Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

The efficacy of eribulin mesylate for patients with cutaneous angiosarcoma previously treated with taxane: a multicentre prospective observational study.

BACKGROUND: Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established. METHODS: We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m-2 on days 1 and 8 in a 21-day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression-free survival (PFS) and toxicity assessment. RESULTS: We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. CONCLUSIONS: ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.

A case of nivolumab-induced acute-onset type 1 diabetes mellitus in melanoma.

Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event.

Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.

PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma.

PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01990859.

Correction of coronal alignment correlates with reconstruction of joint height in unicompartmental knee arthroplasty.

OBJECTIVES: Because there have been no standard methods to determine pre-operatively the thickness of resection of the proximal tibia in unicompartmental knee arthroplasty (UKA), information about the relationship between the change of limb alignment and the joint line elevation would be useful for pre-operative planning. The purpose of this study was to clarify the correlation between the change of limb alignment and the change of joint line height at the medial compartment after UKA. METHODS: A consecutive series of 42 medial UKAs was reviewed retrospectively. These patients were assessed radiographically both pre- and post-operatively with standing anteroposterior radiographs. The thickness of bone resection at the proximal tibia and the distal femur was measured radiographically. The relationship between the change of femorotibial angle (δFTA) and the change of joint line height, was analysed. RESULTS: The mean pre- and post-operative FTA was 180.5° (172.2° to 184.8°) and 175.0° (168.5° to 178.9°), respectively. The mean δFTA was 5.5° (2.3° to 10.1°). The joint line elevation of the tibia (JLET) was 4.4 mm (2.1 to 7.8). The δFTA was correlated with the JLET (correlation coefficient 0.494, p = 0.0009). CONCLUSIONS: This study indicated that there is a significant correlation between the change of limb alignment and joint line elevation. This observation suggests that it is possible to know the requirement of elevation of the joint line to obtain the desired correction of limb alignment, and to predict the requirement of bone resection of the proximal tibia pre-operatively. Cite this article: Bone Joint Res 2015;4:128-133.

Triple-marker PCR assay of sentinel lymph node as a prognostic factor in melanoma.

BACKGROUND: Metastasis of sentinel lymph node (SLN) is generally evaluated on histopathological examination and controversy still exists over the usefulness of PCR assay of SLN. OBJECTIVE: To investigate the prognostic value of triple-marker PCR assay of SLN. METHODS: A total of 165 patients with primary cutaneous melanoma who underwent SLN biopsy were included. Clinical and histopathological data were retrieved from each patient's file and triple-marker PCR assay (tyrosinase, GP-100 and MART-1) was performed on the SLN as well as routine histopathological evaluation. PCR positivity was defined as the expression of all three PCR markers. To evaluate melanoma-specific survival (MSS) and disease-free survival (DFS), we used the Kaplan-Meier method and the log-rank test. Multivariate analyses using the Cox proportional hazards regression model were also performed. RESULTS: Sentinel lymph nodes were identified in all 165 patients: 61 patients (37.0%) were male and 104 (63.0%) were female, with a mean age of 60.2 years. Of the 165 melanomas, 81 (49.1%) were acral lentiginous melanomas. Compared with the patients with PCR positivity (1-2 markers) or PCR negativity, patients with PCR positivity (3 markers) had significantly poor MSS (5-year survival rate, 58.7% vs. 84.4%; P < 0.0001) and DFS (5-year survival rate, 25.0% vs. 83.9%; P < 0.0001), with median follow-up of 42 months for MSS and 38 months for DFS. These survival rates of patients with PCR positivity (3 markers) were lower than those of patients with histopathologically positive SLN. In multivariate analysis, PCR positivity (3 markers) was an independent prognostic factor for both MSS (hazard ratio [HR], 2.81; 95% confidence interval [CI], 1.07-7.33; P = 0.035) and DFS (HR, 2.48; 95% CI, 1.08-5.69; P = 0.032). CONCLUSIONS: The expression of three PCR markers was a significant prognostic factor for both MSS and DFS and might be closely correlated to a dismal prognosis.

