Aluminum Chloride-Induced Apoptosis Leads to Keratinization Arrest and Granular Parakeratosis.

Aluminum chloride (AlCl3) is the main active ingredient in commonly used antiperspirant. Antiperspirant use may cause a rare keratinization disease, granular parakeratosis (GP), then AlCl3 may be associated with the etiology of GP. The objective of this study is to elucidate the skin effect of topical aluminum application using a mouse model. We sprayed 20% aluminum chloride every day on the depilated mice skin and analyzed the skin clinically, histopathologically, and immunohistologically. We have succeeded in the histological replication of GP on mouse skin. The basophilic granules in the stratum corneum contained filaggrin, and processing of profilaggrin to filaggrin was disrupted in aluminum-treated mouse skin (Al-mouse). In Al-mouse, cytochrome c and cleaved-caspase 3 were upregulated mainly in the granular layer, and caspase 3 p20 subunit was upregulated. TUNEL-positive cells increased significantly in the Al-mouse from the granular to the horny layer. Caspase 3 inhibitor inhibited granular parakeratotic change of Al-mouse. Our results indicated that aluminum-induced apoptosis leads to keratinization arrest and acceleration of nuclear degradation before completion of profilaggrin processing. This could lead to retention of the basophilic granules composed of underprocessed profilaggrin in the horny layer of Al-mouse skin, the hallmark of GP.

Histopathological Findings and Increased D-Dimer Are Predictive Factors of Systemic Thromboses in Eosinophilic Granulomatosis With Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA; ie, Churg-Strauss syndrome) is one of the antineutrophil cytoplasmic antibody-associated vasculitis syndromes. Although extravascular granulomatoses are a well-known histopathological feature, the diverse histopathologic spectrum of cutaneous lesions has not been described in detail. Thus, this study sought to investigate the possible correlation between the clinical features and histopathology of cutaneous lesions in EGPA cases, focusing on systemic thrombogenic conditions, such as visceral infarction and deep vein thrombosis. Fourteen cases of EGPA diagnosed at the Department of Dermatology in Asahikawa Medical University from 1977 to 2017 were clinically and histopathologically reviewed. In 6 (43%) cases, skin lesions were the initial manifestation of EGPA. Among the cutaneous lesions, purpura and erythema were the most common. Persistent proteinuria and macrohematuria were observed in only 2 myeloperoxidase-antineutrophil cytoplasmic antibody-positive cases. Systemic thrombotic symptoms, such as cerebral infarction and deep vein thrombosis, were detected in 5 (36%) cases, and, in 3 of those cases, thromboses in dermal or subcutaneous vessels were observed histopathologically. Elevation of plasma D-dimer level (>2.5 µg/mL) was significantly correlated with concomitant systemic thrombotic symptoms (P = 0.0152, Fischer exact test). The histopathological finding of thrombotic features and increased plasma D-dimer were predictive factors of EGPA accompanied with systemic thromboses, such as deep vein thromboses and cerebral infarction.

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene.

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.

Clinical Characteristics of Psoriasis Cases Treated by Biologics With an Extended Administration Interval: A Single-Center, Retrospective Observational Study.

Background Psoriasis is a chronic inflammatory skin disease with multiple organ manifestations such as arthritis and cardiovascular diseases. While recent therapeutic advancements in systemic biologics have demonstrated efficacy against psoriasis, a complete cure has not been achieved and patients require lifelong treatment to control symptoms. Objective This study aimed to clarify the clinical characteristics of psoriasis patients treated with biologics at an extended interval. Methods This study included patients with psoriasis who were administered biologic therapy for longer than the standard interval (at least a week) and who objectively maintained favorable conditions (static Physician's Global Assessment ≤ 0 to 1). Clinical characteristics, such as body weight (BW), body mass index (BMI), and body fat percentage, were compared to those of patients who were administered biologic therapy at standard intervals. Results Among 162 Japanese patients with psoriasis, 35 were treated with biologics at extended intervals. In the group with extended treatment intervals, patients treated with interleukin (IL)-17 inhibitors (n = 15) presented statistically lower BMI than those treated with IL-23 inhibitors (n = 17) (P < 0.016). The group treated with IL-17 inhibitors at extended intervals showed significantly lower BMI and body fat percentage than the group at standard intervals (P < 0.05). Conclusion Trends in our hospital suggest that psoriasis patients with low BMI and body fat percentage can maintain good status with extended interleukin (IL)-17 inhibitor dosing intervals (static Physician's Global Assessment ≤ 0 to 1).

