F. Fantini

Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemical study

The distribution and localization of several neuropeptides were investigated in the lichenified lesions of 11 patients with atopic dermatitis using indirect immunofluorescence. Substance P‐positive nerve fibres were observed in most of the cases of atopic dermatitis, but not in normal controls. Somatostatin immunoreactive nerves were not found in the skin of atopic dermatitis, whereas a normal pattern of immunoreactivity could be detected in most of the healthy subjects. Neuropeptide Y‐positive dendritic epidermal cells were observed in lesional skin from patients with atopic dermatitis, but not in controls. Calcitonin gene‐related peptide and vasoactive intestinal polypeptide immunoreactivity in patients with atopic dermatitis did not differ from that in healthy subjects. With galanin antiserum a diffuse intracellular staining was observed in the epidermis of both atopic patients and controls, while no positive staining was found with either neurotensin or neurokinin A antibodies in either group. These findings suggest a possible involvement of some neuropeptides in the pathomechanisms of atopic dermatitis.

Neuropeptides and Skin Inflammation

Neuropeptides (NP) are protein compounds contained both in the central and peripheral nervous system. They can be antidromically released from sensory nerves and are implicated in the so-called neurogenic inflammation. They also exert a number of functions within the immune system and are thought to act as trophic as well as mitogenic substances. Several NP have been detected in human skin by immunohistochemical and radioimmunological techniques, and recent reports have demonstrated that NP could be involved in the mechanisms of certain dermatoses. The involvement of NP in either physiological or pathophysiological skin conditions is discussed. Moreover, a few questions, which still need to be addressed, are raised, and future directions this field of research should take are outlined.

Survivin Identifies Keratinocyte Stem Cells and Is Downregulated by Anti-β1 Integrin During Anoikis

Survivin belongs to the family of inhibitor of apoptosis proteins and is involved in regulation of cell death as well as cell division. Here, we show that wild‐type (WT) survivin is expressed in a subpopulation of basal keratinocytes in normal human skin at the cytoplasmic level. WT survivin is highly expressed in keratinocyte stem cells (KSCs), whereas its mRNA level decreases in transit amplifying (TA) cells and disappears in postmitotic (PM) cells. Likewise, WT survivin protein is expressed in KSCs, almost undetectable in TA cells, and absent in PM cells. Real time polymerase chain reaction demonstrates that the putative antiapoptotic isoforms survivin‐2B and survivin‐ΔEx3 are expressed at the highest levels in KSCs, whereas they tend to decrease in TA cells and disappear in PM cells. On the contrary, the putative proapoptotic variants of survivin, survivin‐3B, and survivin‐2α tend to be high in PM and TA cells and are almost absent in KSCs. By confocal microscopy, survivin is predominantly expressed at the nuclear level in KSCs, which proliferate significantly better than TA cells, which, in turn, express mostly cytosolic WT survivin. Blocking β1 integrin signal downregulates WT survivin mRNA and protein expression and induces apoptosis (anoikis) in KSCs. On the other hand, inhibition of β1 integrin upregulates mRNA expression of survivin‐2α. Taken together, these results indicate that survivin identifies human KSCs. Expression of nuclear survivin could reflect the different behavior between KSCs in vitro and in vivo, in terms of proliferation. Finally, survivin could be part of the “niche” protection by preventing anoikis in KSCs.

Photodynamic therapy for basal cell carcinoma: clinical and pathological determinants of response

Background  Photodynamic therapy (PDT) is increasingly used in the treatment of basal cell carcinoma (BCC). However, scant information is available about the impact of both patient‐ and lesion‐related characteristics on the effectiveness of therapy. Therefore, on the basis of the current data, it is difficult to draw clear‐cut indications to use PDT for treatment of BCC in clinical practice.

Substance P levels are decreased in lesional skin of atopic dermatitis

Abstract There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 ± 0.03 vs. 0.97 ± 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.

Cutaneous lesions as initial signs of interferon α-induced sarcoidosis: report of three new cases and review of the literature

Sarcoid reactions are well‐recognized adverse events during interferon (IFN) therapy. They are frequently underdiagnosed because misinterpreted as IFN‐induced side effects. Sarcoid cutaneous lesions may therefore represent useful hints to an early diagnosis, but their incidence is unknown. We report three new cases of mono‐localized, purely cutaneous IFNα‐induced sarcoidosis. In addition, an extensive review of the literature, with special attention to skin involvement, was performed through a PubMed search. The analysis of the retrieved articles showed that cutaneous lesions are frequent signs of IFN‐induced sarcoidosis. Skin involvement is documented in 56% of the reports and it appears among the presenting and diagnostic signs of a sarcoid reaction in 51%. Special attention to dermatologic signs is imperative in the course of IFN therapy because even minimal skin involvement may offer a clue to an early diagnosis of IFN‐induced sarcoidosis.