Narrow-margin excision is a safe, reliable treatment for well-defined, primary pigmented basal cell carcinoma: an analysis of 288 lesions in Japan.

BACKGROUND: Complete excision is the most promising treatment for basal cell carcinoma (BCC) and a surgical margin of at least 4 mm is recommended. However, little is known about the appropriate surgical margin of pigmented BCC. OBJECTIVE: To investigate the reliability of narrower margin excision of well-defined, pigmented BCC. METHODS: We identified a total of 263 patients with 288 well-defined, primary pigmented BCC at the Department of Dermatology, Kyushu University (Fukuoka, Japan), between January 2006 and December 2013. All lesions were surgically excised with 1-6-mm margins and analysed. For 30 recent lesions out of the 288 lesions, border gaps between dermoscopy and histopathology were assessed. RESULTS: Of the 288 lesions, 218 (75.7%) were excised with a narrow margin (≤ 3 mm) and 60 lesions (24.3%) with a wide margin (≥ 4 mm). Only two lesions (0.7%), which were excised with 2-mm margins, were associated with tumour-positive margins. Narrow-margin excision showed a complete removal rate of 99% (2-mm margins, 95.3%; 3-mm margins, 100%). Dermoscopically determined borders almost exactly corresponded to the histopathological ones; 71.2% of border gaps between dermoscopy and histopathology were within 1 mm and there were no cases in which tumours spread beyond 1 mm of their dermoscopic borders. CONCLUSION: Surgical excision with a 2-3-mm margin is reliable treatment for well-defined, primary pigmented BCC, with a complete removal rate of 99%.

Stromal expression of cathepsin K in squamous cell carcinoma.

BACKGROUND: Cathepsin K (CTSK), a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, may be produced by neoplastic cells as well as stromal macrophages and fibroblasts. Its expression is suggested as associated with increased invasive and metastatic potential. OBJECTIVES: The aim of this study is to examine stromal expression of cathepsin K in skin tumors. METHODS: A series of 13 normal skin and 109 skin tumours, including 51 benign and 58 malignant epidermal tumours were tested for CTSK and Ki-67 expression by immunohistochemical analysis. RESULTS: Stromal CTSK expression and the tumoral Ki-67 labelling index were significantly higher in invasive squamous cell carcinoma (SCC) than in other epidermal tumours. CONCLUSION: Cathepsin K-positive stromal fibroblasts may play a crucial role in SCC progression by promoting extracellular matrix degradation, thereby facilitating SCC growth and invasion into surrounding tissue and vasculature. CTSK inhibitors may be a potential novel therapeutic option to decrease SCC progression.

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease.

BACKGROUND: We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget's disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin-dependent kinases, is a key regulator of G(1)-S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT-mTOR-p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. OBJECTIVE: To investigate the immunohistochemical staining of the AKT-mTOR-p70S6K pathway in EMPD and to evaluate the relationships among the components. METHODS: Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)-AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-p70S6K/S6K1, p-ribosomal protein S6 (p-S6) and CDK2. Ten normal skin samples served as a control. RESULTS: Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1, p-S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1 and p-S6 and CDK2. CONCLUSIONS: The activation of the AKT-mTOR-p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT-mTOR-p70S6K pathway might be a potential therapeutic target in EMPD.

Activation of the mammalian target of rapamycin signalling pathway in epidermal tumours and its correlation with cyclin-dependent kinase 2.