Effectiveness of brodalumab in improving itching and skin pain in Japanese patients with psoriasis: The ProLOGUE study.

Itching and skin pain are bothersome symptoms of psoriasis, but evidence is limited regarding the treatment effectiveness on these symptoms in daily clinical settings. We assessed the changes in the levels of itching and skin pain after brodalumab treatment in Japanese patients with psoriasis using patient-reported outcomes (PROs). Patients with psoriasis who have inadequate response to existing treatments were enrolled in the single-arm, open-label, multicenter, prospective ProLOGUE study and received brodalumab 210 mg subcutaneously in daily clinical practice. Psoriasis Area and Severity Index (PASI) and PRO assessments were performed at baseline and weeks 12 and 48. Seventy-three patients (men, 82.2%; median age, 54.0 years) were enrolled. The Itch Numeric Rating Scale (NRS; p < 0.0001 at weeks 12 and 48) and Skin Pain NRS (week 12, p = 0.0004; week 48, p < 0.0001) scores significantly decreased from baseline. The Itch NRS score was significantly higher in patients with a Dermatology Life Quality Index (DLQI) score of ≥2 (vs. 0/1; p < 0.0001 at weeks 12 and 48) and in patients with a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) global satisfaction domain score of ≤70% (vs. >70%; week 12, p = 0.0120; week 48, p = 0.0348). The Itch NRS score cutoff value for achieving a PASI score of ≤2, DLQI score of 0/1, and TSQM-9 global satisfaction domain score of >70% was 1 at week 12 and 0 at week 48. Brodalumab treatment was associated with improvement in itching and skin pain in Japanese patients with psoriasis. An Itch NRS score of 0 can be a long-term treatment goal for psoriasis (Japan Registry of Clinical Trials identifier: jRCTs031180037).

Treatment with brodalumab is not associated with improved sleep problems in real-life patients with plaque psoriasis: Results of the ProLOGUE study.

Psoriasis impacts various aspects of patients' health-related quality of life and is associated with sleep problems. However, research discussing the associations between interleukin-17 blockage therapies and sleep problems in patients with psoriasis is insufficient. We aimed to assess the effectiveness of brodalumab in alleviating sleep problems in real-life patients with plaque psoriasis. This analysis was part of the single-arm, open-label, multicenter, prospective, cohort study, ProLOGUE (study period October 2017-March 2020), which involved Japanese patients with plaque psoriasis. Assessments included correlation of Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R) scores (Sleep Problems Index-II [SPI-II] and MOS Sleep-R subscale scores) with multiple patient-reported outcome scores and the Psoriasis Area and Severity Index (PASI) at baseline. Additionally, change from baseline in MOS Sleep-R scores was assessed at weeks 12 and 48 of brodalumab treatment. Seventy-three patients were enrolled (male 82.2%, median age 54.0 years). At baseline, the SPI-II score correlated with the Patient Health Questionnaire-8 score (Spearman correlation coefficient [ρ] = -0.474) and weakly correlated with the Itch Numeric Rating Scale (NRS; ρ = -0.366), Skin Pain NRS (ρ = -0.275), and all Treatment Satisfaction Questionnaire for Medication-9 domain scores (ρ = 0.270, ρ = 0.303, and ρ = 0.322 for effectiveness, convenience, and global satisfaction, respectively) but did not correlate with the PASI score. The SPI-II score and MOS Sleep-R subscale scores, except the Snoring score (p = 0.0319), did not significantly change from baseline to week 12 of brodalumab treatment. In conclusion, treatment with brodalumab did not improve overall sleep problems in real-life patients with plaque psoriasis, suggesting that sleep problems require attention in daily clinical practice (Japan Registry of Clinical Trials identifier, jRCTs031180037).

Clinical characteristics of peristomal pyoderma gangrenosum: A Single Center Retrospective Observational Study.

