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Background Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. Objective To evaluate the frequency and prognostic significance of associated HM and non‐HM in LyP patients. Methods In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. Results After a median follow‐up of 120 months (range, 6–585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large‐cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B‐cell (n = 14) or myeloid origin (n = 5). Even after a 25‐year follow‐up period, percentages of associated HM did not exceed 20%. Thirty‐nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow‐up, after a median of 68 months (range of 3–286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin‐limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4–3.3) for non‐HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. Conclusions An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring., Linked article: F. Rongioletti. J Eur Acad Dermatol Venereol 2020; 34: 216–217. https://doi.org/10.1111/jdv.16157.

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BackgroundThere is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment.ObjectivesTo assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies.MethodsIn this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11).ResultsTreatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%).ConclusionsPatients with five or less lesions should be treated with low-dose RT (2 x 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease.What's already known about this topic?There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). New targeted therapies are evaluated without knowledge of the efficacy of conventional therapies.What does this study add?This study evaluated the efficacy of conventional therapies for multifocal C-ALCL. Radiotherapy and low-dose methotrexate are suitable options in patients with five or less and more than five lesions, respectively. Targeted therapies may be considered in rare patients who are refractory to methotrexate or developing extracutaneous disease.Linked Comment:Kempf. Br J Dermatol 2018; 179:565-566. Respond to this article

Background: Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin-directed therapies (SDTs). Recent studies distinguished indolent (early-stage FMF) and more aggressive (advanced-stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined.Objectives: To evaluate initial treatment results in patients with early-and advanced-stage FMF.Methods: A study was undertaken of 203 patients (84 early-stage, 102 advanced-stage, 17 extracutaneous FMF) included in the Dutch Cutaneous Lymphoma Registry between 1985 and 2014. Type and results of initial treatment were retrieved from the Dutch Registry. Main outcomes were complete remission (CR); sustained complete remission; partial remission (PR), >50% improvement; and overall response (OR; CR + PR).Results: Patients with early-stage FMF were treated with nonaggressive SDTs in 67 of 84 cases resulting, respectively, in CR and OR of 28% and 83% for monotherapy topical steroids, 0% and 83% for ultraviolet B (UVB), and 30% and 88% for psoralen plus ultraviolet A (PUVA). In patients with advanced-stage FMF these SDTs were less effective (combined CR and OR 10% and 52%, respectively). In patients with advanced-stage FMF local radiotherapy (CR 63%; OR 100%), total skin electron beam irradiation (CR 59%; OR 100%) and PUVA combined with local radiotherapy (CR 5%, OR 75%) were most effective.Conclusions: The results of the present study demonstrate that not all patients with FMF should be treated aggressively. Patients with early-stage FMF may benefit very well from standard SDTs also used in early-stage classic MF and have an excellent prognosis.

Contains fulltext : 171336.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe trends in incidence, treatment and survival of patients with basal cell carcinomas and melanomas of the vulva. Also to compare survival of vulvar and cutaneous melanoma patients. METHODS: All women with a vulvar malignancy between 1989 and 2012 were selected from the Dutch Cancer Registry (n=6436). Standardized incidence rates, estimated annual percentage change (EAPC) and 5-year relative survival rates were calculated for basal cell carcinomas (BCCs) and melanomas. Patients with vulvar melanomas were matched to women with cutaneous melanomas on period of diagnosis, age, Breslow thickness, tumour ulceration, lymph node status and distant metastases. Differences in survival were evaluated using Kaplan-Meier curves and the log rank test. RESULTS: 489 women were diagnosed with a BCC and 350 with a melanoma of the vulva. The EAPC in incidence for melanomas was 0.2% and 1.1% for BCCs. Eighty-six percent of patients with BCC underwent surgical treatment in 1989-2006 and 95% in 2005-2012. Forty-five percent with BCC and 79% with melanoma were treated in a referral centre. Five-year relative survival for BCCs was 100% and for melanomas survival increased from 37% (95%CI 28-47%) in 1989-1999 to 45% (95%CI: 37-54%) in 2000-2012. Five years after diagnosis survival of women with vulvar melanoma was 15% lower compared to matched cutaneous melanoma patients (p=0.002). CONCLUSION: No trends in age-adjusted incidence have been observed but more patients with BCC received surgical treatment over time. Having had vulvar BCC did not affect life expectancy. Well-known prognostic factors explained most of the differences in survival between cutaneous and vulvar melanoma patients, however a difference of 15% remained unexplained.

