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Refractoriness to platelet transfusion is a major problem in a small group of patients, and large-scale manufacturing of clinical grade functional platelets ex vivo has remained an elusive goal. Sugimoto et al report on the results of the first clinical trial of an autologous transfusion of induced pluripotent stem cell (iPSC)-derived platelets in a patient who had severe aplastic anemia but no compatible platelet donor. Using methodology described in a complementary article in Blood Advances, the results provide proof-of-principle and illustrate the challenges to be faced in taking this approach further.

Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.

Trial design Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. Methods Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. Results A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. Conclusions No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.

3022 Background: Human papillomaviruses (HPVs) infect uterine cervical epithelial cells, leading to cervical intraepithelial neoplasia (CIN) and cervical cancer. However, there is no treatment for HPV infection in the uterine cervix prior to vaccination. We recently reported that cyclin dependent kinase 9 (CDK9) plays a critical role in viral RNA transcription of DNA viruses such as HPVs in host cells, and that FIT-039, a specific inhibitor of CDK9, suppresses the proliferation of several DNA viruses. Here, we evaluated the safety and antiviral effect of a FIT039-releasing vaginal tablet (FIT039CT) for CIN1 or 2 (CIN1/2). Methods: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial involving 2 cohorts was designed to evaluate the safety of transvaginal FIT039CT for CIN1/2 as follows:. In the first cohort, 8 healthy women were randomized into FIT039CT (50mg/day or 100mg/day) or control group. In the second cohort, 14 women with a primary diagnosis of CIN1/2 were randomized into either FIT039CT (100mg/day) or control group. The primary endpoints were adverse events and plasma concentrations of FIT039. Results: 22 patients (8 volunteers, 11 CIN1 and 3 CIN2) were enrolled. There were no serious adverse events. Adverse events considered related to treatment were mild (vaginal discharge Grade 1: FIT039CT 16/17 women [94%] vs placebo 2/6 [33%]) and self-limiting in both cohorts. No patient discontinued this study due to adverse events. Maximum concentration (C max) and terminal elimination half-life (t 1/2) of serum FIT039 concentrations after single transvaginal treatment of FIT039CT were similar between the two doses as follows; C max (mean ± standard deviation) was 4.5 ± 0.5 ng/mL (50mg/day) and 4.4 ±1.4 ng/mL (100mg/day) at 6-7 hours; mean t1/2 was 14.8 ± 2.1 hours (50mg/day) and 12.1 ± 2.6 hours (100mg/day) hours. Conclusions: This study demonstrated the safety and validity of transvaginal FIT039CT once a day and may contribute to the development of an antiviral agent that can cure CIN1/2, and supports the design of the ongoing phase 2 clinical study. Clinical trial information: jRCT2051180201.

Background:. Although traditional wound dressings such as collagen scaffolds promote granulation tissue formation, the efficacy of these dressings in chronic wounds is limited because of high susceptibility to bacterial growth. Biomaterials that can be applied to chronic wounds should have an anti-bacterial function. We previously reported that administering a silk-elastin solution that forms moisturizing hydrogels to wound surfaces of diabetic mice reduced bacterial growth and promoted granulation tissue formation compared with control or carboxymethyl cellulose hydrogels. We hypothesized that silk-elastin promotes wound healing in human chronic wounds by suppressing bacterial growth. Methods:. An open-label, clinical case series was conducted with a prospective, single-arm design at Kyoto University Hospital in Kyoto, Japan. In this study, 6 patients with chronic skin ulcers of any origin (2 < ulcer area (cm2) < 25) on their lower extremities were included; patients with critical ischemia were excluded. Silk-elastin sponges were applied and covered with a polyurethane film without changing the dressing for 14 days. Inflammation triggered treatment discontinuation due to fear of infection. The primary study endpoint was adverse events, including inflammation and infection. Results:. Poor hydrogel formation, possibly due to continuous exudation, was observed. No serious adverse events were noted. Two patients discontinued treatment on day 6 and day 7, respectively, due to inflammation, but they were not infected. The other 4 patients completed the 14-day silk-elastin sponge treatment without infection. Conclusion:. Silk-elastin sponge is safe for chronic skin ulcers, and its ability to promote wound healing should be determined by confirmatory clinical trials.

Background Cutaneous warts are caused by human papilloma virus (HPV) infection. FIT039, a specific inhibitor of CDK9, suppresses the proliferation of DNA viruses in vitro. Purpose We evaluated the safety, plasma concentrations, and efficacy of FIT039 delivered by single application of an adhesive skin patch on normal back skin and cutaneous warts. Patients and Methods In this placebo-controlled, dose-escalation, open-label, two-cohort phase I/II clinical trial, after a single administration of a 1% FIT039 patch, 3% FIT039 patch, or placebo on back skin, patients with cutaneous warts were treated with cryotherapy followed by a 1% FIT039 patch for 24 h in the first cohort. In the second cohort, cutaneous warts were treated with cryotherapy followed by a 3% FIT039 patch for 24 h. Adverse events and adverse drug reactions, the concentrations of FIT039, and surface area of cutaneous warts were evaluated. Results Neither irritant reactions nor symptoms related to FIT039 occurred when the FIT039 patches were applied to patients’ backs or on warts in ten patients. The concentrations of FIT039 were under 0.1 ng/ml at every time point. The median wart surface area at 1 week after application of the 1% FIT039 patch was similar to baseline, while that of the 3% FIT039 patch was smaller than baseline. Conclusion The FIT039 patch showed no topical or systemic adverse reactions when applied on normal skin or cutaneous warts. The safety and good adherence of the FIT039 patch are encouraging and support further studies to evaluate the efficacy of FIT039 in patients with cutaneous warts. Electronic supplementary material The online version of this article (10.1007/s40261-018-0712-7) contains supplementary material, which is available to authorized users.

Introduction Adjuvant bisphosphonates lead to better prognosis in postmenopausal breast cancer. However, the association between clinical outcomes and immune modulation by them is still unclear. Methods In this prospective, open-label phase II study, postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer received neoadjuvant letrozole (LET) for one month, followed by treatment with a single dose of zoledronic acid. The patients underwent an additional 5 months of treatment with LET prior to surgery. The primary endpoint was the tumor objective response rate (ORR) determined by diameter via MRI. The association between the ORR and γδT cell frequencies was assessed as a secondary endpoint. Results Out of sixty patients, 55 patients were evaluable for response by MRI. The ORR for LET with zoledronic acid was 38.2% (21/55), which was comparable to that of historical controls (45%). A decrease in the frequency of the Vδ2 T cell subset was observed throughout treatment, and Vδ2 T cells were activated for 6 months. In planned subgroup analyses, patients with low frequencies of Vδ2 T cells prior to zoledronic acid infusion experienced a favorable tumor response compared to those with high frequencies (59.3% [16/27] vs 17.9% [5/28], p = .002). There were no serious adverse events with this treatment regimen. Conclusion These results showed that neoadjuvant LET with zoledronic acid could not achieve overall effect for local tumor response. However, patients with a low frequency of γδ T cells would benefit from the treatment including zoledronic acid. (UMIN 000008701).

Introduction: Platelet transfusion have saved lives of patients with thrombocytopenia through preventing or treating bleeding complications. Currently, platelet products are provided from blood banks which collect blood from healthy donors. However, our ageing society bears the risk of supply in the future. Furthermore, although the rate is decreasing, alloimmune platelet transfusion refractoriness (allo-PTR) is still found in 5% of platelet transfusion patients. Gestation and previous platelet transfusion cause sensitization to produce alloantibodies mostly against class I human leukocyte antigens (HLA-I) and less frequently against human platelet antigens (HPA), resulting in allo-PTR. In these cases, platelets from compatible donors are transfused, but for patients with rare HLA or HPA, donors are difficult to find. As a possible solution, we proposed the application of platelets from induced pluripotent stem cells (iPSC-platelets), which we have succeeded in the ex vivo production at clinical scale. iPSC-platelets are produced from expandable megakaryocyte cell lines (imMKCLs) as master cells and using a "turbulent flow" bioreactor and various new drugs. imMKCLs are established from iPSCs during megakaryocytic differentiation by overexpression of c-MYC, BMI1 and BCL-XL under the doxycycline control promoter. Switching off these transgenes leads to the maturation of imMKCLs. Turbulent flow was found to be a crucial factor in efficient ex vivo production of healthy iPSC-platelets from imMKCLs. We also developed TA-316, a thrombopoietin mimetic compound, KP-547, an ADAM17 inhibitor that inhibits CD42b shedding and stores platelet function, and also found the combination of AhR antagonist and ROCK inhibitor enables feeder-free liquid culture in imMKCL maturation. Aim: To evaluate the safety of autologous iPS-platelets administered to an aplastic anemia patient with allo-PTR due to anti-HPA alloantibody, who experienced systemic post-transfusion purpura-like complication and have no compatible donor in Japan. Methods and Results: Preclinical studies showed that iPSC-platelets were competent in in vitro assays and mouse and rabbit models for circulation and hemostasis, and pathogen and tumorigenicity free. The clinical study was approved by the Certified Special Committee for Regenerative Medicine of the Kyoto University and by the Health Sciences Council of the Japan Ministry of Health, Labour and Welfare as meeting the Act on the Safety of Regenerative Medicine. The clinical study started in March 2019. Using imMKCL master cells derived from the patient, iPS-platelets were manufactured at the Facility for iPS Cell Therapy (FiT) in Center for iPS Cell Research and Application (CiRA), Kyoto University according to the GMP standard. Three doses of 1x10^10, 3x10^10 and 1x10^11 were administered in a dose escalation single-center open-label uncontrolled study at Kyoto University Hospital. The primary endpoint was safety as measured by frequency and extent of adverse events, which were evaluated by the Efficacy Safety Assessment Committee for each dose cohort. Three doses of the administration of autologous iPS-platelets have been completed. No significant adverse event was observed during the full observation period of one year after the last dose. Conclusion: The iPLAT1 study completed the administration of iPSC-platelets for the first time and confirmed the safety in an allo-PTR patient who would otherwise have no HPA-compatible platelet product. The insights gained from the current study should further contribute to development of allogeneic iPSC-platelet products that can be readily administered to wide range of patients. (Japan Registry of Clinical Trials number jRCTa050190117) Figure 1 Figure 1. Disclosures Sugimoto: Astellas Pharma Inc.: Honoraria; Ebara Corporation: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Consultancy, Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Kanda: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; NextGeM Inc: Patents & Royalties; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Amgen Astellas BioPharma: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria. Kondo: Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; MSD Pharmaceutical: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Shimizu: Megakaryon co: Consultancy. Hirai: Kyowa Kirin: Patents & Royalties, Research Funding; Bristol-Myers K.K.: Research Funding; CSL Behring: Research Funding; Mitsubishi Tanabe Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Eto: Megakaryon co: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria; Takeda Pharmaceutical Co Ltd: Honoraria; Kowa Co Ltd: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria; Kyoto Manufacturing Co., Ltd.: Research Funding.