Peristomal pyoderma gangrenosum (PPG), a variant of pyoderma gangrenosum, occurs adjacent to intestinal or urinary stomas and are typically seen in patients with active inflammatory bowel diseases (IBD). The present study evaluated 14 cases of PPG among 537 patients that had undergone ostomy surgery at Asahikawa Medical University Hospital from January 2017 to December 2021. The incidence of PPG among ostomy cases was calculated as 1.01 per 100-person-years. The median period from ostomy surgery to PPG onset was 192.5 days (36-1224 days). Significant differences in gender and ostomy subtype were observed in patients with PPG compared to all patients that had undergone ostomy surgery. IBD prevalence was comparable between groups. Topical corticosteroids or tacrolimus were sufficient for controlling PPG lesions in all cases other than one case controlled with oral prednisolone administered for a separate condition. Clinicians should be aware of recent developments in IBD therapies that may modify the risk of developing PPG. The present study results add to current knowledge of the pathogenesis of PPG.

Itch as a critical factor in impaired health-related quality of life in patients with plaque psoriasis achieving clear or almost-clear skin: Analysis of the single-arm, open-label, multicenter, prospective ProLOGUE study.

Background: Patients with psoriasis report impaired health-related quality of life (HRQoL; Dermatology Life Quality Index score ≥ 2) even after achieving clear or almost-clear skin with biologic treatment. Objective: To assess the effectiveness of brodalumab in HRQoL improvement and the factors associated with incomplete HRQoL improvement in Japanese patients with psoriasis. Methods: As a part of the single-arm, open-label, multicenter, prospective ProLOGUE study (Japan Registry of Clinical Trials identifier: jRCTs031180037), patients were treated with 210 mg of subcutaneous brodalumab in daily clinical practice until week 48. The absolute Psoriasis Area and Severity Index scores and patient-reported outcomes were assessed at baseline and weeks 12 and 48. Results: Seventy-three patients (male, 82.2%; median age, 54.0 years) were enrolled. The Dermatology Life Quality Index and European Quality of Life 5-Dimension 5-Level Utility Index scores significantly improved from baseline to weeks 12 and 48. At week 48, all 13 patients with a Dermatology Life Quality Index score of ≥2 and an absolute Psoriasis Area and Severity Index score of 0 to ≤2 reported itching. Limitations: Unclear generalizability of the results to other biologics. Conclusion: Treatment with brodalumab improved HRQoL in patients with psoriasis. Itching may contribute to incomplete HRQoL improvement in patients who have achieved clear or almost-clear skin.

Tight junctions in the stratum corneum explain spatial differences in corneodesmosome degradation.

To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin-1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket-weave-like appearance of the stratum corneum.

Psoriasis: Recent progress in molecular-targeted therapies.

Psoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by bothersome scaly reddish plaques especially on frequently chafed body parts, such as the extensor sites of the extremities and scalp. Nonetheless, through recent advance in molecular-targeted therapies including biologics and small-molecule inhibitors, even the severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be excellently treated. The superb clinical effects lead to not only remarkable alleviation of symptoms but also a deep understanding of patients' impaired "quality of life" caused by this disease. Along with the development of novel treatment options targeting various specific molecules, such as proinflammatory cytokines and signal transduction-associated molecules, clinicians have thoroughly understood the molecular mechanism of psoriasis, and discovered that the IL-23/IL-17 axis mainly depending on Th17 cell function is a crucial pathogenesis of this disease. Accumulation of knowledge about the working mechanism and clinical effect of molecular-targeted therapies is indispensable for clinicians to establish a more refined therapeutic strategy for treating psoriasis.

Molecular Pathogenesis of Psoriasis and Biomarkers Reflecting Disease Activity.

Psoriasis is a chronic inflammatory skin disease induced by multifactorial causes and is characterized by bothersome, scaly reddish plaques, especially on frequently chafed body parts, such as extensor sites of the extremities. The latest advances in molecular-targeted therapies using biologics or small-molecule inhibitors help to sufficiently treat even the most severe psoriatic symptoms and the extra cutaneous comorbidities of psoriatic arthritis. The excellent clinical effects of these therapies provide a deeper understanding of the impaired quality of life caused by this disease and the detailed molecular mechanism in which the interleukin (IL)-23/IL-17 axis plays an essential role. To establish standardized therapeutic strategies, biomarkers that define deep remission are indispensable. Several molecules, such as cytokines, chemokines, antimicrobial peptides, and proteinase inhibitors, have been recognized as potent biomarker candidates. In particular, blood protein markers that are repeatedly measurable can be extremely useful in daily clinical practice. Herein, we summarize the molecular mechanism of psoriasis, and we describe the functions and induction mechanisms of these biomarker candidates.

