Newly Developed Biocompatible Material: Dispersible Titanium-Doped Hydroxyapatite Nanoparticles Suitable for Antibacterial Coating on Intravascular Catheters.

BACKGROUND: Thirteen patients with chlorhexidine-silver sulfadiazine-impregnated catheters have experienced serious anaphylactic shock in Japan. These adverse reactions highlight the lack of commercially available catheters impregnated with strong antibacterial chemical agents. A system should be developed that can control both biocompatibility and antibacterial activity. SUMMARY: Hydroxyapatite (HAp) is biocompatible with bone and skin tissues. To provide antibacterial activity by using an external physical stimulus, titanium (Ti) ions were doped into the HAp structure. Highly dispersible, Ti-doped HAp (Ti-HAp) nanoparticles suitable as a coating material were developed. In 3 kinds of Ti-HAp [Ti/(Ca + Ti) = 0.05, 0.1, 0.2], the Ti content in the HAp was approximately 70% of that used in the Ti-HAp preparation, as determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES). ICP-AES and X-ray diffraction showed Ti ions were well substituted into the HAp lattice. The nanoparticles were almost uniformly coated on a polyethylene (PE) sheet in a near-monolayer with a surface coverage ratio >95%. The antibacterial activity of the Ti-HAp nanoparticles containing 7.3% Ti ions and coating the sheet was evaluated by calculating the survival ratio of Pseudomonas aeruginosa on the coated sheet after ultraviolet (UV) irradiation. The Ti-HAp-coated sheet showed a 50% decrease in the number of P. aeruginosa compared with that on an uncoated control PE sheet after UV irradiation for 30 s. Key Messages: A system of biocompatibility and antibacterial activity with an on/off switch controlled by external UV stimulation was developed. The system is expected to be applicable in long-term implanted intravascular catheters.

Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines).

The 3rd version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine, which was published in October 2013 in Japanese. Here, we briefly describe new or changed recommendations with a special reference to the two algorithms for surveillance, diagnosis, and treatment.

[Usefulness of group work as a teaching strategy for long-term practical training in the 6-year pharmaceutical education].

At the initiation of long-term practical training in the 6-year pharmaceutical education, there are many issues to be solved. For example, it is necessary for teaching pharmacists, who are in charge of both staffing and teaching pharmacy students, to manage their workload with other staff pharmacists. To overcome this situation and to improve the motivation of teaching pharmacists towards student practical training, we twice held group work (GW) sessions for teaching pharmacists, and then evaluated whether such training was effective for their understanding of the Model Core Curriculum for Practical Training and for promoting a higher level of motivation. During the two-day GW discussions, teaching pharmacists, who work daily in the dispensing area, were separated into two groups to discuss teaching skills. A questionnaire survey was completed by participants before and after each GW session. According to the survey, more than 90% of the pharmacists had a higher motivation level for practical training after the sessions. Particularly in the second GW training, the response rate of "being actively involved" improved from 40% to 70%. Furthermore, "The Educational Evaluation Testing" was conducted, which confirmed the increased participant comprehension. The median scores of the comprehensive exams significantly (p<0.01) improved in twice GW, respectively. Therefore, we conclude that GW sessions are a useful tool for both improving professional knowledge about the Model Core Curriculum and motivating teaching pharmacists involved in the practical training of students. We hope that this exercise will lead to higher student motivation and satisfaction during their practical training.

Clinico-roentogenologic findings in hepatocellular carcinoma fed by the right inferior phrenic artery at the initial chemoembolization.