Photodynamic therapy (PDT) showed promising efficacy for local failure after chemoradiotherapy (CRT) for esophageal cancer. However, PDT required long sun shade period. This study aimed to evaluate the safety and efficacy of PDT using second generation photosensitizer, talaporfin sodium for local failure after CRT. This was the multi-institutional non-randomized phase II study. Patients with histologically proven local failure limited within the muscularis propria after 50Gy or more radiotherapy (RT) for esophageal cancer were eligible. We set the primary endpoint as local complete response (L-CR) per patients. And, secondary endpoints were confirmed L-CR, local progression free survival (L-PFS), progression free survival (PFS), overall survival (OS), L-CR per lesions (Lesion L-CR), and confirmed Lesion L-CR. The PDT procedure commenced with intravenous administration of a 40 mg/m2 dose of talaporfin sodium followed by diode laser irradiation at a 664 nm wavelength. 26 eligible patients were enrolled and all were treated with PDT. Twenty three patients with 25 lesions were assessed L-CR after PDT; the L-CR rate per patients was 88.5% (95% CI: 69.8%-97.6%). No skin phototoxicity was observed, and no grade 3 or worse non-hematological toxicities related to PDT were observed. PDT using talaporfin sodium and a diode laser is a safe and curative salvage treatment for local failure after CRT or RT for patients with esophageal cancer., This study is supported by Health and Labor Sciences Research Grant, Research on Clinical Trial on Development of New Drugs and Medical Devices (H24-012).

Background Human papilloma viruses (HPVs) infect squamous epithelial cells and form verrucous lesions, or warts. Besides the psychosocial problems caused by the disfiguring warts, a subset of HPVs can be the primary etiologic agent for malignancies such as cervical cancer. However, there is no curative antiviral therapy for HPV infection. We recently found that the viral RNA transcription of DNA viruses requires cyclin dependent kinase 9 (CDK9) in the host cells, and that FIT039, a specific inhibitor of CDK9, suppressed the proliferation of DNA viruses such as herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, human cytomegalovirus, hepatitis virus B, and HPVs. Here, we describe a protocol to evaluate the safety and antiviral effect of FIT039 on common warts in human skin. Methods and design A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial was designed to evaluate the safety and efficacy of FIT039 on common warts on the extremities. A total of 44 adults with a primary diagnosis of verruca vulgaris on the extremities without serious comorbidities will be randomized into either the intervention group with an FIT039-releasing transdermal patch or a control group for a duration of 14 days. Outcomes will be assessed at baseline and postintervention. Participants will be further assessed at 2 months follow-up. The primary endpoint for efficacy is the resolution of the warts. The safety endpoint is the incidence of adverse events and adverse drug reactions. The secondary endpoints are changes in the dimensions of the wart, the cross-sectional area of the wart, and the number of clots within the area of the wart. Discussion This study is the first to assess the efficacy of FIT039 and will contribute to the development of antiviral agents that can cure refractory common warts in immunocompromised patients. Trial registration UMIN Clinical Trials, UMIN000029695. Registered on 1 November 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3570-6) contains supplementary material, which is available to authorized users.

Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4–48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 μg (low-dose) in the first three patients and 50 μg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed., 新規神経保護剤「KUS121」の投与安全性と有効性を医師主導治験にてヒトで初めて確認 --治療薬を網膜中心動脈閉塞症患者へ--. 京都大学プレスリリース. 2020-03-03.

Idiopathic osteonecrosis of femoral head (ION) is a painful disorder that progresses to collapse of the femoral head and destruction of the hip joint. Although its precise pathology remains unknown, the loss of blood supply causing the loss of living bone-forming cells is a hallmark of the pathophysiology of osteonecrosis. Transplantation of multipotent mesenchymal stromal cells (MSCs) is a promising tool for regenerating the musculoskeletal system. The aim of the present study was to assess the safety and efficacy of transplantation of cultured autologous bone marrow-derived MSCs mixed with β-tricalcium phosphate (β-TCP) in combination with vascularized bone grafts for the treatment of advanced stage ION in a clinical trial. Ten patients with stage 3 ION were enrolled in this study. Autologous bone marrow-derived MSCs were cultured with autologous serum, and cells (0.5-1.0×10(8)) were transplanted after mixing with β-TCP granules in combination with vascularized iliac bone grafts. Patients were assessed 24 months after treatment. The primary and secondary endpoints were progression of the radiological stage and changes in bone volume at the femoral head, and clinical score, respectively. Nine of ten patients completed the protocol, seven of whom remained at stage 3, and the remaining two cases progressed to stage 4. The average bone volume increased from 56.5±8.5 cm(3) to 57.7±10.6 cm(3). The average clinical score according to the Japan Orthopaedic Association improved from 65.6±25.5 points to 87.9±19.0 points. One severe adverse event was observed, which was not related to the clinical trial. Although the efficacy of cell transplantation was still to be determined, all procedures were successfully performed and some young patients with extensive necrotic lesions with pain demonstrated good bone regeneration with amelioration of symptoms. Further improvements in our method using MSCs and the proper selection of patients will open a new approach for the treatment of this refractory disease.

AIM: Some previous studies have shown a positive relation between geomagnetic disturbances and an increased incidence of suicide. If such a relation exists, stronger geomagnetic fields may affect the number of suicides, because stronger geomagnetic fields generally cause larger geomagnetic field disturbances. Therefore, we here investigated the relation between local geomagnetic field magnetic flux density and the standardized morbidity ratios (SMR) for suicide by each prefecture in Japan. METHODS: Monthly suicide data for each prefecture in the period January 1999 to December 2008 was obtained, and it was found that a total of 216 171 male individuals and 85 154 female individuals committed suicide during this period. A multiple linear regression analysis was carried out with a backward elimination procedure. The SMR for suicide by each prefecture was taken as the response variable and the explanatory variables were each prefecture's local geomagnetic field magnetic flux density (nT), north latitude (°), monthly mean unemployment rate (%), monthly mean air pressure (hPa), monthly mean air temperature (°C), monthly mean humidity (%), and monthly total day length (hours). Analyses were carried out separately for each sex. RESULTS: In the multiple linear regression analysis for male subjects, the local geomagnetic field magnetic flux density (nT), monthly mean unemployment rate (%), and monthly mean humidity (%) were associated with the incidence of suicide, but in the multiple linear regression analysis of female subjects, only north latitude was associated with that. CONCLUSION: In this study, we generated a hypothesis that stronger geomagnetic fields affect the number of cases of male suicide. Language: en

The majority of patients with systemic sclerosis (SSc) have gastrointestinal (GI) tract involvement, but therapies using prokinetic agents are usually unsatisfactory. Ghrelin stimulates gastric motility in healthy human volunteers. In this study, we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc. The study was performed in a randomized, double-blind, placebo-controlled crossover fashion on two occasions. Ten SSc patients with GI tract involvement received an infusion of either ghrelin (5.0 μg/kg) or saline, and gastric emptying rate was evaluated by ¹³C-acetic acid breath test. Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc (ghrelin vs. saline: 43.3 ± 11.4 min vs. 53.4 ± 5.4 min, P=0.03). No serious adverse effects were observed. Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc.