Survey to detect tick-borne encephalitis virus from human-feeding ticks in Hokkaido, Japan.

A tick infestation is one of the most common arthropod-related skin diseases in Hokkaido, the northernmost island of Japan. Ticks also act as an infectious disease vector for humans. Tick-borne encephalitis (TBE), a highly mortal central nervous system infection caused by TBE virus (TBEV), has sporadically occurred there recently. However, there have been no epidemiological data on the current surveillance of human tick bites and the prevalence of TBEV in human-feeding ticks. This study was performed to clarify those indeterminate issues. One hundred and fifty-three ixodid ticks feeding on humans were collected from 150 outpatients in Hokkaido during the season of April to August 2018. None of the cases showed any infectious symptoms. These ticks were morphologically identified to species, and a cytopathic assay on baby hamster kidney cells was carried out to detect TBEV from each tick. The tick collection consisted of 108 Ixodes persulcatus (one nymph and 107 adult females), 44 female Ixodes ovatus, and one female Haemaphysalis japonica. No tick extracts showed positive results of the cytopathic assay, suggesting the non-existence of TBEV in the present specimens. However, the survey to detect TBEV from human-feeding ticks is still important to monitor the occurrence of TBE, because human tick bites by I. ovatus, a possible vector of TBEV, are increasing even in the northern and eastern areas of Hokkaido.

Efficacy and safety of tildrakizumab in Japanese patients with moderate to severe plaque psoriasis: Results from a 64-week phase 3 study (reSURFACE 1).

Tildrakizumab is a high-affinity, humanized immunoglobulin G1κ, anti-interleukin-23p19 monoclonal antibody recently approved in Japan for treatment of plaque psoriasis. We report results from Japanese patients treated with tildrakizumab in the multinational, randomized, double-blind, placebo-controlled reSURFACE 1 study (clinicaltrials.gov NCT01722331). Adults with moderate to severe plaque psoriasis were randomized (2:2:1) to receive subcutaneous tildrakizumab 100 or 200 mg or placebo every 12 weeks. Placebo recipients were rerandomized to tildrakizumab 100 or 200 mg at week 12. The global study coprimary endpoints were the proportions of patients achieving 75% improvement from baseline Psoriasis Area and Severity Index (PASI 75) and Physician Global Assessment (PGA) response (0/1 with ≥2 grade reduction from baseline) at week 12. Analyses included 158 Japanese patients randomized to tildrakizumab 100 (n = 64) or 200 mg (n = 62) or placebo (n = 32). Japanese patients had higher mean baseline body surface area involvement and PASI versus all reSURFACE 1 patients. At week 12, significantly more Japanese patients receiving tildrakizumab 100 and 200 mg versus placebo achieved PASI 75 (54.7% and 54.8% vs 6.3%, respectively, both nominal p < 0.001) and PGA 0/1 response (54.7% and 56.5% vs 9.4%, respectively, both nominal P < 0.001). Response rates increased over time with maximal efficacy after 22-28 weeks; >80% of patients achieving PASI 75 or PASI 90 at week 28 and continuing tildrakizumab treatment at the same dose maintained response at week 64. From baseline to week 28, absolute PASI decreased from >12 in all patients to ≤2 in >40% and ≤3 in >50% of patients receiving tildrakizumab. Tildrakizumab was generally well tolerated with an adverse event profile similar to that of placebo. Tildrakizumab treatment was associated with durable efficacy in Japanese patients with moderate to severe plaque psoriasis despite greater baseline disease severity versus the global reSURFACE 1 population.

Utility of the Dermatology Life Quality Index at initiation or switching of biologics in real-life Japanese patients with plaque psoriasis: Results from the ProLOGUE study.

