Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma.

BACKGROUND: This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α-2a (PEG-IFN α-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: PEG-IFN α-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 µg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: PEG-IFN α-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360-µg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-µg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-µg group (CR, 50%; PR, 0%), 83% in the 270-µg group (CR, 67%; PR, 17%), and 66% in the 360-µg group (CR, 33%; PR, 33%). CONCLUSION: PEG-IFN α-2a at doses up to 360 µg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-α preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA).

Lipocalin-2 is expressed by activated granulocytes and keratinocytes in affected skin and reflects disease activity in acne inversa/hidradenitis suppurativa.

BACKGROUND: Acne inversa (AI)/hidradenitis suppurativa is a chronic inflammatory disease characterized by painful axillary, inguinal and perianal skin lesions with deep-seated nodules, abscesses and fistulae. OBJECTIVES: This study aimed to identify and characterize the key players in AI pathogenesis. METHODS: Epidemiological and anamnestic data for patients with AI were collected, and blood and skin samples were also taken. Healthy participants and patients with psoriasis served as controls. Assessment of samples and cultures of primary cells was performed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction on reverse transcribed mRNA, and immunohistochemistry. RESULTS: Of 35 mediators quantified in the blood of patients with AI, lipocalin-2 (LCN2) appeared as one of the most significantly upregulated parameters compared with healthy participants [85·8 ± 12·2 (n = 18) vs. 41·8 ± 4·2 (n = 15); P < 0·001]. Strongly elevated LCN2 expression was present in AI lesions, with granulocytes and keratinocytes being sources of this expression. In vitro, these cells upregulated LCN2 production in response to tumour necrosis factor (TNF)-α, and a positive relationship between systemic TNF-α and LCN2 levels (rs = 0·55, P = 0·011; n = 20) was evident for AI. LCN2 blood levels correlated with AI disease severity (rs = 0·65, P < 0·001; n = 29), but not with disease duration, age, sex, body mass index or smoking habit. Detailed analyses revealed a link with the number of skin regions containing nodules and fistulae, but not scars. CONCLUSIONS: LCN2 might serve as a blood biomarker for the objective assessment of inflammatory activity in AI. We suggest a self-amplification loop comprising TNF-α, neutrophilic granulocytes and LCN2, which contributes to the recurrent skin neutrophil infiltration in AI, clinically evident as pus.

Pattern of response in patients with moderate-to-severe psoriasis treated with etanercept.

BACKGROUND: Etanercept (ETN) 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks, followed by 50 mg QW in all subjects to Week 24 improved psoriasis in patients with concomitant psoriatic arthritis in the PRESTA trial. OBJECTIVES: To use data from PRESTA to evaluate the effect of ETN in the treatment of psoriasis by Psoriasis Area Severity Index (PASI) body-region and component, and determine if PASI responses correlate with the Dermatology Life Quality Index (DLQI). METHODS: Median time to 75% improvement in PASI (PASI75), body- and component-specific subscales over 24 weeks were estimated. Pearson correlation coefficients determined the association between DLQI score and PASI total score, body- and component-specific subscales with ETN treatment at baseline and up to Week 24. RESULTS: In total, 748 patients from PRESTA were included (ETN 50 mg QW/QW, n = 371; BIW/QW, n = 377). Patients achieved PASI75 total score and 75% improvements in all body regions and components faster on ETN 50 mg BIW/QW than QW/QW (all P < 0·05). Median time to 75% improvement was faster for the head and trunk followed by upper and lower extremities, and for induration and desquamation followed by erythema and total area. Weak to moderately positive correlations between improvements in DLQI and PASI total score (r = 0·223-0·463), all PASI body-specific (r = 0·114-0·432) and component-specific (r = 0·178-0·478) subscales were observed over 24 weeks. CONCLUSIONS: Etanercept treatment-response appears to occur in a body- and component-specific manner. Changes in quality of life are not captured by PASI or its subscales.

Cutaneous carotenoids: the mirror of lifestyle?

