FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling.

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the antitumor activity of FPFT-2216-a novel low molecular weight compound-in lymphoid tumors and elucidated its molecular mechanism of action. In addition, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic antiproliferative activity and induced rapid tumor regression in immunodeficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after 10 days; this was continuously observed in 5 of 7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the antitumor activity of rituximab and showed antitumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NFκB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NFκB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma. SIGNIFICANCE: We found potential vulnerability to CK1α degradation in certain lymphoma cells refractory to IKZF1/3 degraders. Targeting CK1α with FPFT-2216 could inhibit the growth of these cells by activating p53 signaling. Our study demonstrates the potential therapeutic application of CK1α degraders, such as FPFT-2216, for treating lymphoma.

The effect of low-dose corticosteroids on short- and long-term renal outcome in patients with cholesterol crystal embolism.

BACKGROUND: The effect of corticosteroids on renal cholesterol crystal embolism (CCE) remains uncertain. The aim of the present study was to elucidate the effect of steroid therapy on short- and long-term renal outcome in CCE patients. METHODS: Fifty-one patients diagnosed with renal CCE were included in this retrospective study. The patients were divided into two groups according to whether or not they had received steroid therapy (steroid therapy (+), n = 32; (-), n = 19). Corticosteroids were administered at an initial dose of 10-20 mg/day after CCE diagnosis. The values of the estimated glomerular filtration rate (eGFR) in the two groups were examined at CCE diagnosis, 4 weeks after diagnosis and the last follow-up. Additionally, the % change in eGFR at 4 weeks after diagnosis and % change per year in eGFR at the last follow-up were calculated for each patient. RESULTS: The median values of eGFR at diagnosis in patients with and without steroid therapy were 16.4 and 17.9 mL/min/1.73 m(2), respectively. The median % change in eGFR between diagnosis and 4 weeks after diagnosis was 24% in patients with steroid therapy and 5% in those without, and this difference was statistically significant. On the other hand, there was no significant difference between the two groups in the % change in eGFR per year between diagnosis and the last follow-up. CONCLUSIONS: During the short period after CCE diagnosis, steroid therapy showed a good renal outcome in CCE patients. However, this treatment did not have a favorable effect on long-term renal outcome.

Concordant overexpression of phosphorylated ATF2 and STAT3 in extramammary Paget's disease.

BACKGROUND: Activating transcription factor 2 (ATF2) and signal transducer and activator of transcription 3 (STAT3) play important roles in the pathogenesis of various tumors, but ATF2 expression/activation and the relationship with STAT3 activation have not yet been investigated in extramammary Paget's disease (EMPD). OBJECTIVE: To investigate potential contributions of ATF2 and STAT3 pathways to the pathogenesis of EMPD. METHOD: Paraffin-embedded 45 EMPD specimens (43 primary EMPD and 2 nodal metastases) were subjected to immunohistochemical staining for ATF2, phosphorylated (p)-ATF2 and p-STAT3. RESULTS: P-ATF2 expression in advanced EMPD, non-invasive EMPD and normal skin (NS) controls were 97.9 +/- 1.8%, 82.0 +/- 23.4% and 45.8 +/- 3.2%, respectively, and p-STAT3 expression in advanced EMPD, non-invasive EMPD and NS were 97.0 +/- 2.9%, 83.2 +/- 23.3% and 50.1 +/- 6.7%, respectively. P-ATF2 and p-STAT3 expressions in EMPD were significantly higher than those in NS, indicating a possible contribution of these pathways to the tumor development. P-ATF2 and p-STAT3 expressions in advanced EMPD were significantly higher than those in non-invasive EMPD, possibly indicating that these pathways might also contribute to the tumor invasion and/or metastasis. We also found an exceptionally high positive correlation between p-ATF2 and p-STAT3 expressions in EMPD. CONCLUSIONS: P-ATF2 and p-STAT3 are concordantly overexpressed in EMPD and their expressions may possibly be associated with the tumor stage.

Bullous pemphigoid followed by pustular psoriasis showing Th1, Th2, Treg and Th17 immunological changes.

Psoriasis vulgaris is occasionally accompanied by autoimmune bullous diseases, but the opposite is very rare. We document here the first reported case of generalized pustular psoriasis that appeared during steroid therapy for bullous pemphigoid. The serum cytokine levels and the results of an immunohistochemical study over the disease course suggest that the immunological state was consistent with a shift from Th2-dominance to Th1-dominance. IL-17-producing cells appeared in the skin lesions when each disease was most exacerbated and disappeared after remission. Thus, the present case demonstrated a dynamic immunological state in which the appearances of Th1 and Th2 as well as Th17 varied during the course of the disease.

Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

Early-onset sarcoidosis mimicking refractory cutaneous histiocytosis.