BACKGROUND: Plaque psoriasis significantly affects patients' health-related quality of life. To aid treatment decisions, not only objective assessment by physicians but also subjective assessment by patients is important. OBJECTIVE: To assess the significance of Dermatology Life Quality Index (DLQI) evaluation at the time of biologics introduction in clinical practice in Japanese patients with plaque psoriasis. METHODS: This was a single-arm, open-label, multicenter study. At baseline, Psoriasis Area and Severity Index (PASI) and DLQI scores were measured and stratified based on DLQI scores ≥6/≤5 and PASI scores ≤10/>10. Other patient-reported outcomes assessed included EQ-5D-5L, itch numerical rating scale (NRS), skin pain NRS, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Sleep Problem Index-II (SPI-II), and Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Of the 73 enrolled patients, 23 had PASI scores ≤10. Those with PASI/DLQI scores >10/≥6 had a significantly higher median PASI score than those with PASI/DLQI scores >10/≤5 (p = 0.0125). Regardless of PASI scores (>10/≤10), median itch NRS and GAD-7 scores were significantly higher in patients with DLQI scores ≥6 than in those with DLQI scores ≤5 (itch NRS, p = 0.0361 and p = 0.0086, respectively; GAD-7, p = 0.0167 and p = 0.0273, respectively). Patients with PASI/DLQI scores ≤10/≥6 had significantly higher skin pain NRS (p = 0.0292) and PHQ-8 (p = 0.0255) scores and significantly lower median SPI-II scores (p = 0.0137) and TSQM-9 Effectiveness domain scores (p = 0.0178) than those with PASI/DLQI scores ≤10/≤5. CONCLUSION: DLQI may be useful for assessing patients' concerns that cannot be identified by PASI alone while initiating biologics or switching from other biologics in clinical practice.

Toxic epidermal necrolysis with prominent facial pustules: a case with reactivation of human herpesvirus 7.

A 37-year-old Japanese man presented with confluent erythemas and progressive erosive lesions on the almost entire body including the oral mucosa and genitalia. This was accompanied with prominent facial pustules. Although a lymphocyte stimulation test was positive only for acetaminophen, he took other agents including carbamazepine for his depression. He was diagnosed as having toxic epidermal necrolysis with prominent facial pustules and treated by methylprednisolone pulse therapy, which resulted in a good response. During the course, human herpesvirus 7 (HHV-7) DNA was detected in his peripheral blood. The HHV-7 reactivation might be related to facial pustulosis, which is occasionally observed in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

Relationship Between Rapid Skin Clearance and Quality of Life Benefit: Post Hoc Analysis of Japanese Patients with Moderate-to-Severe Psoriasis Treated with Ixekizumab (UNCOVER-J).

INTRODUCTION: Ixekizumab has demonstrated rapid onset of action, high levels of skin clearance, and improvements in quality of life in patients with moderate-to-severe psoriasis, including plaque, erythrodermic, or generalized pustular psoriasis. METHODS: This was a post hoc analysis of UNCOVER-J, a phase 3, multicenter, single-arm, open-label study of ixekizumab for treatment of Japanese patients with psoriasis. The objective was to assess the proportion of patients who achieved Dermatology Life Quality Index (DLQI) (0,1) and Itch Numeric Rating Scale (NRS) (0) at weeks 4 and 12 according to Psoriasis Area and Severity Index (PASI) percentage improvement levels. All intent-to-treat patients with plaque, erythrodermic, or generalized pustular psoriasis were analyzed. RESULTS: A total of 91 patients were treated with ixekizumab and included in the analysis. Rapid improvements in PASI at weeks 4 and 12 were associated with improvements in DLQI (0,1) response at week 4 and at week 12. Complete skin clearance (PASI 100) achieved either at week 4 or week 12 was associated with a higher Itch NRS (0) response at week 12. CONCLUSIONS: Patients with rapid improvement in clinical symptoms of psoriasis had better patient outcomes than those with slower responses. These findings highlight the clinical importance of achieving a fast response in patients with psoriasis, which may lead to better treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01624233.

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study.

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.

Focal adhesion kinase as an immunotherapeutic target.

BACKGROUND: Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune cellular responses. METHODS: To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients. RESULTS: Two synthetic peptides, FAK(143-157) and FAK(1,000-1,014), induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient's CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients. CONCLUSIONS: Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors.