Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.

OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

An Open-label Single-arm Trial of a Novel Extramedullary Guide Coordinated with 3D Surgical Assistive Software for Total Knee Arthroplasty.

There is no assistive device for extramedullary surgery coordinated with 3D surgical assistive software for the total knee arthroplasty (TKA). We developed a novel extramedullary universal guide coordinated with 3D surgical assistive software and a novel extramedullary patient-specific assistive guide for the placement of femoral components by referring to an area not affected by cartilage or bone spurs, and filed a patent application. In this study, we visualize and reconstruct the total alignment of the lower extremity in TKA using these surgical devices, and validate their precision. A report releasing study results will be submitted in an appropriate journal.

Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease.

Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of four family members in a pedigree with RAK. Fifty-three SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of four other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of four additional unrelated RAK patients revealed four additional ADAM10 mutations. We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD.

Monte Carlo simulation for speckle reduction by a moving diffuser on the natural test image.

We present a precise Monte Carlo simulation of speckle reduction on the natural test image, which will serve as a digital image embedded with speckle under control. In simulating the conditioned time averaging for the square modulus of the random phasor sum in speckle reduction by a moving diffuser, after initial upconversion of the test image amplitudes, downconversion of their product with an independent set of time-varying, random phasors is repeated to sum up the square moduli. Validity of the simulation is rigorously confirmed on the test image array consisting of random real amplitude. As a more practical digital test image for speckle evaluation, the well-known Lena test image is promising as the standard for this application from the point of view of sufficiently small excess noise, primarily due to low pixel-neighbor correlations.

Clinicopathologic analysis of 66 Japanese thin melanomas with metastasis of sentinel or regional lymph node.

BACKGROUND: Assessment of sentinel lymph node status is commonly performed in the treatment of cutaneous melanoma. However, there are no definite guidelines for thin melanomas with Breslow tumor thickness <1.0 mm, in part because thin melanomas are relatively infrequently positive for lymph node metastasis. METHODS: We analyzed the clinicopathologic relationship among tumor thickness, mitotic index, tumor infiltrating lymphocytes (TIL), tumor size, regional lymph node metastasis and prognosis in 66 Japanese patients with thin melanomas. Immunohistochemical evaluations for TIL were also performed. RESULTS: Thirty-one of the 66 melanomas were Clark level I without lymph node metastasis (0/31, 0%). In tumors of Clark level II or higher (35/66), there were five (14%) regional lymph node metastasis. Melanomas with two or more mitoses in 1 mm(2) per high-power fields showed higher frequencies of lymph node metastasis (2/3, 67%), compared to those with fewer than two mitoses (3/32, 9%). Tumors with intensive TIL that partially or completely surrounded the tumor revealed higher frequencies of lymph node metastasis (5/28, 18%), compared to those with none or slight TIL (0/7, 0%). The main components of TIL were CD8-positive T lymphocytes. No metastasized tumors were under 2.0 cm(2) . CONCLUSIONS: The presence of mitotic activity, large tumor size and an intense lymphocytic infiltrate should prompt sentinel lymph node biopsy in thin melanomas.

Primary cutaneous CD30 positive T-cell lymphoproliferative disorders with aberrant expression of PAX5: report of three cases.

Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs.

The Efficacy and Safety of a Novel Extramedullary Guide Coordinated with 3D Surgical Assistive Software for Total Knee Arthroplasty: an Open-Label Single-Arm Trial.

To improve component-placement accuracy in total knee arthroplasty, we developed two devices: an original extramedullary patient-specific guide for the femur and an original extramedullary universal guide for the tibia (EM-TIBIA). We also developed a new function in ZedView, a three-dimensional surgical assistive software, that provides the parameters necessary to install the EM-TIBIA. Compared with conventional manual methods based on X-ray two-dimensional images or ZedView, these newly developed devices function as an extramedullary intraoperative support guide in conjunction with ZedView, simplifying surgical procedures. We conducted a study to evaluate the efficacy and safety of the surgery using the new guides and software function. Nineteen patients underwent surgery. On the femoral side, the mean absolute difference of the installation alignment was within 3° for all parameters. On the other hand, on the tibial side, the mean absolute difference from the preoperative plan for the rotation was 5.26±5.30°. The proportion of patients whose difference fell within ±3° was 52.6% (95% confi dence interval: 28.9 to 75.6%), and did not meet the pre-specified criteria for efficacy (P=0.261). No serious adverse events were reported, and no excessive bleeding, thrombosis, infections, or intraoperative or postoperative fractures were noted. The two new guides can easily reproduce the preoperative plan as 3D intraoperative support jigs, but errors can occur on the tibia side due to soft tissue that is not recognized by CT, creating problems in installation accuracy.