BACKGROUND/AIMS: The purpose of this study was to investigate factors that may predict the development of the right inferior phrenic artery (RIPA) as a feeding artery in hepatocellular carcinoma (HCC) at the initial (first session) chemoembolization. METHODOLOGY: From January 1997 to June 2002, 538 patients with HCC were treated with a first session of transcatheter arterial chemoembolization (TACE). Twenty-six of these patients underwent TACE via both the Hepatic artery (HA) and RIPA at the initial TACE. We retrospectively analyzed the Child-Pugh's classification, macroscopic tumor type, location and size of the tumor, past history of intervention, complications and outcome in these 26 patients with HCC fed by the RIPA. RESULTS: The incidence of HCC fed by both the HA and RIPA at the initial TACE was 4.8% (26/538 patients). No hepatic arterial occlusion or attenuation was found in any of these 26 patients. All of the tumors abutted the diaphragm and were located at the surface of the liver. All of the tumors that were larger than 5 cm in diameter protruded from the surface of the liver. Seven of the 9 patients with HCC smaller than 5 cm in diameter had a defect in the liver capsule induced by previous intervention for the treatment of a different tumor, such as hepatic resection or percutaneous ablation therapy. There were no serious complications after TACE. CONCLUSION: The RIPA can be an extrahepatic feeding artery for HCC even at the initial TACE. A high incidence of HCC fed by the RIPA was recognized in cases in which a large tumor protruded from the surface of the liver, and when the liver capsule was damaged due to previous intervention such as hepatic resection or in ruptured HCC even at the initial TACE.

Successful embolization of pancreaticoduodenal artery pseudoaneurysm in a patient with common hepatic arterial occlusion after modified pancreatoduodenectomy with preservation of arteries in the head of pancreas.

Pancreaticoduodenectomy (PD) with preservation of the arcade in the head of the pancreas was performed in a 73-year-old male with ampullary adenocarcinoma associated with occlusion of the common hepatic artery (CHA) in another hospital. He developed active bleeding from his drain site, at 18 days after the operation. He was transferred to our hospital for emergent embolization. Celiac arteriogram showed complete occlusion of the CHA, posterior superior pancreaticoduodenal artery (PSPDA) pseudoaneurysm 1.7 cm in diameter and development of an enlarged tortuous dorsal pancreatic artery (DPA), posterior pancreatico-duodenal artery (PPDA), and gastroduodenal artery (GDA). Complete hemostasis was obtained without major complications by the transcatheter arterial embolization (TAE) with microcoils.

International exchange activities with East Asian countries through mammography.

The Japanese NPO Central Committee on Quality Control of Mammographic Screening has initiated international exchange activities regarding quality control of mammographic screening with the concerned organizations in East Asian countries with the objective of contributing to reducing breast cancer mortality in the region. This paper describes the status of the international exchanges that are being carried out in various East Asian countries in relation to mammography and also discusses future aspects.

[Frequency of decreased renal function between patients treated with brand and generic products of vancomycin hydrochloride injection].

The frequency of decreased renal function was compared between patients treated with brand and generic products of vancomycin injection (VCM) in a retrospective manner based on the clinical examination records archived in Okayama University Hospital. A total of 122 patients were found to have been solely treated with vancomycin injection for MRSA infection, and their examination records were analyzed. The renal function of those patients was evaluated based on the serum creatinine concentration (SCr), and patients whose SCr was maximally elevated above the defined upper limit of the normal range (1.20 mg/dl for males and 0.96 mg/dl for females) were considered to show decreased renal function. Although the amount of VCM administered to patients was larger in the case of generic rather than brand products, the percentage of patients whose renal function was decreased during VCM treatment was not significantly different between the VCM products, in which 2 among 62 patients receiving the brand product and 4 among 60 receiving the generic product were reported to show decreased renal function. It was additionally revealed that 3 of those 4 patients with a decreased renal function related to the generic product were not treated as instructed by the package insert, and their trough VCM concentration exceeded the recommended level of 10 microg/ml. With these findings, the brand and generic VCM products are considered to be similar regarding the adverse effect of decreasing renal function.

Surgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.

BACKGROUND/AIMS: The treatment of choice for HCC remains controversial. We evaluated the therapeutic impact of surgical resection, PEI, and RFA for HCC on outcomes. METHODS: A database derived from a Japanese nationwide survey of 17,149 patients with HCC treated by resection, PEI, or RFA between 2000 and 2003 was used to identify 7185 patients with no more than 3 tumors (< or = 3 cm) and a liver function of Child-Pugh class A or B. The patients classified into either a resection (n=2857), RFA (n=3022), or PEI group (n=1306) and their long-term outcomes were compared. RESULTS: The median follow-up period was 10.4 months. The 2-year time-to-recurrence rate was 35.5%, 55.4%, and 73.3% in the resection, RFA, and PEI groups, respectively, while the number of recurrences was 2410, 2368, and 862. Although the number of deaths was 55 (1.9%), 49 (1.6%), and 39 (3.0%), the overall survival rates were not different. In a multivariate analysis, surgical resection was a significant negative factor for recurrence as compared with RFA (relative risk, 0.62 [95% confidence interval, 0.54-0.71], P<0.0001) and PEI (0.45 [0.38-0.52], P<0.0001). CONCLUSIONS: This preliminary report suggested that surgical resection may provide less time-to-recurrence rate than either RFA or PEI in patients with HCC.

