Satoko Shibata

Induction of Efficient Antitumor Immunity Using Dendritic Cells Activated by Recombinant Sendai Virus and Its Modulation by Exogenous IFN-β Gene

Dendritic cell (DC)-based cancer immunotherapy has been paid much attention as a new and cancer cell-specific therapeutic in the last decade; however, little clinical outcome has been reported. Current limitations of DC-based cancer immunotherapy include sparse information about which DC phenotype should be administered. We here report a unique, representative, and powerful method to activate DCs, namely recombinant Sendai virus-modified DCs (SeV/DC), for cancer immunotherapy. In vitro treatment of SeV without any bioactive gene solely led DCs to a mature phenotype. Even though the expression of surface markers for DC activation ex vivo did not always reach the level attained by an optimized amount of LPS, superior antitumor effects to B16F1 melanoma, namely tumor elimination and survival, were obtained with use of SeV-GFP/DC as compared with those seen with LPS/DC in vivo, and the effect was enhanced by SeV/DC-expressing IFN-β (SeV-murine IFN-β (mIFN-β)/DC). In case of the treatment of an established tumor of B16F10 (7–9 mm in diameter), a highly malignant subline of B16 melanoma, SeV-modified DCs (both SeV-GFP/DC and SeV-mIFN-β/DC), but not immature DC and LPS/DC, dramatically improved the survival of animals. Furthermore, SeV-mIFN-β/DC but not other DCs could lead B16F10 tumor to the dormancy, associated with strongly enhanced CD8+ CTL responses. These results indicate that rSeV is a new and powerful tool as an immune booster for DC-based cancer immunotherapy that can be significantly modified by IFN-β, and SeV/DC, therefore, warrants further investigation as a promising alternative for cancer immunotherapy.

Long-term effects of polychlorinated biphenyls and dioxins on pregnancy outcomes in women affected by the Yusho incident.

Background Maternal exposure to polychlorinated biphenyls (PCBs) is associated with increased proportions of spontaneous abortion and stillbirth in animal studies. In Japan in 1968, accidental human exposure to rice oil contaminated with PCBs and other dioxin-related compounds, such as polychlorinated dibenzofurans (PCDFs), led to the development of what was later referred to as Yusho oil disease. Objective The aim of this study was to investigate the association of maternal PCB and dioxin exposure with adverse pregnancy outcomes in Yusho women. Methods In 2004, we interviewed 214 Yusho women (512 pregnancies) about their pregnancy outcomes over the past 36 years. Pregnancy outcomes included induced abortion, spontaneous abortion, preterm delivery, and pregnancy loss. Results In pregnancy years 1968–1977 (within the first 10 years after exposure), the proportions of induced abortion [odds ratio adjusted for age at delivery (ORadj) = 5.93; 95% confidence interval (CI), 2.21–15.91; two-tailed p < 0.001) and preterm delivery (ORadj = 5.70; 95% CI, 1.17–27.79; p = 0.03) were significantly increased compared with the proportions in pregnancy years 1958–1967 (10 years before the incident). Spontaneous abortion (ORadj = 2.09; 95% CI, 0.84–5.18), and pregnancy loss (ORadj = 2.11; 95% CI, 0.92–4.87) were more frequent (OR = 2.18; 95% CI, 1.02–4.66), but these were not significant (p = 0.11 and p = 0.08, respectively) in pregnancy years 1968–1977. We found no significant increases in the proportions of these adverse pregnancy outcomes in pregnancies occurring during 1978–1987 or 1988–2003 compared with those in pregnancies before 1968. Conclusion High levels of PCB/PCDF exposure had some adverse effects on pregnancy outcome in Yusho women.

Association of clinical findings in Yusho patients with serum concentrations of polychlorinated biphenyls, polychlorinated quarterphenyls and 2,3,4,7,8-pentachlorodibenzofuran more than 30 years after the poisoning event