Extrinsic compression of the left main coronary artery: A rare cause of cardiogenic shock.

A left main coronary artery (LMCA) stenosis due to extrinsic compression by mediastinal tumor is a rare finding. In this case reports, we present a 63-year-old woman, who was transferred to the emergency department with chief complains of persistent chest and back pain. An electrocardiogram revealed diffuse ST-segment depression (elevation in lead aVR). Contrast-enhanced computed tomography (CT) showed a huge cystic mass above the left atrium. After the CT examination, she was temporarily in shock. Compression of the LMCA was evident on the CT angiography and a diagnosis of acute myocardial infarction due to compression of the LMCA by a tumor was made. An emergent resection of the tumor was performed. Histopathological assessment of the resected cyst revealed that it was a schwannoma. She made an uneventful postoperative recovery. A follow-up 3-dimensional CT scan performed after the operation confirmed no evidence of LMCA compression.

CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling.

Immune cells are critical to the wound-healing process, through both cytokine and growth factor secretion. Although previous studies have revealed that B cells are present within wound tissue, little is known about the role of B cells in wound healing. To clarify this, we investigated cutaneous wound healing in mice either lacking or overexpressing CD19, a critical positive-response regulator of B cells. CD19 deficiency inhibited wound healing, infiltration of neutrophils and macrophages, and cytokine expression, including basic and acidic fibroblast growth factor, interleukin-6, platelet-derived growth factor, and transforming growth factor-beta. By contrast, CD19 overexpression enhanced wound healing and cytokine expression. Hyaluronan (HA), an endogenous ligand for toll-like receptor (TLR)-4, stimulated B cells, which infiltrates into wounds to produce interleukin-6 and transforming growth factor-beta through TLR4 in a CD19-dependent manner. CD19 expression regulated TLR4 signaling through p38 activation. HA accumulation was increased in injured skin tissue relative to normal skin, and exogenous application of HA promoted wound repair in wild-type but not CD19-deficient mice, suggesting that the beneficial effects of HA to the wound-healing process are CD19-dependent. Collectively, these results suggest that increased HA accumulation in injured skin induces cytokine production by stimulating B cells through TLR4 in a CD19-dependent manner. Thus, this study is the first to reveal a critical role of B cells and novel mechanisms in wound healing.

Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis.

OBJECTIVES: Myositis-specific autoantibodies are useful for diagnosing PM/DM. Recently, two new myositis-specific autoantibodies against melanoma differentiation-associated gene 5 (MDA5) and transcriptional intermediary factor 1-gamma (TIF1-gamma) were identified in DM. Here, we detected these autoantibodies in patient sera using new assays with recombinant MDA5 and TIF1-gamma, and associated clinical features with the presence of anti-MDA5 or anti-TIF1-gamma antibodies. METHODS: We screened 135 Japanese patients with various CTDs, including 82 with DM. DM patients were classified as clinically amyopathic DM (CADM), cancer-associated DM or classical DM without cancer. Anti-MDA5 and anti-TIF1-gamma antibodies were detected by their ability to immunoprecipitate biotinylated recombinant proteins. RESULTS: Sera from 21 (26%) of 82 DM patients immunoprecipitated MDA5, and every anti-MDA5-positive patient had DM (except one patient with SSc). Sera from 20 (65%) of 31 CADM patients reacted with MDA5. Notably, anti-MDA5-positive DM patients had significantly more interstitial lung disease than anti-MDA5-negative DM patients (95 vs 32%, P < 0.001). Sera from 12 (15%) of 82 DM patients immunoprecipitated TIF1-gamma, and anti-TIF1-gamma antibodies were only detected in DM patients. Strikingly, 7 (58%) of 12 patients with cancer-associated DM had sera that reacted with TIF1-gamma. Anti-TIF1-gamma-positive DM patients had significantly more internal malignancies than anti-TIF1-gamma-negative DM patients (58 vs 9%, P < 0.001). CONCLUSIONS: Anti-MDA5 and anti-TIF1-gamma antibodies were confirmed to be serological DM subset markers. Anti-MDA5 and anti-TIF1-gamma antibodies were detected based on their ability to immunoprecipitate biotinylated recombinant MDA5 and TIF1-gamma, and were closely associated with life-threatening complications in DM.

Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes.

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is a transducer of mitogenic signals, and is involved in the pathogenesis and progression of a number of cancers, including non-small cell lung cancer (NSCLC). Gefitinib is an EGFR-TK inhibitor that is clinically used to treat NSCLC; however, this drug frequently causes adverse effects, including skin eruptions. The mechanism underlying these skin reactions is elusive, although it is assumed that they are caused by the inhibition of EGFR-TK signalling in epidermal and adnexal cells. In this article, we demonstrate by immunocytochemistry that the skin lesions of patients treated with oral gefitinib had higher expression of CCL2 and CCL5 compared to normal human epidermis. Further, PD153035, a gefitinib prototype, induced CCL2 and CCL5 mRNA and protein expression in HaCaT and HSC-1 keratinocyte cell lines with or without interleukin-1 (IL-1) treatment in vitro. PD153035 also reduced the levels of interleukin-1 receptor 2 (IL-1R2), an IL-1 decoy receptor. Moreover, we demonstrate that reduction in IL-1R2 by RNA interference increased IL-1-mediated CCL2 and CCL5 mRNA and protein expression. Taken together, our data strongly suggest that IL-1-mediated signalling is activated to induce the high expression of CCL2 and CCL5 via reduction in IL-1R2 in the skin lesions caused by gefitinib.

beta2-Adrenoceptor agonists enhance cytokine-induced release of thymic stromal lymphopoietin by lung tissue cells.

BACKGROUND: Whilebeta(2)-adrenoceptor agonists (beta(2)-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of beta(2)-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of beta(2)-agonists are not fully understood. In this study, we examined the effects of beta(2)-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells. METHODS: Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-alpha cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of beta(2)-agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined. RESULTS: The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-alpha significantly induced TSLP production, and beta(2)-agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and beta(2)-agonist resulted in a marked decrease in TSLP production. CONCLUSIONS: beta(2)-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous beta(2)-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.

Primary cutaneous T-cell lymphoma of unspecified type with cytotoxic phenotype: clinicopathological analysis of 27 patients.

The objective of our study was to investigate the clinicopathological features of the currently ill-defined subtype of primary cutaneous T-cell lymphoma of unspecified type (CTCLU) with a cytotoxic phenotype and no Epstein-Barr virus (EBV) association. A series of 27 patients with CTCLU (median age 49 years; range 25-87 years; 18 men) was reviewed. Performance status scores above 1 (7%), clinical stages above 2 (15%), B symptoms (26%), extracutaneous involvement (30%), and a fatal course within 1 year of diagnosis (19%) were observed infrequently. The International Prognostic Index was high or high to intermediate in 11%, and the Prognostic Index for Peripheral T-cell Lymphoma unspecified was above group 2 in 22%. Notably, the rates of spontaneous regression and T-cell receptor gene rearrangements by polymerase chain reaction analysis were seen in 26 and 17% of our cases, respectively. Histologically, 22 patients had subcutaneous involvement of whom eight showed a lethal clinical course, and five patients without subcutaneous involvement were all survivors. Immunophenotypical and morphological features allowed us to subclassify our cases according to the following four categories: (1) epidermotropic CD8+ T-cell lymphoma (n=5); (2) cutaneous gamma/delta T-cell lymphoma (n=8); (3) cutaneous alpha/beta pleomorphic T-cell lymphoma (n=8); and (4) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified (n=6). All four of these groups of lymphomas exhibited a relatively favorable clinical course compared to previous reports. However, epidermotropic CD8+ T-cell lymphoma appeared to be unique with a higher ratio (80%) of spontaneous regression, a lower ratio (40%) of subcutaneous involvement, and a more favorable clinical course than the other three subcategories.