We previously showed that the agamid lizard Pogona vitticeps responded to an extremely low-frequency electromagnetic field (ELF-EMF, frequency: 6 and 8 Hz, peak magnetic field: 2.6 &micro, T, peak electric field: 10 V/m) with tail-lifting behavior. In addition, the tail-lifting response to ELF-EMF disappeared when the parietal eyes of the lizards were covered by small round aluminum caps. This result suggests that the parietal eye contributes to light-dependent magnetoreception. In the present study, we set up an ELF-EMF group to evaluate the long-term effect of the ELF-EMF on lizards&rsquo, behavior and examine our hypothesis that exposure to ELF-EMFs increases the magnetic field sensitivity in lizards. We therefore include the lunar phase (full moon/new moon) and K index as environmental factors related to the geomagnetic field in the analysis. The number of tail lifts per individual per day was the response variable while calendar month, daily mean temperature, daily mean humidity, daily mean atmospheric pressure, full moon, new moon, and K index were the explanatory variables. We analyzed an ELF-EMF group and a control group separately. In a multiple linear regression analysis, the independent determinants associated with the number of tail lifts were the full moon, the temperature, February, March, April, and May in the ELF-EMF group and March, April, May, and June in the control group. The P. vitticeps in the ELF-EMF group responded to the full moon whereas those in the control group did not. In addition, in the ELF-EMF group, the number of tail lifts was higher on days when the K index was higher (P = 0.07) in the first period whereas there was no such tendency in either period in the control group. There is the possibility that the exposure to ELF-EMFs may increase magnetic-field sensitivity in lizards.

Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in healthcare. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), which is capable of sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Patients with chronic skin ulcers that had not healed in at least 4 weeks were treated with CGS impregnated with bFGF at 7 or 14 μg/cm(2) after debridement, and the wound bed improvement was assessed 14 days after application. Wound bed improvement was defined as a granulated and epithelialized area on day 14 with a proportion to the baseline wound area after debridement of 50% or higher. The wound area, the wound area on day 14, and the granulation area on day 14 were independently measured by blinded reviewers in a central review using digital images of wounds taken with a calibrator. Patients were followed up until 28 days after application to observe the adverse reactions related to the application of CGS. From May 2010 to June 2011, 17 patients were enrolled and, in 16 patients, the wound bed improved. Among the randomized patients in step 2, no significant difference was seen between the low-dose group and the high-dose group. No serious adverse reactions were observed. Adverse reactions with a clear causal relationship to the study treatment were mild and patients quickly recovered from them. This study is the first-in-man clinical trial of CGS and showed the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. This combination therapy could be a promising therapy for chronic skin ulcers.

There is some evidence that exposure of various animals to a power-frequency magnetic field can cause increases in body mass. However, the precise nature of the relationship is not clear, particularly for long-term exposure. To clarify the relationship between long-term power-frequency magnetic field exposure (2 years) and animal body mass, we conducted a pooled analysis of data in two studies to examine the impact of power-frequency magnetic field exposure on body mass as compared with sham-exposed rats of both sexes. Relative body mass was the response variable, and the study duration (in weeks), magnetic flux density ($\upmu$T), and daily exposure time (hours/day) were the explanatory variables with adjustment for the study. We analyzed by sex. The P-value (P) was defined as the probability of having observed our data (or more extreme data) when the null hypothesis was true. In multiple linear regression analyses of male and female rats, performed separately, we obtained estimates of the effect on relative body mass of study duration (coefficients 0.0225 and 0.0201, respectively; both P

The effects of extremely low-frequency electromagnetic fields (ELF-EMFs) on blood pressure (BP) are controversial. In this double-blind, randomized, sham-controlled study, we examined the effects of repeated exposure to a 1-μT ELF-EMF on BP in 20 humans with mild-to-moderate hypertension. Subjects were randomly assigned to either the ELF-EMF group or the sham group. Subjects in the ELF-EMF group were exposed to an ELF-EMF (6- and 8 Hz, respectively, peak magnetic field 1 μT, peak electric field 10 Vm(-1)) for at least two 10- to 15-min sessions per week, over a period of 4 weeks. In the sham group, the EMF-generating apparatus was not active. We obtained systolic and diastolic BP (SBP and DBP, respectively) measurements at registration and before and after each ELF-EMF exposure session. Subjects in the ELF-EMF and sham groups had mean ages of 52.8 and 55.1 years, and were exposed to a mean of 9.9 and 9.0 sessions, respectively. There was a significant difference between the ELF-EMF and sham groups with respect to change in SBP value between baseline and the end of the exposure regimen (P=0.02), but not with respect to change in DBP (P=0.21). There were no adverse events other than mild paresthesia of the hands of two subjects in the ELF-EMF group. Our results suggest that repeated exposure to an ELF-EMF has a BP-lowering effect on humans with mild-to-moderate hypertension.