BackgroundThe Yusho poisoning incident, which was caused by rice bran oil contaminated with polychlorinated biphenyls (PCBs), polychlorinated quarterphenyls (PCQs) and polychlorinated dibenzofurans (PCDFs) generated by heat denaturation of PCB, occurred in 1968 in western Japan. Annual physical, dermatological, dental, ophthalmological and laboratory examinations were conducted for Yusho patients after the incident. From 2001, blood levels of individual PCDF congeners were also measured. The blood levels of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF), PCBs and PCQs in Yusho patients were found to be significantly higher than those of the general population. We investigated the relationships between blood concentrations of 2,3,4,7,8-PeCDF, PCBs and PCQs in Yusho patients and the items measured in the annual medical examination.MethodsMedical and laboratory examination data from 501 Yusho patients enrolled in the study from 2001 to 2004 were analyzed. The relationships between blood 2,3,4,7,8-PeCDF, PCB and PCQ concentrations and medical/laboratory examination data were investigated using principal components and logistic regression analyses.ResultsSerum Concentrations of 2,3,4,7,8-PeCDF, PCBs and PCQs in blood tended to correlate with either acneform eruptions, black comedones, cutaneous and mucosal pigmentation, and hypersecretion of meibomian glands as well as general fatigue, headaches, cough/sputum, abdominal pain, arthralgia, increased blood sugar, increased serum γ-GTP and decreased total bilirubin. The majority of these signs and symptoms are included in the diagnostic criteria for Yusho.ConclusionAfter Yusho patients had suffered chronic exposure to these chlorinated compounds for more than 35 years, the serum concentration of 2,3,4,7,8-PeCDF in blood was significantly related to arthralgia and decreased albumin/globulin (A/G) ratio; the serum concentration of PCBs was significantly related to ophthalmologic symptoms; and the serum concentration of PCQ to increased total cholesterol. These findings suggest that the co-contaminants may affect other functions than those originally associated with Yusho.

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.

Complete elimination of established neuroblastoma by synergistic action of |[gamma]|-irradiation and DCs treated with rSeV expressing interferon-|[beta]| gene

Dendritic cell (DC)-based immunotherapy has been investigated as a new therapeutic approach to intractable neuroblastomas; however, only limited clinical effect has been reported. To overcome the relatively low sensitivity of neuroblastomas against immunotherapy, we undertook a preclinical efficacy study to examine murine models to assess the combined effects of γ-irradiation pretreatment and recombinant Sendai virus (ts-rSeV/dF)-mediated murine interferon-β (mIFN-β) gene transfer to DCs using established c1300 neuroblastomas. Similar to intractable neuroblastomas in the clinic, established c1300 tumors were highly resistant to monotherapy with either γ-irradiation or DCs activated by ts-rSeV/dF without transgene (ts-rSeV/dF-null) that has been shown to be effective against other murine tumors, including B16F10 melanoma. In contrast, immunotherapy using DCs expressing mIFN-β through ts-rSeV/dF (ts-rSeV/dF-mIFNβ-DCs) effectively reduced tumor size, and its combination with γ-irradiation pretreatment dramatically enhanced its antitumor effect, resulting frequently in the complete elimination of established c1300 tumors 7–9 mm in diameter, in a high survival rate among mice, and in the development of protective immunity in the mice against rechallenge by the tumor cells. These results indicate that the combination of ts-rSeV/dF-mIFNβ-DCs with γ-irradiation is a hopeful strategy for the treatment of intractable neuroblastomas, warranting further investigation in the clinical setting.

Variation in half-life of penta-chlorodibenzofuran (PeCDF) blood level among Yusho patients

Yusho (oil disease) is the name given to a food poisoning incident caused by rice bran oil that occurred in west Japan in 1968. The causative agents of Yusho are currently considered to be polychlorinated biphenyls (PCBs) and their by-products, such as dioxin like compounds. The levels of 2,3,4,7,8-penta-cholorodibenzofuran (PeCDF) are measured in the blood of Yusho patients who attend medical check-ups. The objectives of this study were to determine the half-life of PeCDF in these patients. Linear regression analysis was performed with the binary logarithm of PeCDF blood levels in Yusho patients as the dependent variable and the measurement year as the independent variable. The linear coefficient determined in this analysis is the reciprocal of the half-life. The half-life of PeCDF varied among patients. Among patients with PeCDF blood levels of 50pgg(-1) or higher, there were two groups: one showing a half-life of approximately 7 years and the other showing no reduction in PeCDF levels over time. The results indicate that there is a group of patients whose PeCDF levels are maintained at a high level. Our study suggests that a more complicated model is required to explain PeCDF excretion in humans.

Leiomyoma of the male nipple.

acitretin but the inflammatory lesions are usually persistent. Erbağcı et al. have found systemic retinoids to be ineffective in EKV. PUVA is an effective therapy for inflammatory dermatoses such as psoriasis and lichen planus. On the basis of these results and the predominance of the inflammatory, erythematous component in our patient, we commenced RePUVA therapy. The treatment was effective both for the hyperkeratotic and the erythematous patches with almost complete normalization of the skin. No adverse reactions were observed during the entire treatment. To the best of our knowledge, this is the first case of EKV successfully treated with Re-PUVA. It seems likely that the combination of acitretin with PUVA increases the effectiveness compared with acitretin alone and Re-PUVA may be considered as an alternative treatment of EKV. On the other hand, further studies with larger series are required to confirm this opinion.