Background Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived myeloid and plasmacytoid dendritic cells (mDCs and pDCs). Methods In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity (DTH)-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and OS. Radiological responses were assessed by regular as well as ferumoxtran-10 enriched MRI and 68Ga-PSMA PET/CT scans according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) DTH-skin test-derived antigen specific T cells were present more frequently in patients with radiological non-progressive disease compared to progressive patients (5/13 (38%) vs. 0/8 (0%)). In dm+ and IFN-γ+ patients median rPFS was 18.8 months vs. 5.1 months in patients without IFN-γ+ antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. Immunological outcomes and clinical correlates will be presented. Conclusions Immunotherapy with primary DC subsets induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with longer rPFS. Clinical trial identification NCT02692976. Legal entity responsible for the study Jolanda de Vries and Winald Gerritsen. Funding This work was supported by Stichting Afweer Tegen Kanker, Dr. Paul A.J. Speth Stichting and H2020 EU grant PROCROP (grant No 635122). Carl G. Figdor received ERC Adv Grant PATHFINDER (269019) and the NWO Spinoza grant. I. Jolanda M. de Vries received NWO-Vici grant (918.14.655). Disclosure All authors have declared no conflicts of interest.

Item does not contain fulltext The Dutch melanoma guideline advises to examine one central block of the re-excision scar in case of a complete primary excision. To increase the evidence for this recommendation, we re-evaluated how often residual melanoma was found in re-excision specimens of a large series of completely excised melanomas. Of 1,209 Dutch melanoma cases, pathology reports of primary excisions were reviewed. Presence of melanoma in the margins was scored. All melanomas with a complete primary excision were included and pathology reports of re-excisions were reviewed. Presence of residual melanoma in the re-excision specimen and the number of blocks were scored. Slides of re-excision specimens containing residual melanoma were reviewed. Eventually, in four out of 812 melanomas (0.5 %) with a complete primary excision, residual melanoma was found in the re-excision specimen. The free margins of the primary melanomas in these cases ranged from 0.5-3.5 mm. In one case, the margin for melanoma in situ was 0.2 mm. In

BACKGROUND: Although scrotal cancer is traditionally regarded as an occupational disease, there is increasing evidence that factors which are involved in cutaneous and genital carcinogenesis might play a role in the carcinogenesis of scrotal cancer. OBJECTIVE: This exploratory study aimed to detect exposures that might have an aetiological relation with scrotal cancer. METHODS: A nationwide population-based case-control study was conducted in the Netherlands. The patients were identified through the Netherlands cancer registry. Controls were recruited among acquaintances of the cancer registry registrars. The participants completed a questionnaire that included questions on occupational exposures, naked sunbathing, use of sunbeds, skin diseases and their treatments, treatments for cancer and sexually transmitted diseases. Age-adjusted odds-ratios (ORs) were calculated. RESULTS: Forty-seven scrotal cancer patients and 125 controls completed the questionnaire. The patients were categorized according to histology of the scrotal tumours. Having had a skin disease (OR = 6.3, 95% CI = 1.8-22), especially psoriasis (OR = 8.7), increased the risk of squamous cell carcinomas (SCC) of the scrotum. A previous cancer diagnosis may affect the risk of scrotal basal cell carcinomas (BCC; OR = 4.9, 95% CI = 0.9-27.3). Furthermore, an association between the number of sexual partners and the occurrence of scrotal sarcoma was found. CONCLUSION: Scrotal SCCs may be related with skin diseases or skin disease treatments. Having had cancer may be a risk factor for a BCC of the scrotum. Scrotal sarcomas seem to be correlated with the number of sexual partners. This study suggests that scrotal cancer has characteristics of both cutaneous and genital carcinogenesis.

On the occasion of the 70th annual meeting of the American Academy of Dermatology in San Diego the ILDS Executive Committee hosted a cocktail reception in the evening of 18 March. The reception, held at the Marriott Hotel on an evening of several competing attractions, was well attended by friends of the ILDS, who stopped by for a drink and a chat. Jean Bolognia and Chris Griffiths acted as official ILDS meeters and greeters for the guests. Our president, Wolfram Sterry gave a short speech of welcome and provided an update for those present on the recent achievements of and plans for the ILDS. The announcement of the Berlin summit was particularly well received by our member societies. Jerry Shapiro then took the floor to apprise us of the arrangements for the Vancouver World Congress, these too were greeted with enthusiasm...