SUMMARY Animals from a wide range of taxa have been shown to possess magnetic sense and use magnetic compasses to orient; however, there is no information in the literature on whether lizards have either of these abilities. In this study, we investigated the behavioral responses of a diurnal agamid lizard (Pogona vitticeps) to a sinusoidal extremely low-frequency electromagnetic field (ELF-EMF; 6 and 8 Hz, peak magnetic field 2.6 μT, peak electric field 10 V m−1). Fourteen adult lizards were divided randomly into two groups (the EMF and control groups; each group had three males and four females). The EMF group received whole-body exposure to ELF-EMF and the control group did not. Lizards in the EMF group were exposed to ELF-EMF for 12 h per day (during the light period). The number of tail lifts was monitored beginning 3 days before exposure and ending after 5 days of exposure. For each individual, the average number of tail lifts per day was calculated. The average number of tail lifts per individual per day was greater in the EMF group than in the control group (20.7±6.3 and 9.1±4.5 tail lifts, respectively, N=7 each, P=0.02). We confirmed the reproducibility of this response by a cross-over trial. These results suggest that at least some lizards are able to perceive ELF-EMFs. Furthermore, when the parietal eye of the lizards was covered with a small round aluminum ‘cap’ which could block light, the tail-lifting response to ELF-EMF disappeared. Our experiments suggest that (1) lizards perceive EMFs and (2) the parietal eye may be involved in light-dependent magnetoreceptive responses.

Objective: The aim of this study was to assess the efficacy and safety of two different types of medical mushrooms in patients with prostate cancer in Japan. Methods: Patients with biochemical failure after radical treatment for non-metastasized prostate cancer were enrolled in this open-label study. For 6 months they ingested one of the two following supplements: Senseiro, containing extracts from the Agaricus blazei Murill mushroom; and Rokkaku Reishi, containing the Ganoderma lucidum mushroom. Levels of serum prostate-specific antigen (PSA) level and PSA doubling time were examined before and after study entry to assess the impact of these supplements on disease progression. The primary end-point of this study was partial response rate (50% or more decrease of serum PSA). Hormonal status, represented by serum testosterone levels, and toxicity were also assessed. Results: A total of 51 patients were enrolled following radical prostatectomy. Forty-seven completed the protocol and could be assessed. Thirty-two patients received Senseiro and the remaining 15 received Rokkaku Reishi. No partial response in terms of PSA was observed. Alteration of PSA doubling time did not correlate with that of serum testosterone levels. Serious adverse effects were not observed. Conclusions: No significant anticancer effects were observed with the intake of these two medical mushrooms.

Purpose: To comprehend the clinical characteristics and factors related to visual prognosis in two major subtypes of neovascular age-related macular degeneration (AMD)—traditional, typical AMD and polypoidal choroidal vasculopathy (PCV). Methods: Medical records of 272 eyes of 216 patients diagnosed with neovascular AMD at Kyoto University Hospital between January 2000 and March 2003 were retrospectively reviewed for up to 3 years. Ophthalmoscopic, angiographic, and optical coherence tomography (OCT) fi ndings were collected, and univariate and multivariate analyses were performed to determine the characteristic factors, the factors associated with initial visual acuity (VA), and visual prognosis in typical AMD and PCV. Results: We studied 154 eyes with typical AMD and 117 eyes with PCV. The presence of classic choroidal neovascularization (CNV) and posterior confl uent drusen were characteristic of typical AMD, whereas PCV was characterized by a larger number of retinal pigment epithelial detachments and a small number of drusen. Poor initial VA (

Laparoscopic surgery is widely used for the treatment of colorectal cancer, but little is known about perioperative risk factors for complications. Clinical data were reviewed for 401 consecutive unselected colorectal cancer patients who underwent laparoscopic surgery at Kyoto Medical Center between 1998 and 2005. The outcome variable was incidence of postoperative complications. Using logistic regression analysis, 58 background, clinical, preoperative, and intraoperative factors were assessed as potential predictors of complications. The set of independent protective factors that had the greatest influence on the incidence of local complications after colon surgery was as follows: cefmetazole use for prophylaxis (versus oral only; adjusted odds ratio (OR) 0.18, 95% confidence interval (CI) 0.06–0.54), high operative infusion rate (per ml/min; OR 0.82, 95% CI 0.70–0.95), regular laxative use (OR 0.33, 95% CI 0.12–0.79), and double-stapled anastomosis (versus hand-sewn; OR 0.15, 95% CI 0.03–0.83). Independent risk factors for local complications after rectal surgery were abdominoperineal resection (versus low anterior resection, OR 4.84, 95% CI 1.64–14.9), long operative time (per hour, OR 1.55, 95% CI 1.11–2.23), and history of heart disease (OR 5.18, 95% CI 1.34–21.5). The occurrence of complications was not found to be associated with overall survival in this study. We identified intraoperative management such as low operative infusion rate is one of the independent significant risk factors for complications after laparoscopic surgery for colorectal cancer in addition to patient characteristics and surgical procedure.

Objective: In a previous paper, we described the major health tragedy that occurred in Japan involving the use of gefitinib, and recommended steps to prevent such problems occurring again. In that paper, we argued that erlotinib should only be approved on the condition that all users are subject to surveillance. Erlotinib was subsequently approved for use in Japan on October 19, 2007. In the present paper, we examine whether our recommendations have been implemented in the safety measures established for erlotinib use. Methods: We comprehensively reviewed reports regarding erlotinib treatment published between 2007 and 2009 by regula- tory agencies and the manufacturer of the erlotinib-containing drug. We evaluated the safety measures established for erlotinib in view of three problems we identified with the treatment of gefitinib marketing: (1) the results of animal experiments and pre-marketing clinical trials, and reports of adverse drug reactions from other countries were not properly incorporated into the product information; (2) indications for the drug were expanded without strict evaluation of the external validity of pre- marketing clinical trials; and (3) despite many serious cases of interstitial lung disease being spontaneously reported, well- designed post-marketing surveillance was not conducted immediately after these problems became evident. Results: We found that appropriate measures were taken for erlotinib in relation to each of the three above-mentioned prob- lems. We found that there were fewer fatal adverse reactions to erlotinib after marketing relative to the pre-marketing period. Conclusions: Our recommendations following the health tragedy caused by gefitinib were implemented in the safety mea- sures for erlotinib, which probably explains the smaller number of fatal adverse reactions to erlotinib in post-marketing surveil- lance than in pre-marketing trials.