Transcatheter arterial chemoembolization (TACE) with lipiodol to treat hepatocellular carcinoma: survey results from the TACE study group of Japan.

The purpose of this study was to retrospectively clarify the current status in Japan of TACE using Lipiodol together with anticancer agents to treat hepatocellular carcinoma (HCC). We retrospectively surveyed 4,659 (average annual total) procedures for HCC over the years 2002-2004 at 17 institutions included in the TACE Study Group of Japan. The survey included six questions that were related mainly to TACE and Lipiodol for HCC treatment. The most frequently applied among the 4,659 procedures at the 17 institutions were TACE (2,310; 50%) and local ablation (1,395; 30%). Five of the institutions applied 201-300 procedures and 4 applied 101-200. Lipiodol was used in "all procedures" and in "90% or more" at seven and nine institutions, respectively. Almost all institutions applied 4-6 (mean, 5) ml of Lipiodol during TACE to treat tumors 5 cm in diameter. In conclusion, this survey clarified that TACE using Lipiodol and anticancer agents is a popular option for HCC treatment in Japan.

Comparison of the outcomes between an anatomical subsegmentectomy and a non-anatomical minor hepatectomy for single hepatocellular carcinomas based on a Japanese nationwide survey.

BACKGROUND: Although a surgical resection is an important modality for the treatment of hepatocellular carcinoma (HCC), the impact of the operative method on both the patient survival and disease-free survival (DFS) still remains controversial. METHODS: Using a nationwide Japanese database, 72,744 patients with HCC who underwent a curative liver resection between 1994 and 2001 were divided into two groups based on whether an anatomical subsegmentectomy (AS) or a non-anatomical minor hepatectomy (MH) was performed. A total of 5,781 patients with single HCCs were selected for the study and divided into 3 subgroups based on the size of the HCCs (less than 2 cm, 2 to 5 cm, and greater than 5 cm in diameter). An AS was performed for 2,267 patients while an MH was performed for 3,514 patients. RESULTS: The overall DFS was significantly better after an AS (P = .0089). When the patients were stratified according to the size of the HCC, a better DFS was seen in the patients with HCC from 2 to 5 cm after an AS (P < .0005). Further stratification according to liver damage did not show any significant differences between an AS and an MH. CONCLUSION: An AS is therefore recommended, especially when the size of HCC ranges from 2 to 5 cm.

Budd-Chiari syndrome: two cases with different courses.

We report two cases of Budd-Chiari syndrome. Case 1: A 57-year-old man presented with leg edema and esophageal varices. Cavography showed obstruction of the inferior vena cava with antiphospholipid syndrome. Further, the patient showed positive serology for hepatitis C virus and consumed large quantities of alcohol. Percutaneous transluminal angioplasty was performed on this patient and anticoagulants administered; leg edema and esophageal varices were ameliorated although liver biopsy showed cirrhosis without evident congestion. More than 9 months since the diagnosis, restenosis of the inferior vena cava has not occurred. Case 2: A 73-year-old woman presented abdominal pain but no edema or varices. Cavography showed membranous obstruction of the inferior vena cava which required no therapy. Manifestation of portal hypertension was not present and liver function was maintained although liver biopsy showed obvious congestion. These cases showed untypical features against histopathology, and careful observation will be required for emergence of hepatocellular carcinoma.

Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan.