BACKGROUND: Knowledge about quality of life and sexual health in patients with genital psoriasis is limited. OBJECTIVES: We studied quality of life and sexual function in a large group of patients with genital psoriasis by means of validated questionnaires. In addition, we evaluated whether sufficient attention is given by healthcare professionals to sexual problems in patients with psoriasis, as perceived by the patients. METHODS: A self-administered questionnaire was sent to 1579 members of the Dutch Psoriasis Association. Sociodemographic patient characteristics, medical data and scores of several validated questionnaires regarding quality of life (Dermatology Life Quality Index) and sexual health (Sexual Quality of Life Questionnaire for use in Men, International Index of Erectile Function, Female Sexual Distress Scale and Female Sexual Function Index) were collected and analysed. RESULTS: This study (n = 487) shows that psoriasis has a detrimental effect on quality of life and sexual health. Patients with genital lesions reported even significantly worse quality of life than patients without genital lesions (mean +/- SD quality of life scores 8.5 +/- 6.5 vs. 5.5 +/- 4.6, respectively, P < 0.0001). Sexual distress and dysfunction are particularly prominent in women (reported by 37.7% and 48.7% of the female patients, respectively). Sexual distress is especially high when genital skin is affected (mean +/- SD sexual distress score in patients with genital lesions 16.1 +/- 12.1 vs. 10.1 +/- 9.7 in patients without genital lesions, P = 0.001). The attention given to possible sexual problems in the psoriasis population by healthcare professionals is perceived as insufficient by patients. CONCLUSIONS: In addition to quality of life, sexual health is diminished in a considerable number of patients with psoriasis and particularly women with genital lesions have on average high levels of sexual distress. We underscore the need for physicians to pay attention to the impact of psoriasis on psychosocial and sexual health when treating patients for this skin disease.

BACKGROUND: Psoriatic lesions may involve nearly all sites of the body. Involvement of the genital skin is frequently classified as part of intertriginous psoriasis without special awareness and treatment for this presentation of the disease. Gaining knowledge about the frequency of the involvement of genital skin in these patients will improve the overall care for patients with psoriasis. OBJECTIVES: We studied the prevalence of genital psoriasis in the Netherlands and epidemiological characteristics of this specific presentation of the disease. Furthermore, we studied the relation between flexural and genital psoriasis. PATIENTS/METHODS: A self-administered questionnaire was sent to all 5300 members of the Dutch Psoriasis Society. Sociodemographic patient characteristics and disease-related data (such as localization of psoriatic lesions, involvement of the genitalia, age at onset of genital psoriasis and severity of genital psoriatic lesions) were collected and analysed. RESULTS: A response rate of 37% was achieved. Almost 46% of the responding patients with psoriasis, that is 16.5% of all potential responders (n = 5300), report genital involvement at some time during the course of their disease. The genitalia can become affected at any age. Many patients with current genital involvement (38%) do not have the flexural skin affected. CONCLUSIONS: A large part of patients with psoriasis suffer from genital psoriasis, which was not associated with flexural involvement in at least one third of them. More attention to the genital region is required in the current standard treatment of both male and female psoriatic patients at any age.