In conventional clinical studies, the costs of data management for quality control tend to be high and collecting paper-based case report forms (CRFs) tends to be burdensome, because paper-based CRFs must be developed and filled out for each clinical study protocol. Use of electronic health records for this purpose could result in reductions in cost and improvements in data quality in clinical studies. The purpose of this study was to develop a data capture system for observational cancer clinical studies (i.e. outcomes studies) that would integrate with an electronic health records system, to enable evaluation of patient prognosis, prognostic factors, outcomes and drug safety. At the Outpatient Oncology Unit of Kyoto University Hospital, we developed a data capture system that includes a cancer clinical database system and a data warehouse for outcomes studies. We expect that our new system will reduce the costs of data management and analysis and improve the quality of data in clinical studies.

Aim: The aim of this study was to determine whether color images can be used as mood stimulants. Methods: Color photographs of natural scenery were shown to an experimental group (n = 10), while the same images in black and white were shown to a control group (n = 10). The test subjects were healthy, adult volunteers who were exposed to psychosomatic stress in mental work rather than physical labor. To determine the effects of the color images, the levels of salivary chromogranin A (CgA) and salivary cortisol were measured as biochemical parameters, and the mood adjective score was examined as an emotional parameter before and after showing the subjects the images. The data obtained were statistically compared. Results: In the experimental group, the salivary CgA level decreased significantly after viewing the color images. In the control group, the salivary cortisol level increased significantly after viewing the black and white images. The changes in the salivary CgA and salivary cortisol values in the experimental group were significantly different from the corresponding changes in the control group. In the experimental group, after viewing the color images, the negative mean mood score decreased, and four subjects were shown to have had their mood changed to a more parasympathetically dominant state, as assessed by alterations in three or more of four stress parameters (CgA, cortisol, Multiple Mood Scale negative and positive factors). Conclusion: Color images might potentially change the mood of a viewer to a more parasympathetically dominant state.

Aging is associated with a decrease in growth hormone (GH) secretion, appetite and energy intake. As ghrelin stimulates both GH secretion and appetite, reductions in ghrelin levels may be involved in the reductions in GH secretion and appetite observed in the elderly. However, only preliminary studies have been performed on the role of ghrelin in elderly subjects. In this study, we sought to clarify the physiologic implications of the age-related alterations in ghrelin secretion by determining plasma ghrelin levels and other clinical parameters in healthy elderly subjects. Subjects were ≥ 65 years old, corresponding to the SENIEUR protocol, had not had a resection of the upper gastrointestinal tract and had not been treated with hormones. One hundred and five volunteers (49 men and 56 women) were admitted to this study (73.4 ± 6.3 years old). Plasma levels of acylated ghrelin in elderly female subjects positively correlated with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. In elderly men, desacyl ghrelin levels correlated only weakly with bowel movement frequency. These findings suggest that the plasma levels of the acylated form of ghrelin may influence the age-related alterations in GH/IGF-I regulation, blood pressure and bowel motility. These observational associations warrant further experimental studies to clarify the physiologic significance of these effects.

OBJECTIVE: It has been demonstrated that ghrelin plays a major role in the regulation of GH secretion and food intake. These actions make ghrelin a strong candidate for the treatment of GH deficiency, anorexia and cachexia. However, only preliminary studies have been performed to assess ghrelin administration in humans. In this study, we have conducted a double-blind, randomized, placebo-controlled trial to investigate the pharmacokinetics, safety, and endocrine and appetite effects of ghrelin in young healthy volunteers. DESIGN: Eighteen male volunteers were randomly assigned into three groups of six subjects: low- and high-dose ghrelin groups, who received intravenous injections of 1 and 5 microg/kg ghrelin (acylated form) respectively, and a placebo group who were injected with mannitol instead of ghrelin. RESULTS: Acylated ghrelin disappeared more rapidly from plasma than total ghrelin, with elimination half life (t(1/2)) of 9-13 and 27-31 min respectively. The number of subjects that experienced adverse effects did not significantly differ among the three groups, and all adverse effects were transient and well tolerated. Both the low and high doses of ghrelin strongly stimulated GH release (peak plasma concentration (C(max,0-90 min)): 124.2+/-63.9 and 153.2+/-52.2 ng/ml for 1 and 5 microg/kg ghrelin respectively). Slight alterations of blood glucose and insulin levels after the injection were observed. Although not statistically significant, ghrelin administration tended to increase hunger sensation in a dose-dependent manner. CONCLUSIONS: These results suggest that ghrelin is safe, and that clinical trials may be started to assess the usefulness of ghrelin for the treatment of disorders related to GH secretion and appetite.

Background Although the efficacy of zoledronic acid in postmenopausal women with breast cancer has been suggested, the underlying mechanism has not been fully clarified. Therefore, which patients may benefit from zoledronic acid and the optimal frequency of zoledronic acid administration are unclear. This study evaluates the effects of zoledronic acid on the tumor response in postmenopausal women with breast cancer and explores the relationship between its efficacy and γδ T cells. Methods/design This study is an open-label, multi-institutional, single-arm, phase II clinical trial. Zoledronic acid will be administered once during preoperative hormonal therapy with letrozole for 24 weeks in postmenopausal women with Estrogen Receptor (ER)-positive , Human Epidermal Growth Factor Receptor 2 (HER2)-negative, clinical T1 or T2 N0M0 breast cancer. The primary endpoint is the objective response rate measured by MRI at 12 and 24 weeks. The secondary endpoints are the associations between the frequency of Vγ2Vδ2 T cells before the administration of zoledronic acid and the objective response, the association between the frequency of Vγ2Vδ2 T cells and the Preoperative Endocrine Prognostic Index score, and the association between the frequency of Vγ2Vδ2 T cells and Ki67 (MIB-1 index). Discussion This study is designed to determine the add-on effect of zoledronic acid during preoperative hormonal therapy and to investigate the changes of the frequency of Vγ2Vδ2 T cells after the administration of zoledronic acid to explore the potential mechanism of zoledronic acid in breast cancer patients. Trial registration This trial was registered at the UMIN Clinical Trials Registry as UMIN000008701.