The Clinical Practice Guidelines for Hepatocellular Carcinoma (HCC), the first evidence-based guidelines for the treatment of HCC in Japan, were compiled by an expert panel supported by the Japanese Ministry of Health, Labour, and Welfare. This set of guidelines covers six research fields: prevention, diagnosis and surveillance, surgery, chemotherapy, transarterial chemoembolization, and percutaneous local ablation therapy. A systematic review of the English medical literature on HCC was performed, and a total of 7192 publications were extracted, mainly from MEDLINE (1966-2002). After the second selection, 334 articles were adopted for the guidelines to form 58 pairs of research questions and recommendations. For the users' convenience, practical algorithms for the surveillance and treatment of HCC were also created, which were based on evidence from the selected articles forthe guidelines and modified according to the current status of medical practice in Japan, where liver resection for HCC is regarded as safe with less than 1% mortality and cadaveric donors for liver transplantation are extremely difficult to obtain. The formation of the guidelines and the outline of their contents are described. The Japanese HCC guidelines may be useful in decision making at every clinical step, both for patients and physicians. Although the main users of these guidelines are assumed to be Japanese physicians, the accumulated evidence and interpretation in the guidelines may attract universal attention.

Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan.

In the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan, 18 213 individuals were newly registered as patients with primary liver cancer at 645 medical institutions over a period of 2 years (from 1 January 2002 to 31 December 2003). Of these patients, 94.2% had hepatocellular carcinoma (HCC) and 4.1% had intrahepatic cholangiocarcinoma (ICC). In addition, 24 705 follow-up patients were registered in the survey. Epidemiological and clinicopathological factors, diagnosis and treatment were investigated in the newly registered patients, and the cumulative survival rates of newly registered patients in the 12th to 17th follow-up surveys conducted between 1992 and 2003 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified by background factors and treatment. The data obtained in this follow-up survey should contribute to future research and medical practice for primary liver cancer.

Detecting breast cancer with non-contrast MR imaging: combining diffusion-weighted and STIR imaging.

We combined diffusion-weighted (DWI) and short TI inversion recovery (STIR) imaging to evaluate the diagnostic capability of non-contrast magnetic resonance (MR) imaging to detect breast cancer. Seventy women patients underwent mammography and MR imaging with combined DWI (b factor: 1000) and STIR that revealed malignancy, and postoperative pathological examination confirmed breast cancer. Interpreted images were evaluated for sensitivity, false negative rate (FN), sensitivity by pT, and sensitivity by background density of the mammary gland. Of the 70 cases, 68 were diagnosed as cancer by DWI and STIR (sensitivity, 97% [68/70]; FN, 2.9% [2/70]). Sensitivities by pT were: pTis, 67% (4/6); pT1, 100% (33/33); and pT2-4, 100% (31/31). No significant differences were observed in sensitivity between pT1 and pT2-4 (P<0.001). Sensitivities by background density of mammary gland were: fatty/scattered fibroglandular tissue, 95% (20/21) and heterogeneous fibroglandular tissue/mostly fibroglandular tissue, 98% (48/49). No significant differences were observed (P<0.001). Two cases, an intraductal and an apocrine carcinoma, were incorrectly diagnosed by MR imaging. Precise diagnosis of breast cancer is possible with combined DWI and STIR, even in non-contrast MR imaging, regardless of the diameter or background density of mammary gland. It is hoped that non-contrast MR imaging that combines DWI and STIR will become an established clinical screening method.

Preoperative extracranial carotid artery examination with ultrasonography in patients undergoing coronary artery bypass grafting in Japan.

PURPOSE: We investigated the incidence, degree, and plaque characteristics of extracranial carotid stenosis with carotid ultrasonography (CUS) in patients undergoing coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Preoperative CUS was performed on 221 patients (442 carotid arteries) undergoing CABG. The degree of extracranial carotid stenosis was calculated based on the area stenosis, and it was classified into six grades as follows: grade (G) 0, G1 (1%-29%), G2 (30%-49%), G3 (50%-69%), G4 (70%-99%), and G5 (occlusion). RESULTS: The incidence of G4 was 4.1% and G5 1.6%. There were 48 arteries rated G3 or G4. Hypoechoic plaque was detected in 28 of the 48 arteries (58%), and heterogeneous plaque was detected in 37 arteries (73%). Ulcerative plaque was detected in 27 arteries (56%); when comparing the G3 and G4 groups, ulcerative plaque was found more frequently in G4 than in G3 (14/18 vs 13/30 arteries, P < 0.02). CONCLUSION: Our study demonstrated that patients undergoing CABG with extracranial severe carotid stenosis tend to have heterogeneous, hypoechoic, and ulcerative plaque. We believe that preoperative CUS should be used to evaluate the plaque characteristics of extracranial carotid stenosis.

Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia: assessment by complementary DNA microarray.