Skin levels of vasoactive intestinal polypeptide in atopic dermatitis

SummaryAtopic dermatitis (AD) can be exacerbated by various factors, including emotional stress, scratching and sweating. The aim of the present study was to evaluate the hypothesis that the inflammatory reaction in AD is also neurogenic. For this purpose, the levels of vasoactive intestinal polypeptide were measured radioimmunologically in whole-tissue homogenates of lesional skin of 13 patients with atopic dermatitis. Radioimmunoassay was performed using an antiserum, AH78, recognizing the carboxy-terminal fragment vasoactive intestinal polypeptide (22–28). Vasoactive intestinal polypeptide immunoreactivity was detected in relatively low amounts in control skin (0.428±0.08 pmol/g tissue), whereas a marked increase in the peptide was observed in lesional skin of patients with atopic dermatitis (5.62±1.25 pmol/g tissue). These results seem to suggest that vasoactive intestinal polypeptide could have a pathogenetic relevance in skin lesions of atopic dermatitis.

Metastatic Basal Cell Carcinoma With Squamous Differentiation Report of a Case With Response of Cutaneous Metastases to Electrochemotherapy

BACKGROUND Metastatic basal cell carcinoma is a rare disease with poor prognosis. Palliative therapeutic approaches include surgery, radiotherapy, and/or chemotherapy. These treatment modalities are invasive and risky and associated with relevant adverse effects. Electrochemotherapy is a recently described therapy that relies on the permeation of cancer cell membranes by electrical pulses to enhance cytotoxic drug penetration. It has been successfully used in the treatment of primary and metastatic skin cancers. We report a case of metastatic basal cell carcinoma in which electrochemotherapy was effective in inducing local regression of skin metastases. OBSERVATIONS A 75-year-old man presented with a pigmented, deeply infiltrating nodule in the right axilla manifesting as basal cell carcinoma with squamous differentiation at histopathologic examination. Despite 2 wide surgical resections involving lymphadenectomy with axillary vein substitution and systemic chemotherapy, a progressive metastatic spreading, both cutaneous and visceral, occurred in the following 2 years. Three successive sessions of electrochemotherapy with bleomycin sulfate were then performed on isolated skin metastases. The treatment was well tolerated and led to a rapid clinical and histologic regression of the treated lesions. Conclusion Electrochemotherapy is an effective and well-tolerated adjunct to the therapeutic options in metastatic basal cell carcinoma, characterized by an advantageous risk-benefit ratio and minimal downtime.

Reconstruction of Nasal Skin Cancer Defects with Local Flaps

Reconstruction of nasal defects must preserve the integrity of complex facial functions and expressions, as well as facial symmetry and a pleasing aesthetic outcome. The reconstructive modality of choice will depend largely on the location, size, and depth of the surgical defect. Individualized therapy is the best course, and numerous flaps have been designed to provide coverage of a variety of nasal-specific defects. We describe our experience in the aesthetic reconstruction of nasal skin defects following oncological surgery. The use of different local flaps for nasal skin cancer defects is reported in 286 patients. Complications in this series were one partial flap dehiscence that healed by secondary intention, two forehead flaps, and one bilobed flap with minimal rim necrosis that resulted in an irregular scar requiring revision. Aesthetic results were deemed satisfactory by all patients and the operating surgeons. The color and texture matches were aesthetically good, and the nasal contour was distinct in all patients. All scars were inconspicuous and symmetrical. No patient had tenting or a flat nose.

Pathologic Changes After Photodynamic Therapy for Basal Cell Carcinoma and Bowen Disease A Histologic and Immunohistochemical Investigation

OBJECTIVE To investigate the in vivo reactions and the mechanisms of cell death after photodynamic therapy (PDT) for cutaneous carcinomas. Photodynamic therapy is a new treatment modality for nonmelanoma skin cancers. Its effects on target tissue have been well investigated in vitro, where apoptosis appears to be the main effector mechanism, but its effects remain undefined in vivo. DESIGN Skin biopsy specimens were obtained sequentially after PDT for basal cell carcinoma and in situ squamous cell carcinoma (Bowen disease). Evidence from routine histologic evaluation was compared with a panel of apoptosis-related (TUNEL [terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling], caspase-3, and Bcl-2) and inflammatory (CD4, CD8, CD20, CD68, and CD56) markers. We used electron microscopy to evaluate cell damage at the ultrastructural level. MAIN OUTCOME MEASURES Evidence of the mechanisms of tumor cell damage after PDT, detection of histologic and/or immunohistochemical signs of apoptosis, and time course of the tumor destruction and inflammatory reaction. RESULTS Early epidermal damage and an acute dermal inflammatory response were detected 15 minutes after PDT. In basal cell carcinoma, nodule damage progressed from scant apoptotic cells seen at the dermal-epithelial junction to massive destruction seen after 1 and 2 days. The periphery of the basaloid nodules consistently showed earlier and predominant damage, as demonstrated by the perfect coincidence of histologic and immunohistochemical evidence with apoptotic markers (TUNEL and caspase-3 staining). Fibrosis and lentigolike changes were seen in late biopsy specimens. CONCLUSIONS This study defines the time course and characteristics of the skin tumor response to PDT. Taken together, our observations suggest that direct damage to cancer cells is the main effector mechanism leading to PDT response. The involvement of apoptosis is demonstrated by the simultaneous appearance of histologic, immunohistochemical, and ultrastructural markers that occur in the early phases of the cutaneous reaction to PDT. These observations could help to develop future refinements of the PDT technique.