Oculocutaneous albinism type IV: A boy of Moroccan descent with a novel mutation in SLC45A2.

Oculocutaneous albinism type IV (OCA4 [MIM606574]) caused by mutations of the SLC45A2 gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye. We had the opportunity to examine a Belgian boy of Moroccan descent with clinically severe OCA and screened the mutation in his SLC45A2 gene. Sequencing of exon 1, of which the PCR product showed aberrant patterns in the SSCP gel, revealed that the patient was a homozygote for p.H38R mutation. We demonstrated that the p.H38R-mutant protein was functionally incapable of melanin synthesis using melanocyte cultures (under white cells; uw) established from a mouse model of OCA4. This is the second report of the occurrence of OCA4 in a member of an African ethnic group.

Establishment of a screening system for chemicals that upregulate a melanoma antigen, Melan-A/MART-1.

Immunotherapy is well-practiced as one of the main adjuvant therapies for melanoma patients. Until now, many immunotherapeutic investigations have focused on improving the effector side of the antitumor response, but only a few studies have been concerned with preventing the loss of tumor-associated antigen (TAA) expression. Loss of TAA should be an important problem for the recognition of tumor cells by cytotoxic T lymphocytes. If any agents that augment the expression of melanoma antigens were found, they could improve the efficacy of immunotherapy by increasing the antigens. To detect effective chemicals, we made a fluorescent cellular reporter system for screening promising candidate chemicals. In this system, the fusion gene of the Melan-A/MART-1 promoter sequence followed by the green fluorescent protein (GFP) coding region was stably transfected into MUX human melanoma cells which are known to express little or no Melan-A/MART-1. Melan-A/MART-1 is a well-known melanoma antigen recognized by autologous cytotoxic T cells, and is a glycoprotein associated with the melanosome, the organelle in which melanin synthesis proceeds. By using this screening system, daunorubicin, doxorubicin and cytochalasin D, which enhanced the green fluorescent, were selected and then were confirmed to actually increase the expression of Melan-A/MART-1 mRNA and protein in human melanoma cells of MU89, MM96L(+) and SK-MEL-28, but also in low-antigen presenting cells such as MM96L(-), MUX, and A375. In conclusion, we have successfully established a well-functioning screening system, which will allow us to find candidate chemicals that up-regulate or maintain the melanoma antigen expression.

[Thrombotic thrombocytopenic purpura with mixed connective tissue disease. A case report].

We reported a very rare case of mixed connective tissue disease (MCTD) with thrombotic thrombocytopenic purpura (TTP). The patient was a 24-year-old female who admitted to our hospital in February 2007 because of swelling of her fingers and Raynaud's phenomenon, and was diagnosed as MCTD. Her symptom was improved with the oral administration of prednisolone 10 mg/day. In September 2007, her blood examination test showed remarkable thrombocytopenia and hemolytic anemia. A significant number of schistocytes were observed in her peripheral blood smear, and a disintegrin-like and metalloproteinase with thrombospondin type1 motifs13 (ADAMTS13) activity in her serum was below the measurement sensitivity, resulted in the diagnosis of TTP. Seven-time plasma exchanges so far cured TTP clinically without any relapse, with remarkable improving of all laboratory data relating to TTP.

An Open-Label, Single-Arm Study of a Patient-Specific Femoral Guide for Total Hip Arthroplasty via the Anterolateral Supine Approach, Linked with Three-Dimensional Surgical Support Software: Study Protocol.

In total hip arthroplasty (THA), it is generally accepted that the bones of the acetabular cup and femur of hip joint must be accurately cut and components (artificial joint parts) be implanted in exact positions at exact angles to achieve improvement of daily living (ADL) and quality of life (QOL). However, with the conventional surgical method, it is difficult to grasp and measure the acetabular cup and femoral stem precisely during surgery, making some kind of reliable guide necessary. Although it was reported that an accurate angle was achieved in acetabular cup implantation by support instruments for surgical planning, an effective support instrument is now being developed for stem implantation on the out-of-reach femur side. This is the first clinical study to assess the efficacy and safety of anterolateral approach THA using an extracorporeal patient-specific femoral guide (PSG) for stem implantation with three-dimensional (3D) surgical support software in patients with hip joint disease.