Changes in the Oral Moisture and the Amount of Microorganisms in Saliva and Tongue Coating after Oral Ingestion Resumption: A Pilot Study

Background and Objective: Tube feeding has been significantly associated with a higher rate of aspiration pneumonia that is mainly related to oral microorganisms and a reduced salivary flow. Thus, the difference in the mode of nutritional intake is expected to affect the oral environment, but this has not yet been fully clarified. The purpose of this study was to investigate, in tube-fed patients, changes in the oral moisture and the counts of microorganisms in saliva and tongue coating, which occur after oral ingestion resumption. Methods: Study participants were 7 tube-fed inpatients of the Niigata University Medical and Dental Hospital (72.7±8.5 years old) who received dysphagia rehabilitation at the Unit of Dysphagia Rehabilitation until oral ingestion resumption. Their oral health, swallowing, and nutrition status, oral mucosal moisture, amount of unstimulated saliva and the counts of microorganisms (total microorganisms, streptococci, Candida) in saliva and tongue coating were investigated and compared before and after the recommencement of oral intake. Results: Tongue coating, choking, oral mucosal moisture and amount of unstimulated saliva were improved significantly after resumption of oral ingestion. The other investigated parameters did not significantly change, except for the streptococci in tongue coating, which significantly increased 1 week after oral ingestion recommencement, but decreased thereafter. Conclusion: After oral intake resumption, oral mucosal moisture and amount of unstimulated saliva were improved. However, because of a transitory increase in the counts of streptococci with oral ingestion recommencement, it is important to appropriately manage oral hygiene in these patients, according to the changes in their intraoral microbiota.

Twenty-year changes of penta-chlorodibenzofuran (PeCDF) level and symptoms in Yusho patients, using association analysis

BackgroundRecently, methods for measurement of dioxins in the blood have improved. Also, techniques for analyzing large quantities of data have been developed, such as data mining. Even in subjects with elusive characteristics, it is becoming possible to find previously unknown characteristics by checking all combinations of symptoms.FindingsUsing association analysis of the data mining technique, we extracted and compared combinations with a strong relationship between recent symptoms (2001-2004) and recent blood PeCDF levels, and between past symptoms (1986-1989) and recent PeCDF levels, in physical, blood, dermatological, dental and ophthalmological examinations.Patients with a higher PeCDF level were more likely to present with symptoms included in the diagnostic criteria, such as pigmentation. In addition, we obtained evidence that recent PeCDF levels had a stronger relationship with recent than past symptoms.ConclusionsRecent PeCDF levels should not be compared directly with past symptoms. However, as the excretion rate of PeCDF has been constant, it is probable that PeCDF levels were higher in the past if recent PeCDF levels were also high. The study confirmed a relationship between past PeCDF levels and past clinical symptoms. For symptoms included in the diagnostic criteria, there was a stronger relationship between PeCDF levels and past symptoms than recent symptoms. Alleviation of symptoms in each patient or aging weakened the relationship between PeCDF levels and symptoms.

Delayed Tissue Necrosis Associated with Mitomycin‐C Administration

To the Editor: Mitomycin C (MMC), an antitumor antibiotic, is active in numerous tumors and has been well used for cutaneous squamous cell carcinoma in association with peplomycin. Although extravasation of MMC to the tissues at the time of administration is a well-known cause of ulceration and tissue necrosis, there have been only infrequent previous case reports of an unexplained, delayed cutaneous ulceration (1-5). Cutaneous ulceration from extravasation of MMC generally occurs one to two weeks after treatment and persists for one to four months (6). We report a case of a patient who developed cutaneous ulceration seven weeks after intravenous MMC infusion without symptoms of tissue injury. Case Report: A 71-year-old woman underwent a resection for perianal squamous cell carcinoma developed from Bowens disease (Bowen-carcinoma) onJune 20th, 1997. She underwent left inguinal lymph node dissection for metastasis in November of 1998 and following local radiation and chemotherapy including MMC and peplomycin in December. Peplomycin was intramuscularly used on the bilateral deltoid muscle from December 1 to December 9. On December 10, she received MMC injection into th left volar antebrachial region adjacent to anticubital fossa. The patient did not notice any pain or incongruity while receiving this MMC infusion. There was no evidence of erythema or infiltration noted at that time. Four days later, the infusion site on her left forearm was slightly inflamed. The symptoms disappeared in several days without any specific treatment. However, seven weeks after the MMC injection, she noted slight induration and burning just on the left anticuboital Letters to the Editor