A 10-year-old female was diagnosed as having early-onset sarcoidosis (EOS) after a prolonged skin disease. A granuloma emerged on the face at age 2 and massive lesions extended to the rest of the body. Repeated biopsies indicated histiocytic proliferation. At age 7, fever, disseminated macular eruptions, and multinucleated giant cells in the bone marrow prompted vinblastine and prednisolone therapy. Five months after stopping therapy, hypercalcemic crisis occurred along with fever, cytopenias, and interferon-gamma-nemia indicating a macrophage activation syndrome. A biopsy of nodules confirmed the diagnosis of sarcoidosis. The atypical EOS should be differentiated from histiocytosis.

Concordant overexpression of p-FAK and p-ERK1/2 in extramammary Paget's disease.

Focal adhesion kinase (FAK) is a tyrosine kinase which is at the crossroad of extracellular signal-regulated kinase-1/2 (ERK1/2), PI3K/Akt, MAPK and JAK/STAT signaling pathways. We have previously reported that p-ERK1/2, p-Akt, p38MAPK and p-STAT3 are overexpressed in extramammary Paget's diseases (EMPD), this study aimed to examine the expression of phosphorylated (p)-FAK and p-ERK1/2 proteins in EMPD and to evaluate the relationships among them. Paraffin-embedded EMPD specimens (35 tissue samples from 33 patients with primary EMPD, including two samples of metastatic lymph nodes from two of the 33 patients) were subjected to immunohistochemical staining for p-FAK and p-ERK1/2. All of the 35 EMPD specimens, including all of six invasive EMPD and two metastatic lymph node specimens, showed cytoplasmic overexpression of p-FAK and nuclear overexpression of p-ERK1/2. The expression levels (% positive cells) of p-FAK and p-ERK1/2 (88.34 +/- 14.66 and 91.26 +/- 11.21%) in EMPD were significantly higher than those in normal skin (22.38 +/- 2.13 and 29.00 +/- 4.44%), respectively. The expression levels of p-FAK (95.38 +/- 4.57%) and p-ERK1/2 (96.25 +/- 5.01%) in the advanced EMPD showed slightly higher than that in the non-invasive EMPD (86.26 +/- 15.99 and 89.78 +/- 12.15%), respectively. There exhibited a significantly high positive correlation between expression levels of p-ERK1/2 and p-FAK in EMPD. The present study shows that the concordant overexpression of p-FAK and p-ERK1/2 in EMPD which is associated with the grade of malignancy of EMPD, indicating that p-FAK and p-ERK1/2 may play pivotal roles in the tumorigenesis and further malignant transduction of EMPD.

Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma.

BACKGROUND: Activating transcription factor-2/Activator protein-1 (AP-1), Signal transducer and activator of transcription-3 and p53 are important regulators of cellular proliferation, apoptosis, differentiation in the pathogenesis of many human tumors, but the expression of phosphorylated (p)-activating transcription factor-2 (p-ATF2), phosphorylated (p)-signal transducer and activator of transcription-3 (p-STAT3) and p53 family (p63 and p73) has not been investigated in cutaneous angiosarcoma (CAS) and pyogenic granuloma (PG) so far. OBJECTIVES: To investigate the expression of p-ATF2, p-STAT3 and p53 and its family in cutaneous vascular tumors (CAS and PG). METHODS: Paraffin-embedded specimens of 14 CAS and 19 PG were subjected to immunohistochemical staining for p-ATF2, p-STAT3, p53, p63 and p73. RESULTS: P-ATF2 was expressed in 13 out of 14 CAS and in all of 19 PG. P-STAT3 was expressed in all of 14 CAS and 19 PG. P53 was expressed in all of 14 CAS and 19 PG, while both p63 and p73 were negative in CAS and PG. The p-ATF2-, p-STAT3- and p53 expression (% positive cells) in CAS and PG were significantly higher than in normal dermal vessels, but none of these transcription factors distinguished malignant (CAS)- from benign (PG) vascular tumor. CONCLUSIONS: The present study suggests that overexpression of p-ATF2, p-STAT3 and possibly p53, but not p63 or p73, may contribute to the tumorigenesis of cutaneous vascular tumors.

Hair follicle nevus - A dermoscopic approach.

We report the case of a 26-year-old man who presented with small soft nodules with tiny hairs that had been present on his nose since childhood. The nodules were initially diagnosed as melanocytic nevi. However, dermoscopy showed many uniform hair follicles and an interfollicular 'pseudo-pigment network' in the nodules. Histologically, many well-differentiated hair follicles and sebaceous glands were seen in the dermis. Serial sectioning revealed neither central cysts nor a central canal. We therefore diagnosed this case as hair follicle nevus. Dermoscopy is now widely used as a non-invasive, in vivo technique for the diagnosis of pigmented skin lesions. Hair follicle nevus is a very rare disease and this is the first report to demonstrate the manifestation of this clinical entity by dermoscopy.