The influence of frailty under direct oral anticoagulant use in patients with atrial fibrillation.

BACKGROUND: Frailty is a prognostic factor in patients with atrial fibrillation (AF). However, there is no report on the associations between frailty and clinical adverse events in patients with AF taking direct oral anticoagulants (DOAC). The factors related to the occurrence of clinical adverse events are still under discussion. Therefore, we examined the associations between frailty and clinical adverse events in patients with AF taking DOAC in daily clinical practice. METHODS: We retrospectively evaluated 240 consecutive patients with AF who had been newly prescribed DOAC in our hospital from April 2016 through May 2017. Data collected included Clinical Frailty Scale (CFS) scores, laboratory results and basic demographic information. RESULTS: During the mean follow-up period of 13.4 months, 20 patients died (7.6 per 100 person-years), stroke or systemic embolism occurred in seven patients (2.6 per 100 person-years) and major bleeding occurred in 11 patients (4.2 per 100 person-years). We defined these adverse events as composite end points, and we estimated adjusted HRs and 95% CIs for risk factors using the Cox proportional hazard regression model. Frailty (defined as a CFS score of 5 or more; HR: 3.71; 95% CI: 1.59 to 8.65), female sex (HR: 3.49; 95% CI: 1.73 to 7.07), serum albumin level (HR: 0.47; 95% CI: 0.28 to 0.79) and malignancy (HR: 4.02; 95% CI: 1.83 to 8.84) were independent predictors of the composite end points. CONCLUSIONS: Frailty, female sex, hypoalbuminaemia and malignancy were associated with clinical adverse events in patients with AF who were prescribed DOAC.

Recent advances in genetic analyses of oculocutaneous albinism types 2 and 4.

Patients with OCA are characterized by reduced skin and hair pigmentation and consequent photosensitivity, actinic damage and risk of skin cancer, and by reduced visual acuity and nystagmus. Our survey of Japanese patients revealed that OCA1 was the most frequent type at 34%, while type 2 was present at less than 10%. OCA3 was absent. OCA4, which is a rare type worldwide, was the second most frequent type at 27%. Unexpectedly 10% of the patients turned out to be Hermansky-Pudlak syndrome type 1. Furthermore, the pathogenic p.A481T allele for OCA2, which has 70% melanogenesis activity, was found in approximately 12% of normally pigmented people, indicating that sub-clinical OCA2 might be more frequent in the Japanese than currently thought. And OCA4 is one of the most common types in Japanese patients, despite being rare worldwide.

A pilot study of human interferon beta gene therapy for patients with advanced melanoma by in vivo transduction using cationic liposomes.

BACKGROUND: Cationic liposomes containing the human interferon beta (HuIFNbeta) gene (IAB-1) was used for the clinical trial for glioma patients. HuIFNbeta gene therapy showed much higher anti-tumor activity compared with the administration of HuIFNbeta protein for melanoma. These results suggest that HuIFNbeta gene therapy is an attractive strategy for the treatment of melanoma. METHODS: Stage IV or III melanoma patients with cutaneous or subcutaneous metastatic lesions were enrolled in this pilot study. IAB-1 was dissolved by sterile PBS at a concentration of 30 microg DNA/ml and was injected into cutaneous or subcutaneous metastatic nodules three times a week for 2 weeks and the effect on the injected and non-injected metastatic lesions was evaluated. RESULTS: Clinical responses were as follows (five patients): mixed response (MR) and no change in each one patient, and progressive disease in three patients. In the MR patient, the IAB-1 injected lesion disappeared clinically and histopathologically and one-half of IAB-1 non-injected skin metastases were transiently inflamed and mostly regressed. In the responded non-injected lesions of this patient, histopathologically, infiltration of CD4 positive T cells was observed around the melanoma cells in the dermis, which expressed the HLA-Class II antigen. Adverse events due to this gene therapy were not recognized in any of the patients. CONCLUSIONS: The efficacy of this gene therapy was generally insufficient; however, some immunological responses were recognized in one patient. No adverse events were observed. HuIFNbeta gene therapy could be an attractive strategy for treatment of a variety of malignancies, including melanoma, though some modifications should be required.