BACKGROUND: The enzyme mammalian target of rapamycin (mTOR) integrates many different cellular signals to control cell growth and proliferation, protein synthesis and breakdown, and other processes. Dysregulation of mTOR is implicated in a range of human diseases, including cancers and cardiovascular disorders. To date, there has been no report on the expression of protein kinase B (AKT)/mTOR cell signalling in epidermal tumours. OBJECTIVES: This study was designed to investigate the activation of the mTOR signalling pathway in epidermal tumours and to correlate this with cyclin-dependent kinase 2 (CDK2) expression. METHODS: Immunohistological staining was performed with phosphorylated (p-) AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-ribosomal protein S6 (p-S6), p-p70 ribosomal protein S6 kinase 1 (p-p70S6K1) and CDK2 in 15 cases each of seborrhoeic keratosis, actinic keratosis, keratoacanthoma and Bowen's disease (BD), and 25 cases of squamous cell carcinoma (SCC). Fifteen normal skin (NS) samples served as control. RESULTS: Among 85 tumours, 40 (47%) were positive for p-AKT, 31 (36%) for p-mTOR, 44 (52%) for p-4EBP1, 38 (45%) for p-S6, and 39 (46%) for p-p70S6K1. CDK2 immunostaining was positive in all cases of SCC and BD, and in 67% of benign tumours. All of these markers were stained much more frequently in malignant tumours than in benign tumours or NS. p-AKT, p-mTOR, p-4EBP1, p-p70S6K1 and p-S6 each showed high correlation with CDK2. CONCLUSIONS: Constitutive activation of the AKT/mTOR pathway was frequent in epidermal tumours, especially in malignant tumours. Activation was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in epidermal tumours.

The evaluation of post-operative alignment in total knee replacement using a CT-based navigation system.

We compared the alignment of 39 total knee replacements implanted using the conventional alignment guide system with 37 implanted using a CT-based navigation system, performed by a single surgeon. The knees were evaluated using full-length weight-bearing anteroposterior radiographs, lateral radiographs and CT scans. The mean hip-knee-ankle angle, coronal femoral component angle and coronal tibial component angle were 181.8 degrees (174.2 degrees to 188.3 degrees), 88.5 degrees (84.0 degrees to 91.8 degrees) and 89.7 degrees (86.3 degrees to 95.1 degrees), respectively for the conventional group and 180.8 degrees (178.2 degrees to 185.1 degrees), 89.3 degrees (85.8 degrees to 92.0 degrees) and 89.9 degrees (88.0 degrees to 93.0 degrees), respectively for the navigated group. The mean sagittal femoral component angle was 85.5 degrees (80.6 degrees to 92.8 degrees) for the conventional group and 89.6 degrees (85.5 degrees to 94.0 degrees) for the navigated group. The mean rotational femoral and tibial component angles were -0.7 degrees (-8.8 degrees to 9.8 degrees) and -3.3 degrees (-16.8 degrees to 5.8 degrees) for the conventional group and -0.6 degrees (-3.5 degrees to 3.0 degrees) and 0.3 degrees (-5.3 degrees to 7.7 degrees) for the navigated group. The ideal angles of all alignments in the navigated group were obtained at significantly higher rates than in the conventional group. Our results demonstrated significant improvements in component positioning with a CT-based navigation system, especially with respect to rotational alignment.

Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma.

BACKGROUND: Cytokeratin 19 (CK19) has been considered to be a putative marker for epidermal stem cells in the hair follicle bulge. Cumulative reports have shown that epidermal stem cells play an important role in skin carcinogenesis. However, to date there has been no report on the clinical alteration of the stem cells in squamous cell carcinoma (SCC). OBJECTIVES: To investigate alteration of the stem cells and proliferating cells and to assess their relationship and potential contribution to SCC. METHODS: Thirty paraffin-embedded neoplastic skin lesions, consisting of 10 cases each of actinic keratosis (AK), Bowen disease (BD) and SCC, were examined immunohistologically for CK19 and Ki-67. RESULTS: Positive reactivity for CK19 was seen in 30% of AK, 50% of BD and 80% of SCC lesions. There was significantly higher expression levels of CK19 in SCC than in AK and BD (P < 0.05). In addition, BD lesions harboured a significantly higher number of CK19-positive cells than did AK lesions (P < 0.05). There were significant differences in Ki-67 labelling indices between AK and BD and between AK and SCC (P < 0.001), but not between BD and SCC (P > 0.05). Furthermore, a serial section comparison study showed that there was a minor population of cells co-expressing CK19 and Ki-67 in a subset of the tumour cells of SCC samples. The percentage of CK19+ cells significantly correlated with that of Ki67+ cells in all examined neoplastic skin lesions. CONCLUSIONS: These results suggest that CK19 expression may be associated with the retention of stem cell characteristics or a state that is uncommitted to terminal squamous differentiation.

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget's disease.