Cultured dermal substitutes have been used for the treatment of chronic skin ulcers; however, the biological risks of animal-derived materials in the culture process such as foetal bovine serum (FBS) have been reported. In this study, we prepared an autologous fibroblast-seeded artificial dermis (AFD) using animal-product-free medium supplemented with 2% patient autologous serum and without any animal-derived materials such as trypsin in the culturing process. We applied the AFD in five patients with diabetic ulcers and investigated its safety and efficacy. As the primary endpoint, we defined 'wound bed improvement' according to the percentage of granulation area to the whole wound area on day 21, and 60% or higher was regarded as improved. The mean age of the patients was 60·6 years and the mean duration of the ulcer was 22·6 months. In the evaluation of the primary endpoint, the 'wound bed' was improved in all patients [proportion of improvement: 100%, 95% confidence interval (CI): 48% to 100%]. Three patients had complete wound healing within 12 weeks after application and two patients had >80% wound healing at 12 weeks. Side effects were not serious. Our AFD may be a safe and effective treatment of diabetic ulcers.

Some previous studies have shown a positive relation between geomagnetic disturbances and an increased incidence of suicide. If such a relation exists, stronger geomagnetic fields may affect the number of suicides, because stronger geomagnetic fields generally cause larger geomagnetic field disturbances. Therefore, we here investigated the relation between local geomagnetic field magnetic flux density and the standardized morbidity ratios (SMR) for suicide by each prefecture in Japan.Monthly suicide data for each prefecture in the period January 1999 to December 2008 was obtained, and it was found that a total of 216 171 male individuals and 85 154 female individuals committed suicide during this period. A multiple linear regression analysis was carried out with a backward elimination procedure. The SMR for suicide by each prefecture was taken as the response variable and the explanatory variables were each prefecture's local geomagnetic field magnetic flux density (nT), north latitude (°), monthly mean unemployment rate (%), monthly mean air pressure (hPa), monthly mean air temperature (°C), monthly mean humidity (%), and monthly total day length (hours). Analyses were carried out separately for each sex.In the multiple linear regression analysis for male subjects, the local geomagnetic field magnetic flux density (nT), monthly mean unemployment rate (%), and monthly mean humidity (%) were associated with the incidence of suicide, but in the multiple linear regression analysis of female subjects, only north latitude was associated with that.In this study, we generated a hypothesis that stronger geomagnetic fields affect the number of cases of male suicide.

Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in health care. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), that is capable of the sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Methods/Seventeen patients (≥ 20 years of age) with chronic skin ulcers that have not healed by conventional therapy for at least 4 weeks are being recruited. Patients will be applied with CGS impregnated with bFGF of 7 μg/cm(2) or 14 μg/cm(2) after debridement, and the wound bed improvement will be assessed 14 days after application. "Wound bed improvement" is defined as a granulated and epithelialized area on Day 14 in proportion to the baseline wound area after debridement of 50% or higher. Patients will be followed up until 28 days after application to observe the adverse events related to the application of CGS.This study has been designed to address the safety and efficacy of CGS impregnated with bFGF. If successful, this intervention may be an alternative to bioengineered skin substitutes and lead to substantial and important changes in the management of chronic skin ulcers such as diabetic ulcers and venous ulcers.

Background A randomized trial of vinorelbine plus gemcitabine followed by docetaxel (VGD) versus paclitaxel plus carboplatin (PC) in patients with advanced non-small-cell lung cancer showed no difference in overall survival (median survival time: 13.6 versus 14.1 months) between the two treatment groups. We report here the results of quality-of-life (QOL) study initiated in the mid-course of this randomized trial. Methods The patients themselves assessed the Functional Assessment of Cancer Therapy (FACT)-Lung (FACT-L), FACT-Taxane and the Functional Assessment of Chronic Illness Therapy - Spirituality (FACIT-Sp) QOL instruments at baseline and 6, 12 and 18 weeks after the treatment. The primary endpoint was a comparison of total QOL score for each assessment instrument between the two groups. Results Sixty-eight patients from the trial (VGD, 34; PC, 34) who submitted baseline questionnaires and at least one questionnaire over the course of treatment were eligible. Longitudinal analysis showed a significant difference in slope of the FACT-Taxane score (p = 0.004) between treatment regimens over time, but no difference was found in FACT-L score (p = 0.311) and FACIT-Sp score (p = 0.466) between the two groups. Conclusions The significant difference in slope of FACT-Taxane score favored the VGD regimen. These data should be considered in treatment decision-making for patients with advanced non-small-cell lung cancer. Trial registration NCT00242983.

Previous studies have shown a positive relationship between geomagnetic disturbances and an increased incidence of suicide. The Japanese suicide rate is the ninth highest in the world, but there have been no reports examining the relationship between geomagnetic disturbance and the number of suicides, and, therefore, this paper examines this relationship.The number of Japanese suicides per month from January 1999 to December 2010 was obtained, and it was found that a total of 262,596 males and 102,539 females committed suicide during this period. To adjust the other factors which affect the number of suicides, a multiple linear regression analysis with backward elimination was carried out, with the monthly number of suicides as the response variable and the monthly mean K index value, monthly mean number of sunspots, monthly mean unemployment rate, proportion of elderly people (%), monthly mean air pressure (hPa), monthly mean air temperature (°C), monthly mean humidity (%), and monthly mean day length (h) as the explanatory variables.In the multiple linear regression analysis for males, the monthly mean K index value was associated with the monthly number of suicides, but in females, the monthly mean K index value was not associated with the monthly number of suicides.In this study, we generated a hypothesis that geomagnetic disturbances may trigger male suicides.