Association factors for atopic dermatitis in nursery school children in Ishigaki islands - Kyushu University Ishigaki Atopic Dermatitis Study (KIDS).

Atopic dermatitis (AD) is a multifactorial disease that usually decreases the quality of life of affected patients. The purpose of this study was to evaluate the associated factors for atopic dermatitis, asthma, rhinitis, and food allergy by physical examination of the skin and a questionnaire in nursery school children in Ishigaki Island, Okinawa, Japan. Enrolled in this study were 460 children from 0 to 6 years of age. Physical examination of skin symptoms and blood tests were performed. Information on past history and family history of atopic dermatitis, asthma, rhinitis, and food allergy were collected by questionnaire. The prevalence of atopic dermatitis was 12.2% (56/460). The cumulative prevalence of asthma, rhinitis, and food allergy was 19.9% (91/458), 3.3% (15/457), and 5.5% (25/456), respectively. In multivariate analysis, maternal history of rhinitis, atopic dermatitis siblings, past history of asthma and food allergy, and elevation of total IgE were significantly related to atopic dermatitis. A high total IgE level was a strong risk factor specific for atopic dermatitis in this population.

Expression of the p38 MAPK, NF-kappaB and cyclin D1 in extramammary Paget's disease.

BACKGROUND: The p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappaB (NF-kappaB)/cyclin D1 signaling pathway has recently been shown to play an important part in the pathogenesis of many human tumors. However, the role of this signal transduction pathway in extramammary Paget's disease (EMPD) remains unknown. OBJECTIVE: This study was designed to investigate the expression of phosphorylated p38 MAP kinasealpha (p-p38 MAPKalpha), phosphorylated NF-kappa B p65 (p-NF-kappaB p65) and cyclin D1 proteins in EMPD and to evaluate the relationship among them. METHODS: Thirty-five tissue samples from 30 primary EMPD cases were analyzed by immunohistochemical staining in formalin-fixed, paraffin-embedded tissue sections for p-p38 MAPKalpha, p-NF-kappaB p65 and cyclin D1. RESULTS: Among the 35 specimens of EMPD, p-p38 MAPKalpha, p-NF-kappaB p65 and cyclin D1 were expressed in 30, 28 and 27, respectively. Moreover, in five metastatic lymph node specimens, all were positive for p-p38 MAPKalpha and p-NF-kappaB p65, four were positive for cyclin D1. There were significant correlations between expression of p-p38 MAPKalpha, p-NF-kappaB p65, and cyclin D1 in EMPD. CONCLUSION: This study provides evidence that p-p38 MAPKalpha, p-NF-kappaB p65, and cyclin D1 was overexpressed in EMPD, suggesting that the p38 MAPK/NF-kappaB/cyclin D1 signaling pathway might participate in the oncogenesis of EMPD.

Community validation of the U.K. diagnostic criteria for atopic dermatitis in Japanese elementary schoolchildren.

BACKGROUND: A simple list of diagnostic criteria for atopic dermatitis for use in epidemiological studies was developed by a U.K. working party. This list served well for both hospital patients with skin diseases and in general population within the U.K. OBJECTIVES: To validate the U.K. diagnostic criteria in Japanese elementary schoolchildren, we collected the questionnaires on regular health checkups, which had been completed by parents of schoolchildren in 2001/2002 and 2004/2005. METHODS: Elementary schoolchildren were examined by dermatologists in eight areas (16,152 children) in 2001/2002 and in three areas (3849 children) in 2004/2005. The questionnaire was distributed to the parents 2 weeks before the skin examination, completed by the parents and collected after the survey. RESULTS: In 2002/2002 comparing the U.K. diagnostic criteria with the findings on clinical examination used as the reference standard, the U.K. criteria (1-year prevalence measure) showed a sensitivity of 71.8%, specificity of 89.3% and positive predictive value of 44.7%. In 2004/2005 we confirmed that the U.K. criteria for a point prevalence measure showed a higher positive predictive value (59.9%) compared with that for 1-year prevalence measure (49.3%). CONCLUSION: Now that we know the sensitivity and specificity of the U.K. criteria in the population examined in this study, we will be able in the near future to estimate the prevalence of atopic dermatitis in a similar population with reverse operation by questionnaires alone using these criteria without examination by dermatologists. Therefore, the validation study of U.K. criteria could be useful for future epidemiologic surveys.

Detection of autoantibodies to desmoplakin in a patient with oral erythema multiforme.