Leukotriene B4 (LTB4) receptor antagonists have been the subject of several studies in the treatment of inflammatory diseases, including psoriasis. A novel oral LTB4 antagonist, VML 295 (LY-293111) has recently been developed and has a pronounced effect on epidermal inflammatory parameters. However, oral treatment of psoriasis for 4 weeks did not result in a decrease in disease severity. The present study was performed in order to investigate whether prolonged treatment with VML 295 up to 8 weeks has a beneficial effect on the overall severity of psoriasis. Moreover, we studied to what extent VML 295 is able to prevent relapse in psoriasis. In the present study, 35 patients with stable chronic plaque psoriasis were included. A representative plaque of at least 16 cm2 was initially treated with clobetasol-17-propionate lotion under hydrocolloid occlusion in all patients. Clearance was achieved within 6 weeks in 31 patients. After clearance, the patients were randomized to treatment and received oral VML 295 capsules 200 mg twice daily or placebo for 8 weeks. Twenty-five patients completed the study. The psoriasis area and severity index (PASI) was assessed before treatment, at clearance, and on days 15, 29, 43 and 5 7 of the treatment period. Biopsies were taken from the treated lesion before treatment, after clearance and at relapse, and cells were analysed by flow cytometry with markers for differentiation (keratin 10), inflammation (vimentin), and proliferation (DNA content). After 8 weeks of treatment, 14 of 15 VML 295-treated patients had relapsed and 11 of 16 placebo-treated patients had relapsed. A total of six patients were withdrawn. The time to relapse and the number of relapsed patients was not significantly different comparing the treatment groups. There was no significant difference in PASI scores between VML 295-treated patients and placebo-treated patients after 8 weeks of treatment. Flow cytometric parameters for differentiation, inflammation and proliferation did not show significant differences between VML 295- and placebo-treated patients. We conclude that oral VML 295 (LY-293111) is not effective in preventing relapse in psoriasis, either clinically or at the cellular level, and that in our group of patients VML 295 had no beneficial effect on overall psoriasis severity. Moreover, we conclude that further development of LTB4 modulating drugs for the treatment of psoriasis is not indicated.

The histological picture of psoriasis has been studied extensively. Several authors have investigated the differences between the centre and the margin of spreading plaques, because the margin is of great pathogenic interest as lesions enlarge by centrifugal expansion. However, little is known about the differences between the centre and the margin of stable plaques. In the present study we investigated quantitatively the differences between the centre and margin of stable psoriatic plaques with respect to differentiation, inflammation and proliferation. To quantify these parameters, we used flow cytometry. From nine patients with nonspreading, stable psoriasis, we obtained punch biopsies from the centre and from the lesional margin of a plaque, and performed a flow cytometric assessment, using the markers keratin 10 for differentiation, vimentin for inflammation, and TO-PRO-3 iodide for proliferation. We found that the quantitative parameters showed a large interindividual variability, and that there was no significant difference in the quantitative parameters for inflammation and proliferation between the centre and margin of stable plaques. However, the percentage of differentiated cells was significantly higher in the margin than in the centre. We conclude that there is a great heterogeneity within stable psoriatic plaques with respect to differentiation, inflammation and proliferation, but further quantitative studies are needed to substantiate the pathogenic relevance of the significant difference in keratinization between the centre and the margin of stable psoriatic plaques.

During the last decade, novel analogues of 1alpha,25-dihydroxy vitamin D3 have been developed for the treatment of psoriasis. Recently, the efficacy of short-term treatment with the novel derivative tacalcitol (1alpha,24-dihydroxy vitamin D3) has been documented. However, data on the long-term effect of tacalcitol on psoriatic skin are sparse. In this study, we assessed the cell characteristics of the psoriatic epidermis after treatment with tacalcitol for up to 24 weeks. We investigated how long-term treatment with tacalcitol modulates the percentages of differentiated keratinocytes, inflammation cells and basal keratinocytes, and the percentage of cells in the SG2M phase in the basal cell population. From 11 patients who were treated with tacalcitol for up to 18 months, we obtained single-cell suspensions of a representative psoriatic lesion after 0, 8, 12, 18 and 24 weeks of treatment. A Psoriasis Area and Severity Index was performed at each visit as well. Cell suspensions were stained with markers for inflammation (Vim3B4), differentiation (RKSE60) and proliferation (TO-PRO-3 iodide) and analysed flow cytometrically. Clinically, patients improved significantly after 8 weeks of treatment. This clinical effect was preserved for the rest of the period of treatment with no further significant improvement. Proliferative activity also decreased significantly after 8 weeks of treatment. Proliferation did not show further significant decreases or habituation after 12, 18 and 24 weeks. For inflammation, no statistically reliable trends could be seen. Differentiation improved significantly after 8 weeks of treatment, but decreased again significantly after 12 weeks. In the period from 12 to 24 weeks, no further significant change was observed. We conclude that tacalcitol is an effective antipsoriatic drug. Prolonged treatment with tacalcitol will generally maintain improvement at the level reached after 8 weeks. Owing to the beneficial effect on both clinical state and proliferation, tacalcitol is likely to be an adequate maintenance therapy.

Item does not contain fulltext Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus-associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs.