Carotenoids could serve as marker substances of the antioxidant status of the human skin. In the present study, an optical skin scanner was used to analyse the carotenoid concentration obtained from 4 volunteers over a period of 13 days. The measurements were taken daily at different time points. In addition, the volunteers were asked to keep track of their daily nutritional behaviour and stress situations in a diary. It was found that the carotenoid values reflect clearly the nutritional behaviour and stress situations of the volunteers. While a steady, increased intake of fruit and vegetables resulted in a gradual increase in the dermal carotenoid values for several days, stressful situations entailed an immediate decline in these values. Although the impact of healthy nutrition on the antioxidant protection system is generally known and notwithstanding the small number of cases, the present study clearly demonstrates that the avoidance and/or reduction of stress is similarly important in order not to counteract or nullify the results achieved by healthy nutrition.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Long-term outcome of intravenous therapy with rituximab in patients with primary cutaneous B-cell lymphomas.

BACKGROUND: The monoclonal antibody rituximab directed against the B-cell antigen CD20 was approved for the treatment of B-cell lymphomas and maintenance therapy in follicular lymphomas more than a decade ago. However, median follow-up in case series of intravenous rituximab therapy in primary cutaneous B-cell lymphomas (CBCL) lasts only up to 3 years. We retrospectively analysed a cohort of CBCL patients treated with rituximab to gain more long term information. PATIENTS AND METHODS: Eighteen patients, treated intravenously with rituximab for a primary cutaneous B-cell lymphoma [follicle centre lymphoma (PCFCL), n = 11; diffuse large B-cell lymphoma, leg type (PCLBCL, leg type), n = 5; marginal zone B-cell lymphoma (PCMZL), n = 2] were included. The response rate (RR), time to relapse (TTR), and course of the disease after treatment were analysed. RESULTS: The overall RR was 89% (16 of 18 patients). Within the median follow-up time of 52 months, 81% (13 of 16) of patients experienced a relapse; the median TTR was 25 months. The duration of remission was significantly shorter in patients presenting with generalized skin lesions at start of therapy. Both nonresponding patients suffered from PCLBCL, leg type, with extracutaneous manifestations. In responders severe adverse events, the occurrence of extracutaneous dissemination or nodal lymphomas were not observed during follow-up. CONCLUSIONS: Therapy with rituximab is effective and safe for the treatment of PCFCL, but relapses, in particular in patients with generalized skin involvement, are commonly observed. However, all patients with relapses responded well to treatment and therefore maintenance therapy does not seem to be indicated. Patients with PCLBCL, leg type, should receive chemotherapy in addition to rituximab.

[CD30-positive anaplastic large cell T-cell lymphoma developing during immunosuppressive therapy of pityriasis rubra pilaris with ustekinumab]. / CD30-positives anaplastisch großzelliges T-Zell-Lymphom unter immunsuppressiver Therapie einer Pityriasis rubra pilaris mit Ustekinumab.

The development of malignancies during therapy with biologics has been discussed controversially. A patient with extensive pityriasis rubra pilaris failed to respond to standard therapeutic approaches. While receiving immunomodulatory therapy, lastly with ustekinumab, the patient developed a CD30(+) anaplastic large cell lymphoma.

Alcohol consumption decreases the protection efficiency of the antioxidant network and increases the risk of sunburn in human skin.

In recent years, epidemiological data has demonstrated that alcohol consumption is a risk factor for sunburn, melanoma and nonmelanoma skin cancer. We hypothesized that if the concentration of the antioxidants in the skin has already decreased due to alcohol consumption, then an adequate neutralization of the free radicals induced by ultraviolet light cannot be performed. Based on this hypothesis, we determined the carotenoid concentration in the skin and the minimal erythema dose (MED) of 6 male human volunteers before and after consumption of alcohol or alcohol and orange juice combined. The results showed a significant decrease in the carotenoid concentration in the skin and the MED after alcohol consumption, but no significant decrease after a combined intake of alcohol and orange juice.

Is 'class effect' relevant when assessing the benefit/risk profile of a biologic agent?

