Efficacy of the polo-like kinase inhibitor rigosertib,alone or in combination with Abelson tyrosine kinase inhibitors,against break point cluster region-c-Abelson-positive leukemia cells

The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In this study, we investigated the efficacy of a combination therapy including rigosertib (ON 01910.Na), a polo-like kinase (PLK) and phosphoinositide 3-kinase (PI3K) inhibitor, and ABL TKIs. A 72-h rigosertib treatment was found to inhibit cell growth, induce apoptosis, reduce phosphorylation of the breakpoint cluster region-c (BCR)-ABL and its substrate Crk-L, and increase the activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). This combination therapy also exerted a synergistic inhibitory effect on Philadelphia chromosome (Ph)-positive cell proliferation and reduced the phosphorylation of BCR-ABL and Crk-L while increasing that of cleaved PARP and the H2A.X histone. Rigosertib also potently inhibited the growth of ABL TKI-resistant cells, and cotreatment with ABL TKIs and rigosertib induced higher cytotoxicity. These results indicate that rigosertib treatment may be a powerful strategy against ABL TKI-resistant cells and could enhance the cytotoxic effects of ABL TKIs.     

Current and future perspectives on the TARGET system: the registration system for Glivec® established by the JSH

Since hematology is a highly specialized field, an individual physician may not have much direct treatment experience with a given disease. Therefore, the Japanese Society of Hematology (JSH) has discussed establishing a registry of hematologic disorders, in order to contribute to improving the quality of treatments and clinical outcomes in this field. As a first step, the Timely and Appropriate Registration System for GLIVEC Therapy (TARGET), a registration system for chronic myeloid leukemia (CML) patients treated with imatinib, was established in October 2003. We present the preliminary results of the first 4 years’ experience with this system. CML patients treated with imatinib in Japan were registered through the website and the patient’s clinical course, including parameters and events like imatinib dose, blood counts, adverse events, and efficacy were recorded in months 1, 3, 6, 9, and 12 and then every 6 months thereafter. By September 2007, 862 patients from 176 hospitals were registered. Follow-up period was 0–54 months, and 127 patients were followed-up for more than 36 months. Based on these cumulative data, present imatinib treatment trends were analyzed and safety and efficacy were compared with international trial data. The part of content in this article was presented in the Joint Annual Conference of the 68th Japanese Society of Hematology (JSH) and the 48th Japanese Society of Clinical Hematology (JSCH) in Fukuoka (Japan) at 7 October 2006. Other participants in the TARGET system are listed in the Appendix.     

Morphological age changes in the diaphragm of rats under different protein diets

Male Donryu rats were housed in a specific pathogen free room and fed with 60% of the mean daily quantity of diet consumed by rats fed ad libitum The animals were divided into three groups of 50 and each group fed different amounts and types of dietary protein. The group P40 was fed with a diet containing 40% of total volume as vegetable protein; the agroup P10 with 10% of total volume as vegetable protein; and the group CE7 with 18% of total volume as mixed vegetable and animal proteins. Subsets of the animals were sacrificed at the ages of 6, 12, 18, 24 and 30 months. The P40 group gained body weight faster than other two groups during the first months. However, after 12 months, the body weight began to decrease, reaching the lowest mean body weight among the three groups by the end of the study. The three groups did not show any significative difference in the muscle fiber number index and in the number of capillaries per muscle fiber. The calculated diaphragm volume index increased up to a peak at 12 months in all three groups decreasing gradually thereafter, but did not show any significant difference due to dietary protein intake. The data suggest that the morphological age changes occurring in the diaphragm muscle are likely unrelated to dietary conditions and are more likely due to other factors such as changes in the neural activity during aging.     

Chronic obstructive pulmonary disease (COPD) burden in Japan--confronting COPD Japan survey

To grasp the burden and management status of COPD in Japan, a large telephone survey was conducted. In initial screening 400 individuals > or =45 years were identified as either having been given a diagnosis of COPD or fulfilling criteria for their respiratory-related symptoms and smoking history (baseline population) and they were recruited for a detailed investigation (interview sample). They were asked about demographic information, exacerbation, impact of COPD on daily life, and management and treatment. Of the 400 interview samples, 209 subjects (52%) had a diagnosis of COPD, and the remaining 191 ones (48%) were not, retrospectively. It was confirmed that proportions of a current smoker in the COPD (35.4%) and non-COPD (35.6%) groups were almost at the same level. The use of inhaled bronchodilators, recommended by guidelines in 157 treated subjects, was 16% or less, whereas respiratory conditions affected daily activities in 70% of all the subjects. In conclusion, COPD in Japanese subjects significantly affects daily life yet is undiagnosed; there is a need to improve COPD diagnosis and management by general practitioners through disseminating guidelines for diagnosis, management, and prevention of COPD in Japan.     

A case of septicemia type Vibrio vulnificus infection with necrotizing fasciitis rescued by lower extremity amputation]

We report a case of septicemia type Vibrio vulnificus infection. The patient was a 74-year-old man who had liver cirrhosis and hepatocelluler carcinoma. He felt a pain in the right femoral lesion after eating raw shellfish (Japanese "Umitake") two days ago. He was admitted to our emergency center due to his shock status and thrombocytopenia two days after the onset. We diagnosed necrotizing fasciitis due to Vibrio vulnificus infection, his life was saved by emergency amputation of the right lower extremity. The culture of the blood and vesicle fluid showed Vibrio vulnificus. There are some reports that the debridement was effective to necrotizing fasciitis due to Vibrio vulnificus infection, but these reports are all about single upper extremity lesion. As far as we know, this is the second report of lower extremity necrotiaong fasciitis due to septicemia type Vibrio vulnificus infection rescued by extremity amputation in Japan. The mortality of septicemia type Vibrio vulnificus infection with necrotizing fasciitis is very high, this is quite a valuable report in making a decision for therapy of septicemia type Vibrio vulnificus infection.