Background: Psoriasis in the genital area is often neglected, although it bothers a substantial number of patients. Objective: To study both the role of the physician in the treatment of genital psoriasis and the symptom intensity of these lesions as experienced by the patients. Methods: A detailed self-administered questionnaire (containing items on the role of the physician and genital symptom intensity, range 0–10) was filled in by members of the Dutch Psoriasis Society. Results: Data of 277 patients with genital psoriasis were analyzed. A total of 45.8% did not discuss the presence of genital psoriasis with their physician, 25% believed that the physician paid sufficient attention to genital lesions, and 67.8% never applied treatment for genital lesions. Mean symptom intensity ranged from 2.4 to 5.1, all scores being significantly higher for women compared to men. Severe symptoms were present in up to 43.5% of patients. Of these patients, up to 38.1% did not discuss the symptoms with their physician. Conclusion: The consultation rate for genital lesions is low, while numerous patients report a significant burden of disease.

The effects of genotype, cold storage and ploidy level were investigated on the morphogenic response of cell suspension cultures in diploid perennial ryegrass (Loliumperenne L., 2n = 2x = 14). The results suggest that the ability of immature inflorescence-derived calli to produce morphogenically-competent suspension cultures is a genotype-dependent trait. Cold storage of suspension cultures at 4°C in the dark not only extended the period of their regeneration competence, but also increased the regeneration frequency. The ploidy level of suspension cells changed from euploidy to aneuploidy with suspension culture age. In six of the nine suspension cultures, the change of ploidy level was associated with a reduction of the capacity for plant regeneration. The majority of regenerated green shoots were diploid, whereas albino shoots obtained from the same cultures were predominantly polyploid, mixoploid and chimeras. The influence of chromosomal instability and the disturbances in gene balance on the loss of morphogenic capacity of suspension cultures is discussed.

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Background: Calcipotriol and corticosteroids are established topical antipsoriatics. Previous studies have shown that combined therapy with calcipotriol and betamethasone dipropionate was more effective than monotherapy. In the present study, a recently developed combination product of calcipotriol and betamethasone dipropionate was compared with both monotherapies and the vehicle. Methods: Twenty-five psoriatic patients were treated twice daily with the combination product, monotherapy or vehicle during 4 weeks. Skin biopsies, taken before and after treatment, were analysed using a multi-parameter flow cytometric method. Parameters of inflammation (vimentin-positive cells), normal differentiation (keratin-10-positive cells) and proliferation (cells in SG2M-phase) were assessed. Results: Flow cytometric analysis showed that the combination product turned out to be more effective in reducing inflammation compared with the other treatments. Restoration of normal differentiation was more advanced in patients treated with the combination product or betamethasone dipropionate compared to the vehicle. The highest number of normally differentiated cells was seen after use of the combination product. All treatments, except for the vehicle, decreased hyperproliferation. Conclusion: This study shows that the combination product is a valuable new approach to the treatment of psoriasis.

Background: Keratin 6 (K6) and keratin 10 (K10) are markers for epidermal hyperproliferation and differentiation, respectively, and are both expressed in the suprabasal layers of the epidermis. They may be co-expressed in different stages of the spreading psoriatic lesion, but single expression can also occur. Objective: To investigate to what extent keratinocytes express K6 and K10, and to what extent they co-express K6 and K10 in different stages of the psoriatic lesion. We studied this in spreading psoriatic plaques. Methods: Three 3-mm punch biopsies were obtained from the inner involved margin of a spreading lesion, from the uninvolved skin immediately adjacent to the spreading plaque, and from the distant uninvolved skin of 8 patients with incipient psoriasis. From 9 healthy volunteers, 3-mm punch biopsies were obtained as controls. After preparation of single cell suspensions of these biopsies, a triple staining protocol was performed with markers for K6 (monoclonal antibody LHK6B), K10 (monoclonal antibody RKSE60) and DNA content (TO-PRO-3 iodide). Subsequently, cells were measured with a flow cytometer and the proportion of the markers was calculated using specific software. Results: We observed a population of K6/K10-co-expressing cells, but also populations expressing only K6. These subpopulations varied with the involvement of the lesion. There was a statistically significant difference between the inner margin and the outer margin with respect to the proportion of K6- and K10-expressing cells, whereas more K6-positive and K10-negative cells were detected in the inner margin of the lesions. The proportion of K6/K10-co-expressing cells in the inner margin was significantly different from the distant uninvolved skin. Conclusion: We confirmed that individual keratinocytes in psoriasis can express K6 or K10 depending on their localization in involved or uninvolved skin. There is a unique subpopulation of cells in the psoriatic plaques which co-express K6 and K10. More studies are required to fully understand the pathogenic relevance of co-expression and single expression of K6 and K10.