Psoriasis is a chronic, genetically predisposed skin disorder, characterised by thickened scaly plaques. Although no therapy is recognised as curative, therapies aimed at symptom control include biologic agents that are generally designed to block molecular activation of cellular pathways of a pathogenic immune response. Although biologics are often described as a class, they can be further sub-classified according to properties including structure and molecular target. For example, the two main groups of biologics for the treatment of psoriasis are those targeting cytokines and those targeting T-cells or antigen-presenting cells. Agents that inhibit cytokines can be broadly split into anti-p40 agents, which target the p40 subunit of IL-12 and IL-23 (such as ustekinumab), and anti-TNF agents. Anti-TNF agents may then be further divided into soluble receptors (etanercept) and monoclonal antibodies (adalimumab and infliximab). Even within the same subclass, agents may display variations in structure, function, route of administration and pharmacokinetics, which are reflected in their clinical profiles. For example, of the TNF antagonists, infliximab, provides a rapid onset of response, high efficacy, high peak serum concentrations, anti-granulomatous activity, potential for tuberculosis reactivation and frequent antibody formation; adalimumab provides a fast response, high efficacy, potential for tuberculosis reactivation and the possibility of antibody formation; and etanercept provides a slower response, good efficacy, rare antibody formation and is rarely linked to tuberculosis cases. This suggests that biologic agents exhibit unique properties, which appear to be more relevant than a 'class effect' in assessing risk-benefit profiles for this diverse group of drugs. With a range of agents available, studying the immunogenesis of psoriasis is likely to be useful in profiling individuals best suited to the characteristics of particular drugs. It should also be noted that because differences between agents may affect safety profiles, long-term patient registries are an important tool to assess tolerability and develop guidelines for the most effective use of these drugs.

[Cutaneous malignant lymphomas. Update on diagnosis and therapy of cutaneous T-cell lymphomas]. / Maligne Lymphome der Haut. Update zu Diagnostik und Therapie kutaner T-Zell-Lymphome.

Cutaneous T-cell lymphomas represent extranodal non-Hodgkin lymphomas of mature T-cells, which accumulate in the skin. They have been recognized as a heterogeneous group with distinct variability in clinical presentation and histopathology, with divergent biological behaviour and prognosis. Therefore the exact diagnosis is an important prerequisite for an adequate and stage-adapted treatment.

The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.

BACKGROUND: Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group with Sézary syndrome (SS) as one of the most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via upregulation of the proto-oncogene MYC. MYC-induced transformation usually requires deleterious alterations of key apoptotic genes including p53; however, p53 functionality and mutation status in SS are unclear. OBJECTIVES: We investigated functionality of p53 signalling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing. METHODS: We analysed the apoptosis induction due to nutlin-3 treatment in various SS cell lines and primary patient samples by annexin V/propidium iodide staining. Induction of p53 target genes was analysed by immunoblotting, and TP53 was sequenced at the mRNA and DNA level. RESULTS: We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells. CONCLUSIONS: In accordance with the importance of MYC deregulation in SS, p53 signalling is frequently nonfunctional in SS. However, although most likely ineffective as exclusive treatment in SS, it remains possible that pharmacological p53 activation could be beneficial in combination with other approaches including classical chemotherapeutics.

Evaluation of different methods in the follow-up of patients with indolent types of primary cutaneous lymphomas.

BACKGROUND: Primary cutaneous lymphomas (CLs) are a heterogeneous group of diseases arising from B or T lymphocytes. CLs are grouped according to their clinical behaviour into indolent, intermediate and aggressive types. Indolent CLs respond well to therapy but frequently relapse, resulting in prolonged periods of follow-up. OBJECTIVES: To evaluate the outcome of follow-up examinations in indolent CL. METHODS: We retrospectively analysed a cohort from a CL outpatient clinic at a tertiary referral centre. Seventy-five patients with indolent cutaneous T-cell lymphomas (CTCLs) and 34 patients with indolent cutaneous B-cell lymphomas (CBCLs) were included. The value of clinical examination, blood tests and imaging procedures for detection of recurrence or progression was assessed. RESULTS: In patients with CTCL all but one disease recurrences were detected by clinical examination. Lymph node or organ involvement was detected by imaging procedures in seven patients, of whom all but one had recurrent or persistent CL lesions. In CBCL all recurrences were detected by clinical examination. CONCLUSIONS: Patients with indolent CL confined to the skin should be followed primarily by clinical examination. However, in patients who are refractory to treatment regular screening of lymph nodes by ultrasound may enable earlier detection of disease recurrence or progression.

Uptake of antioxidants by natural nutrition and supplementation: pros and cons from the dermatological point of view.

The pros and cons of the systemic and topical application of antioxidant substances are a subject of intense discussion among experts, with resulting confusion for consumers and producers. The objective of the present article is to clarify the various uncertainties relating to the use of antioxidant substances in dermatology. Whereas inappropriate application of antioxidant substances (concerning their concentration and composition) might induce harmful effects, the consumer will definitively benefit from physiological concentrations and compositions of antioxidants. The most suitable method is the consumption of natural antioxidants in the form of fruit and vegetables, for example. In addition, the skin, which also accumulates antioxidant substances, may profit from a sufficient antioxidative level, as damage induced by sun radiation in addition to skin aging is reduced.

Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sézary syndrome.

Despite recent therapeutic improvements, the prognosis for patients suffering from Sézary syndrome (SS), a disseminated form of cutaneous T-cell lymphomas, is still poor. We identified bi- and monoallelic deletions of the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) in a high proportion of SS patients as well as biallelic A20 deletion in the SS-derived cell line SeAx. Furthermore, we demonstrate that inhibition of A20 activates the NF-κB pathway thereby increasing the proliferation of normal T lymphocytes. On the other hand, the reconstitution of A20 expression slowed down the cell cycle in SeAx cells. Recently A20 inactivation has been reported in various B-cell lymphomas. In this study, we show that A20 is also a putative tumor suppressor in the T-cell malignancy-SS.

Algorithm for detection of small-bowel metastasis in malignant melanoma of the skin.

BACKGROUND AND STUDY AIM: The aim of this study was to develop an algorithm to detect small-bowel metastasis (SBM) of melanoma by sequential laboratory parameters and pan-intestinal endoscopy (PIE) including video capsule endoscopy (VCE). PATIENTS AND METHODS: A total of 390 melanoma patients (AJCC stage I/II/III/IV, 140/80/121/49) were screened for signs of intestinal blood loss (fecal occult blood test [FOBT] or overt bleeding) in an open, multicenter, prospective study, and those who were positive underwent PIE. Independent of the presence of intestinal bleeding, all stage IV patients were offered PIE. Follow-up was obtained in 357 patients (91.5 %) for a median of 16 months. We undertook to identify possible associations between SBM and clinical and laboratory data. Survival data were analyzed with regard to clinical and laboratory data and small-bowel findings. RESULTS: Intestinal blood loss was suspected in 49 of 390 patients (12.6 %), 38 of whom (77.6 %) agreed to undergo endoscopy. In 10 patients, SBM was detected by VCE (intention-to-diagnose, 20.4 %; AJCC III, n = 2; AJCC IV, n = 8). The SBM was resected in five patients. Total detection rates of SBM were 14 of 49 patients in stage IV (28.6 %, intention-to-diagnose), 2 of 121 in stage III (1.7 %), and 0 in stage I/II. In FOBT-positive patients, SBM detection rates were 72.7 %, 14.3 %, and 0 % in tumor stages IV, III, and I/II, respectively. Positive FOBT proved to be an independent negative prognostic factor for total survival in stage III and IV melanoma. CONCLUSIONS: SBMs are frequent in advanced melanoma. In stage III patients, screening for intestinal blood loss by PIE may help to identify SBMs. In stage IV, indication for PIE should depend on the individual consequences of detecting SBM, but not on bleeding symptoms alone.

Interaction between carotenoids and free radicals in human skin.

Environmental factors like air pollutants, radiation of the sun and stress factors such as illness, smoking, or alcohol abuse produce free radicals in the human tissue as well as in the skin. Free radicals serve as the main cause for premature skin aging. Additionally, they also contribute towards immunosuppression and the formation of skin diseases including cancer. The human organism has developed a protection system against the destructive action of free radicals by means of the antioxidant network. In the present study, the interaction of free radicals and carotenoid antioxidants in the human skin under in vivo conditions was investigated and summarized. The measurement of carotenoids in human skin was performed in vivo using resonance Raman spectroscopy.

Non-invasive diagnosis and monitoring of actinic cheilitis with reflectance confocal microscopy.

BACKGROUND: Actinic cheilitis (AC) represents the equivalent of actinic keratosis on the lip. Various treatment modalities are available and the efficacy of diclofenac in hyaluronic acid has recently been described. Reflectance confocal microscopy (RCM) is a non-invasive imaging technique which has recently been applied for the diagnosis of actinic keratoses. Herein, we describe the applicability of RCM for the diagnosis of AC and for monitoring of treatment response of AC to diclofenac in hyaluronic acid. METHODS: Ten Caucasian patients with clinical suspicion for AC were included in this study. To obtain a non-invasive diagnosis, RCM was performed at baseline, followed by biopsy and respective confocal-histopathological correlation. Six patients with a histological diagnosis of AC were treated with diclofenac in hyaluronic acid, whereby monitoring was performed by RCM. RESULTS: Reflectance confocal microscopy was able to correctly identify 6/7 cases of AC and 3/3 cases of benign lesions. The most important RCM criteria for diagnosis of AC were cellular atypia at the stratum spinosum and granulosum with atypical honeycomb pattern. One patient with AC was misclassified as inflammatory cheilitis by RCM as it showed marked inflammatory response and lacked clear signs of cellular atypia on RCM imaging. Following topical treatment with diclofenac gel, 5/6 patients (83%) showed a good treatment response with regression of dysplasia on consecutive RCM examination. CONCLUSIONS: Reflectance confocal microscopy is a promising tool for the non-invasive diagnosis and monitoring of actinic cheilitis. However, marked inflammation represents a potential diagnostic pitfall. In this regard, biopsy should be performed in doubtful cases.