Anti-desmoplakin (DP) I and II are detected in patients with paraneoplastic pemphigus. However, these autoantibodies have also been detected in patients with other disorders. A 73-year-old woman presented with a 20-year history of erosions and ulcers of the tongue and oral mucosa. Biopsy specimens of the oral mucosa showed several necrotic keratinocytes in the mucosal epithelium. The patient's serum was negative for anti-desmoglein 1 and anti-desmoglein 3 antibodies by ELISA, although anti-keratinocyte cell surface antibodies were detected by indirect immunofluorescence. On immunoblotting using protein extracts of normal human epidermis, the patient's serum was found to contain autoantibodies to 250 kDa and 210 kDa proteins, indicating the presence of autoantibodies to DP I and II. Based on these results, the diagnosis of erythema multiforme was made. An immunofluorescence and immunoblotting are crucial for the differential diagnosis between an erythema multiforme which is positive for anti-DP I and II antibodies and other autoimmune bullous diseases.

Systemic varicella zoster virus reinfection in a case of angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of peripheral T-cell lymphoma that causes immunological disorders such as immunosuppression, autoimmune disease-like symptoms and allergy. We report a case of a 67-year-old man with AITL who had a serious varicella zoster virus (VZV) reinfection that appeared clinically to be varicella. Forty percent of cases of AITL are associated with skin rash. A variety of cutaneous manifestations have been reported; however, the majority are macropapular eruptions that are often diagnosed as drug associated. Our study emphasizes the need to correctly diagnose opportunistic infections, such as the varicella that is documented in our patient, at early stages in AITL.

Case of adult T-cell leukemia/lymphoma manifesting marked purpura.

We present a case of a 62-year-old woman with marked purpura, first appearing on both legs, then spreading over the whole body, including the face. At presentation, the patient was thought to have Henoch-Schonlein purpura. However, a skin biopsy from a purpuric lesion revealed prominent infiltrations of atypical lymphocytes into the papillary dermis and marked extravasation of erythrocytes through the epidermis and upper dermis. Antibody to human T-lymphotropic virus type 1 (HTLV-1) was present in the serum and samples from skin lesions revealed HTLV-1 proviral DNA integration, as well as a clonal T-cell receptor Cbeta1 gene rearrangement. We therefore diagnosed this case as adult T-cell leukemia/lymphoma (ATL), and the purpuric lesions as ATL-specific. Soon after the initiation of chemotherapy, these purpuric lesions began to resolve with pigmentation.

Interdigital amelanotic spindle-cell melanoma mimicking an inflammatory process due to dermatophytosis.

Herein, we report a rare case of amelanotic spindle-cell melanoma on the interdigit of the left fifth toe of an 83-year-old woman. She also had tinea pedis on the same part for more than 2 years, and the part in which the tumor developed had been macerated and colonized with both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Histopathologically, the biopsy specimen was indistinguishable from that of nonspecific inflammatory granulation. Two biopsies could not lead us to the correct diagnosis until the totally excised specimen was evaluated with immunohistochemical analysis including S-100 and other melanocyte markers. The patient died with multiple metastases of the tumor 18 months after her first visit. This case suggests that refractory interdigital dermatophytoses should be treated by considering the possibility of concomitant malignant neoplasms, and immunohistochemical analysis is indispensable for differential diagnosis of malignant neoplasms suggesting nonspecific granulation.

Erythema multiforme and Stevens-Johnson syndrome following radiotherapy.

Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) are thought to be hypersensitivity syndromes with various causes, and radiotherapy might be one of the causes of these syndromes. We herein report two cases of EM/SJS following radiotherapy. The first case was a 63-year-old woman with breast cancer. At the end of postoperative radiotherapy with 60 Gy, severe pruritic erythema appeared in the irradiated area and spread over the whole body. She was diagnosed with EM by a skin biopsy. The second case was a 77-year-old woman with uterine cervical cancer who underwent postoperative radiotherapy. At a dose of 30.6 Gy, pruritic redness appeared in the irradiated area and the precordial region, and it became widespread rapidly with polymorphic transformation. Although without any histological confirmation, SJS was strongly suspected because of her pruritic conjunctivitis. Because both patients were given medicines during irradiation, radiotherapy may not be the only cause of EM/SJS. However, it should be noted that radiotherapy might trigger EM/SJS.

[Cutaneous reactions induced by pegylated-interferon plus ribavirin combination therapy in a patient with chronic hepatitis C].

A 67 years old woman with chronic hepatitis C was treated with pegylated-interferon plus ribavirin combination therapy. Three weeks after starting the therapy, severe cutaneous adverse reaction occurred on her. Specific treatment successfully suppressed the symptom and pegylated-interferon plus ribavirin combination therapy was completely done. Cutaneous reactions induced by pegylated-interferon plus ribavirin combination therapy was reviewed.