In human skin, epidermal differentiation occurs in two ways: normal differentiation, characterized by keratin 10 expression, and alternative differentiation. Alternative differentiation can be hyperproliferation-associated differentiation (expression of keratin 16) or the reinduction of an embryonic type of differentiation (expression of keratin 13). This embryonic type of differentiation is also seen following treatment with retinoids. In the present study, the hypothesis that hyperproliferation-associated and retinoid-induced differentiation are separate processes was investigated. Two areas of normal skin were treated for 24 h with 0. 1% all-trans-retinoic acid. Subsequently, one of the areas was tape-stripped and treatment was continued for 48 h. Multiparameter flow cytometry permitted simultaneous measurement of two coexpressed differentiation markers (retinoid-induced and normal differentiation or retinoid-induced and hyperproliferation-associated differentiation) and the proliferation characteristics (cells in S/G(2)M phase). Concerning normal and retinoid-induced differentiation, the all-trans-retinoic acid-induced expression of keratin 13 was only seen in tape-stripped retinoid-treated skin and exclusively together with that of keratin 10. The assessment of hyperproliferation-associated and retinoid-induced differentiation showed slight expression of keratin 13 without expression of keratin 16 in tape-stripped skin. Coexpression of keratins 16 and 13 was exclusively seen in tape-stripped retinoid-treated skin. The finding that keratin 13 expression following treatment with all-trans-retinoic acid occurred exclusively in hyperproliferative skin suggests that retinoid-induced and hyperproliferation-associated differentiation are coupled. Coexpression of keratins 13 and 16 provides direct experimental evidence for this association.

The epidermis of uninvolved psoriatic skin is characterised by a slight hyperproliferation and an increase in inflammatory parameters, whereas no differentiation abnormalities are seen. Data with respect to the response of distant uninvolved psoriatic skin to standardised injury are not uniform. In this study, a recently developed multiparameter flow cytometric assay was used to compare the response to tape stripping of uninvolved psoriatic and normal skin. With this method, a parameter for proliferation, differentiation and inflammation was measured simultaneously. Concerning these parameters, no statistically significant differences were found between uninvolved psoriatic skin and normal skin. The mechanism that underlies hyperproliferation in distant uninvolved psoriatic skin does not indicate an intrinsic abnormality in keratinocytes. Inflammatory signals might play a role in this process.

Multi parameter flow cytometrical assays permit simultaneous assessment of proliferation, differentiation, and inflammation parameters. In this study, the validation of TO-PRO-3 iodide (TP3) compared to propidium iodide (PI) and DE-K10 compared to RKSE60 were evaluated in tape stripping induced hyperproliferation. No occlusion, Duoderm (intermediate occlusion) and Blenderm (maximal occlusion) were used as a model to evaluate the effect of occlusion on epidermal regeneration. Proliferation in the keratin 10-negative compartment measured with TP3 proved to be a good approximation of proliferation measured with PI. Other epidermal subpopulations (keratin 10-dim and -bright cells) did not make a relevant contribution to hyperproliferation. DE-K10 is probable more sensitive than RKSE60 to distinguish populations that differ in degree of differentiation. Occlusion of tape stripped skin resulted in decreased proliferation and increased differentiation. This effect was most pronounced with maximal occlusion. This study showed that occlusion is a therapy, which realises normalisation of hyperproliferative skin disorders.

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Purpose BMS-936558 is a monoclonal antibody that blocks the PD-1 co-inhibitory receptor expressed by activated T cells. This study describes its activity and safety in pts with previously treated advanced MEL. Methods BMS-936558 was administered IV q2wk to pts with various tumors at 0.1 - 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response. Clinical activity was assessed by RECIST v1.0. Results As of Feb 24, 2012, 104 MEL pts had received BMS-936558 at 0.1 (n = 17), 0.3 (n = 19), 1 (n = 31), 3 (n = 17), or 10 mg/kg (n = 20). ECOG performance status was 0/1/2 in 63/38/3 pts, respectively. Most pts (67/104) had received prior immunotherapy (IT); prior anti-CTLA-4, -PD-1, or -PD-L1 was not permitted. The number of prior therapies was 1 (39%), 2 (35%), or ≥3 (26%). Median therapy duration was 20 wks (range 2.0 - 121.7 wks). The incidence of grade 3 - 4 related AEs was 20% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity (responses or prolonged stable disease) was observed at all doses (Table). Of the 26/94 (28%) evaluable responders, 19 (73%) are ongoing ranging from 1.9+ to 24.9+ months. For the 23 responders followed ≥6 months from first dose on study, 16 (70%) are progression free. ORs occurred in pts with visceral or bone metastases. Six pts (6%; 95% CI 2 - 13%) had prolonged SD (≥24 wk); 3 pts had a persistent decrease in target lesion tumor burden in the presence of new lesions and were not categorized as responders. Conclusions BMS-936558 had durable clinical benefit in pts with advanced MEL, including those who had received prior IT. Additional long-term follow-up data will be reported. Dose, (mg/kg) No. ptsa ORR, No. pts (%) [95% CI] PFSR at 24 wk (%) [95% CI] 0.1 14 4 (29) [8 - 58] 40 [13 - 66] 0.3 16 3 (19) [4 - 46] 31 [9 - 54] 1 27 8 (30) [14 - 50] 45 [26 - 65] 3 17 7 (41) [18 - 67] * 55 [30 - 80] 10 20 4 (20) [6 - 44] 30 [9 - 51] * 1 CR aResponse-evaluable pts dosed by 7/01/2011 ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate. Disclosure J. Sosman: Research Funding: Bristol-Myers Squibb (myself). M. Sznol: Consultant or Advisory Role: Bristol-Myers Squibb (myself, compensated). Research Funding: Bristol-Myers Squibb (myself, clinical trials funding). D.F. McDermott: Advisory Board Role: Bristol-Myers Squibb (myself). R. Carvajal: Research Funding: Bristol-Myers Squibb (myself). S.L. Topalian: Consultant or Advisory Role: Bristol-Myers Squibb (myself, immediate family member, uncompensated). Research Funding: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or Leadership Position: Bristol-Myers Squibb (myself, employment, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb/BMY stocks (myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). F.S. Hodi: Consultant or Advisory Role: Bristol-Myers Squibb (myself, uncompensated). Research Funding: Bristol-Myers Squibb (myself). All other authors have declared no conflicts of interest.

Introduction The identification of responding patients early during treatment would greatly improve the efficacy of novel and costly immunotherapies. Bioassays which accurately link preceding immune responses to clinical outcome are therefore needed. The mainstay of immunotherapy is to induce, enhance or sustain TAA-specific effector T cell immunity. Consequently, evaluation of the migratory-, antigen recognition-, as well as the effector function of tumor-specific cellular responses is critical. Methods A large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic cell (DC)-based vaccination protocols was retrospectively analyzed for overall survival (OS) in relation to skin-test infiltrating lymphocyte (SKIL) cultures characteristics. Increasingly stringent criteria were defined identify long-term survivors. Results The presence of TAA-specific CD8+ T cells (criterion I: detection by tetrameric MHC-peptide complexes) in SKIL cultures associated with improved OS; 14.1 versus 10.9 months, p = 0.055. Further analyses showed that the presence of multiple specificities was highly predictive for long-term survival. Tumor recognition by TAA-specific CD8+ T cells on peptide level (detected by specific production of Thelper 1 (Th1) cytokines (criterion II; e.g. IFNg and/or IL-2) or cytotoxicity and no Thelper 2 (Th2) cytokines) was strongly associated with improved OS; 14.2 versus 10.2 months, p = 0.003. Recognition of naturally processed antigen by specific production of Th1 cytokines or cytotoxicity and no Th2 cytokines ((criterion III), maximized the accuracy of the test; 24.1 versus 9.9 months, p = 0.001. Conclusion Our results demonstrate that analyzing SKIL cultures is a solid bioassay to predict overall survival in metastatic melanoma patients. This bioassay is simple, feasible and integrates multiple aspects of cellular functions needed for effective immune responses. Disclosure All authors have declared no conflicts of interest.