Background: We compared the sensitivity of 2 diagnostic procedures—tissue biopsy and cytologic examination— for detecting endometrial carcinoma and hyperplasia in outpatients. The patients’ degree of acceptance of these methods was also evaluated. Methods: The study included 124 women who had been diagnosed with carcinoma and hyperplasia by histological examination in private clinics or were suspected to have endometrial carcinoma and hyperplasia—for example, those presenting with uterine bleeding and/or abnormal endometrial morphology on cytologic examination—at Jikei University Hospital, University of Yamanashi Hospital and National Hospital Organization Kure Medical Center from January 28, 1999, to August 28, 2006. Both cytologic examination (using Endocyte ® ) and tissue biopsy (using Suresample ™ ) of the endometrium were performed before complete curettage and/or hysterectomy. The diagnosis made using these two outpatient procedures was compared to the final diagnosis made using curettage and/or hysterectomy. McNemar’s chi-square test was used to evaluate the statistical significance. Results: The sensitivity of tissue biopsy for detecting endometrial carcinoma and hyperplasia was 84% and 91%, respectively, and that of cytologic examination was 78% and 55%, respectively. There was a significant difference in the sensitivity of the 2 methods for detecting hyperplasia (p =0.045). No patients complained of severe pain, and no other complication occurred during both methods. Both methods were well tolerated by the patients. Conclusion: Our data indicate a certain diagnostic superiority of tissue biopsy over cytologic examination.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL. METHODS: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy. RESULTS: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed. CONCLUSIONS: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids., 突発性難聴に対するIGF1治療について. 京都大学プレスリリース. 2010-11-30.

The aim of this study was to assess the efficacy and safety of two different types of medical mushrooms in patients with prostate cancer in Japan.Patients with biochemical failure after radical treatment for non-metastasized prostate cancer were enrolled in this open-label study. For 6 months they ingested one of the two following supplements: Senseiro, containing extracts from the Agaricus blazei Murill mushroom; and Rokkaku Reishi, containing the Ganoderma lucidum mushroom. Levels of serum prostate-specific antigen (PSA) level and PSA doubling time were examined before and after study entry to assess the impact of these supplements on disease progression. The primary end-point of this study was partial response rate (50% or more decrease of serum PSA). Hormonal status, represented by serum testosterone levels, and toxicity were also assessed.A total of 51 patients were enrolled following radical prostatectomy. Forty-seven completed the protocol and could be assessed. Thirty-two patients received Senseiro and the remaining 15 received Rokkaku Reishi. No partial response in terms of PSA was observed. Alteration of PSA doubling time did not correlate with that of serum testosterone levels. Serious adverse effects were not observed.No significant anticancer effects were observed with the intake of these two medical mushrooms.

PURPOSE: The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer. METHODS: Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m(2), days 1-14, oral) and docetaxel (40 mg/m(2), day 1, intravenous) every 3 weeks. RESULTS: No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7-34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study. CONCLUSIONS: The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.

Background In Japan, high incidences of interstitial lung disease (ILD) and ILD-related deaths have been reported among gefitinib-treated patients with non-small cell lung cancer (NSCLC). We investigated the efficacy of gefitinib, the incidence of ILD and risk factors for ILD in these patients. Findings We obtained patient data retrospectively using questionnaires sent to 22 institutions. We asked for demographic and clinical data on NSCLC patients for whom gefitinib treatment had begun between July 2002 and February 2003. Data from a total of 526 patients were analyzed. The patient characteristics were as follows: 64% male, 69% with adenocarcinoma, 61% with a performance score of 0–1, and 5% with concurrent interstitial pneumonitis. The objective response proportion was 80/439 (18.2%; 95% CI: 14.7–22.0). ILD developed in 17 patients (3.2%; 95% CI 1.9–5.1%), of whom 7 died. According to multivariate analysis, female sex, history of prior chemotherapy, low absolute neutrophil count before gefitinib treatment, and adenocarcinoma histology were associated with response to gefitinib treatment. None of the factors we evaluated were associated with the development of ILD. Conclusion The results of this study are consistent with previously published values for treatment response proportions and incidence of ILD during gefitinib treatment in Japanese patients. Future studies should be aimed at identifying factors indicating that a patient has a high probability of receiving benefit from gefitinib and a low risk of developing ILD.

Background Lymph node dissection has proven prognostic benefits for patients with ovarian or uterine carcinoma; however, one of the complications associated with this procedure is lymphedema. We aimed to identify the factors that are associated with the occurrence of lymphedema after lymph node dissection for the treatment of ovarian or uterine carcinoma. Methods A total of 694 patients with histologically confirmed ovarian (135 patients) or uterine cancer (258 with cervical cancer, 301 with endometrial cancer) who underwent lymph node dissection were studied retrospectively. Logistic regression analyses were used to identify the risk factors associated with occurrence of lymphedema. Results Among ovarian and uterine cancer patients who underwent pelvic lymph node dissection, post-operative radiotherapy (odds ratio: 1.79; 95% confidence interval: 1.20–2.67; p = 0.006) was statistically significantly associated with occurrence of lymphedema. Conclusion There was no relationship between any surgical procedure and occurrence of lymphedema among patients undergoing pelvic lymphadenectomy. Our findings are supported by a sound biological rationale because they suggest that limb lymphedema is caused by pelvic lymph node dissection.