BACKGROUND: The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget's disease (EMPD). AIM: To investigate the potential contribution of p53, p63 and p73 in the pathogenesis of EMPD. METHODS: In total, 35 paraffin wax-embedded tissue samples from patients with EMPD were examined using immunohistochemical staining for p53, p63 and p73. RESULTS: All of the 35 EMPD specimens, including all 6 invasive EMPD and 2 metastatic lymph-node specimens, showed nuclear overexpression of both p53 and p73. The expression levels (percentage of positive cells) of p53 and p73 (90.66 +/- 12.53% and 80.20 +/- 13.07%) in EMPD were significantly higher than those of normal skin. There was a significant correlation between the expression levels of p53 and p73 in EMPD. In 29 of 35 EMPD specimens, there was no nuclear expression of p63, and weak or moderate staining was found in only 6 specimens. The expression level of p63 in EMPD was significantly less than that in normal skin. CONCLUSIONS: Our study shows that the concordant overexpression of p53 and p73 and the decreased expression of p63 may play a pivotal role in the pathogenesis of EMPD. The decreased expression of p63 may play a more important role in the pathogenesis of EMPD than the overexpression of p53 and p73.

Engagement of human monocyte-derived dendritic cells into interleukin (IL)-12 producers by IL-1beta + interferon (IFN)-gamma.

Dendritic cells (DCs) are potent antigen-presenting cells and can induce tumour- or pathogen-specific T cell responses. For adoptive immunotherapy purposes, immature DCs can be generated from adherent monocytes using granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-4, and further maturation is usually achieved by incubation with tumour necrosis factor (TNF)-alpha. However, TNF-alpha-stimulated DCs produce low levels of IL-12. In this study, we compared the effects of TNF-alpha, interferon (IFN)-gamma, IL-1beta or IFN-gamma + IL-1beta on the phenotypic and functional maturation of DCs. Our results show that IFN-gamma, but not IL-1beta, augmented the surface expression of CD80, CD83 and CD86 molecules without inducing IL-12 production from DCs. However, IL-1beta, but not IFN-gamma, induced IL-12 p40 production by DCs without enhancing phenotypic maturation. When combined, IFN-gamma + IL-1beta treatment profoundly up-regulated the expression of CD80, CD83, CD86 and major histocompatibility complex (MHC) class II antigens. Furthermore, IFN-gamma + IL-1beta-treated DCs produced larger amounts of IL-12 and induced stronger T cell proliferation and IFN-gamma secretion in primary allogeneic mixed lymphocyte reaction (MLR) than did TNF-alpha-treated DCs. Our results show that IFN-gamma + IL-1beta induced human monocyte-derived DCs to differentiate into Th1-prone mature DCs.

Spontaneous regression of multiple seborrheic keratoses associated with nasal carcinoma.

Seborrheic keratoses are very common epidermal neoplasms. We describe a patient with seborrheic keratoses presenting multifocal spontaneous regression. The patient had a concurrent nasal adenoid cystic carcinoma. The simultaneous regression of seborrheic keratoses ceased after total resection of the nasal carcinoma. Histological examination revealed marked infiltration of mononuclear cells, including CD4+, CD8+, CD68+ and cutaneous lymphocyte-associated antigen-positive cells, with profound accumulation of CD1a+ dendritic cells. Although apoptotic keratinocytes were not found in the lesional epidermis by histology, the majority of keratinocytes in the regressing seborrheic keratosis were positively stained by the TUNEL method. We postulate that the internal malignancy may induce spontaneous regression of seborrheic keratoses.

Cytokines and chemokines in the epidermis.

Keratinocytes (KC) produce a vast repertoire of cytokines, including interleukins, growth factors, colony stimulating factors, and chemokines. Under normal conditions, most of them are not synthesized or remain in the cytoplasm, but external stimuli, such as trauma, bacterial infections, chemical substances, or ultraviolet irradiation induce the production and release of these cytokines from KC. KC-derived cytokines regulate the immune and inflammatory responses through their receptors on KC, Langerhans cells, dermal fibroblasts and endothelial cells, and infiltrating T-cells.