[cFLIP diminishes CD95-induced apoptosis of CD30-stimulated cutaneous anaplastic large T cell lymphoma (cALCL) cells]. / Kutanes anaplastisches großzelliges Lymphom. Apoptoseresistenz durch CD30-induzierte cFLIP-Expression.

Stimulation of the TNF receptors CD30 and CD95 exerts opposite effects. Crosstalk of both receptors is unknown. We aimed to reveal regulatory mechanisms of CD30-induced effects on CD95 signaling of cALCL cell lines. "CD30/CD95 crosstalk analysis" was performed in cALCL cell lines by comparison of CD30 or CD95 stimulation and CD30/CD95 costimulation. Receptor expression and induction of apoptosis was investigated by flow cytometry. mRNA expression of CD30-inducible genes (cFLIP, TRAF1, cIAP2, and A20) was compared by semiquantitative reverse transcription (RT-RQ-) PCR in stimulated and unstimulated cells. Protein expression of IκBα, p100/p52, caspase-8, caspase-3, and cFLIP was analyzed by immunoblotting. A lentiviral-based shRNA-mediated approach was used to inhibit cFLIP expression. CD30/CD95 crosstalk experiments revealed that CD30 ligation leads to NFκB-mediated cFLIP upregulation in cALCL cells, which in turn enhanced resistance to CD95-mediated apoptosis. This effect is based on the CD30-induced upregulation of cFLIP. Knockdown of cFLIP restores sensitivity to CD95-mediated apoptosis. We conclude that the anti-apoptotic function of CD30 antibodies should be kept in mind if CD30 antibody-based therapeutic concepts for ALCL lymphoma are considered.

Diagnostic tools in mycosis fungoides.

Cutaneous T-cell lymphomas (CTCL) represent clonal proliferations of neoplastic skin homing T-cells. Within the group of primary CTCL, mycosis fungoides (MF) is the most common entity, affecting the skin as a primary site. MF initially presents in the skin with a slow indolent course of a characteristic stepwise progression from patches to plaques and tumors accompanied by distinctive histological changes. Routine diagnosis is based on these clinical and histological features. However, due to similarities with benign lymphoproliferative or reactive skin diseases, especially at the initial presentation of the disease, diagnosis can be difficult. Although the etiology of mycosis fungoides is still unknown, important insights have been gained in the immunological and genetic perturbations, which are associated with the disease. In the last years the emergence of molecular genetic techniques allowing to analyze the clonality status in lymphocytic infiltrates, has provided new tools with the potential to increase the accuracy of diagnosis, staging and therefore stage-adapted treatment. Nevertheless, it is important to notice that some limitations restrict the predictive value of the results obtained by these analyses. Diagnostic tool of MF, including clinical, histo- and immunohistological findings as well as molecular genetic analysis will be covered in this review.

Diagnostic tools in Sezary syndrome.

Primary cutaneous T-cell lymphomas (CTCL) mycosis fungoides (Mf) and Sézary syndrome (SS) belong to the group of non-Hodgkin lymphomas which are characterized by clonally proliferating CD4+ cells localized in the skin. SS is a leukemic variant of CTCL and is characterized by erythroderma, generalized lymphadenopathy, and circulating atypical T-cells with cerebriform nuclei, so-called Sézary cells. Palmoplantar hyperkeratosis, generalized alopecia, and severe pruritus are additional symptoms that are associated with SS. Patients have a poor prognosis with an estimated five year survival of 12.5 to 27 percent and estimated median survival of 14.5 to 18 months. The incidence of MF and also SS has increased with time and may be in part due to improved clinical awareness and especially advances in diagnostic testing.