serum were found to be potent inducers of SKALP expression at both the mRNA and the protein levels. SB202190 or SB203580, two specific p38 MAP kinase inhibitors almost completely blocked the induction of SKALP expression by TNF-alpha and serum. These results suggest that in keratinocytes, p38 activity is crucial for the induction of SKALP gene expression. These findings could be relevant for the elucidation of the mechanisms involved in normal and disturbed epidermal differentiation.     

Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial)

Background

Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life.

Methods/design

In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described.

Conclusion

The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life.

Trial Registration Number

Netherlands Trial Register (NTR): NTR2579     

Type 2 helper T-cell cytokines induce morphologic and molecular characteristics of atopic dermatitis in human skin equivalent

Both the immune system and the epidermis likely have an important role in the pathogenesis of atopic dermatitis (AD). The objective of the present study was to develop a human skin equivalent model exhibiting morphologic and molecular characteristics of AD in a controlled manner. Skin equivalents generated from normal adult human keratinocytes were stimulated with type 2 T-helper cell (Th2) cytokines IL-4 and IL-13, and morphologic features and gene expression of the epidermis were studied. Th2 cytokines induced intercellular edema similar to spongiotic changes observed in lesional AD as assessed at histopathologic analysis and electron microscopy. Furthermore, genes known to be specifically expressed in epidermis of patients with AD such as CAII and NELL2 were induced. In contrast, expression of psoriasis-associated genes such as elafin and hBD2 was not changed. Th2 cytokines caused DNA fragmentation in the keratinocytes, which could be inhibited by the caspase inhibitor Z-VAD, which suggests that apoptosis was induced. In addition, up-regulation of the death receptor Fas was observed in keratinocytes after Th2 cytokine stimulation. IL-4 and IL-13 induced phosphorylation of the signaling molecule STAT6. It was concluded that the skin equivalent model described herein may be useful in investigation of the epidermal aspects of AD and for study of drugs that act at the level of keratinocyte biology.     

Optimising surgical accuracy in palpable breast cancer with intra-operative breast ultrasound--feasibility and surgeons' learning curve

Aims

To evaluate if intra-operative guidance with ultrasonography (US) could improve surgical accuracy of palpable breast cancer excision, and to evaluate the performance of surgeons during training for US-guided excision.

Materials and methods

Thirty female patients undergoing breast-conserving surgery for palpable T1-T2 invasive breast cancer were recruited. Three individual breast surgeons, assisted by US, targeted and excised the tumours. The main objective was to obtain adequate resection margins with optimal resection volumes. The specimen volume, tumour diameter and histological margin status were recorded. The specimen volume was divided by the optimal resection volume, defined as the spherical tumour volume plus a 1.0-cm margin. The resulting calculated resection ratio (CRR) indicated the amount of excess tissue resected.

Results

All tumours were correctly identified during surgery, 29 of 30 tumours (96.7%) were removed with adequately negative margins, and one tumour was removed with focally positive margins. The median CRR was 1.0 (range, 0.4-2.8), implying optimal excision volume. For all breast surgeons, CRR improved during the training period. By the 8th procedure, all surgeons showed proficiency in performing intra-operative breast US.

Conclusion

Surgeons can easily learn the skills needed to perform intra-operative US for palpable breast tumour excision. The technique is non-invasive, simple, safe and effective for obtaining adequate resection margins. Within the first two cases, resections reached optimal volumes, thereby, presumably resulting in improved cosmetic outcomes. In a multicentre, randomised, clinical trial, intra-operative US guidance for palpable breast tumours will be evaluated for oncological and cosmetic outcomes.