Follicular lymphoma (FL) is pathologically categorised as a low-grade B-cell lymphoma and histopathologically shows follicular proliferation of neoplastic B cells. In the neoplastic follicles of FL, the presence of T cells, macrophages and follicular dendritic cells (FDCs) suggests that these cells may promote a favourable environment for the growth of FL cells. Because FL cells are generally associated with FDCs, FDCs may be considered an important source of cytokines and chemokines. FDCs form the framework for germinal centres and also provide networks for nodules of FL. To evaluate the gene expression in neoplastic follicles of FL and reactive follicles of reactive follicular hyperplasia (RFH), we performed gene expression profiling of FL (n=5) and RFH (n=5) using complementary DNA (cDNA) microarray of cytokines/chemokines and their receptors. FL and RFH exhibited a diffuse down-regulated profile compared with normal peripheral blood cells, which were used as controls, although some genes displayed up-regulated profiles. Hierarchical clustering analysis separated FL and RFH into two distinct groups based on their gene expression profiles. FL cases exhibited significantly higher expression of interleukin 3 receptor alpha (IL-3Ralpha) than RFH. Immunohistochemically, neoplastic follicles of FL frequently expressed IL-3Ralpha, especially in FDCs, but not in FL cells. However, IL-3Ralpha expression was rare or weak in the reactive follicles of RFH. These findings suggest the importance of the micro-environment for FL cell growth. Further studies of cDNA microarray should provide new insight into the molecular pathology of FL and may allow the design of improved therapies.

Differential expression of chemokines, chemokine receptors, cytokines and cytokine receptors in diffuse large B cell malignant lymphoma.

Host immunity, particularly T cell immunity (Th1/Th2 balance), plays an important role in clinicopathological features of malignant disease. However, the T cell immunity has not been fully investigated in patients with lymphoid malignancies. Recent studies suggested the important role of dysregulation of the endogenous immune system in lymphomagenesis. The relationships between cytokines/chemokines and their receptors, are important in determining the selectivity of local immunity. To investigate differences in the endogenous immune system of diffuse large B cell lymphoma (DLBL), we performed gene expression profiling using cDNA microarrays of cytokines/chemokines and their receptors. We studied 5 cases each of primary central nervous system lymphomas (PCNSL), extranodal and nodal lymphomas. PCNSL exhibited diffuse down-regulated profiles, compared to normal peripheral blood lymphocytes. While extranodal and nodal lymphomas also exhibited diffuse down-regulated profiles, some genes displayed up-regulated profiles. Hierarchical clustering analysis separated PCNSL and extranodal lymphomas into distinct groups based on their gene expression profiles, as well as extranodal and nodal, but not PCNSL and nodal. PCNSL exhibited significantly lower expression of BLC/BCA-1 and CCR-3 (Th2 type), and higher expression of IL-8 and MIP-1beta (Th1 type) than extranodal lymphomas. Immunohistochemistry and RT-PCR revealed frequent CCR-3 and BLC/BCA-1 expression in extranodal lymphomas, compared with PCNSL. Our results provide new insights into the pathogenesis of each DLBL. A better understanding of the immune response in each DLBL could help in the design of novel therapeutic strategies based on cytokines/chemokines and their receptors.

Current status and goals of mammographic screening for breast cancer in Japan.

In Europe and the United States, the proportion of women receiving mammographic screening for breast cancer has increased to 60-80%, resulting in an increase in the detection of early-stage cancer and a reduction in the mortality rate. The objectives of breast cancer screening have thus already been achieved there. In Japan, both the incidence and mortality of breast cancer have increased recently. Breast cancer screening has long been performed by clinical breast examination (CBE) alone. A reduction in the mortality of breast cancer cannot be expected from CBE. Mammographic screening for breast cancer was recommended in a notification issued by Ministry of Health, Labour and Welfare in 1999. An important aspect of mammographic screening is quality control. The Central Committee on Quality Control of Mammographic Screening(Central Committee)was organized by six screening-related societies, and attempts have since been made to establish a quality control system. Both the social recognition of the Central Committee and its cooperation with the "Quality Control Committee " of each community will become important. The cover rate of nationwide breast cancer screening by CBE alone is 12-13%, while the implementation rate of mammographic screening is presently very low and its cover rate is considered to be about 2%. With such a low cover rate, it is absolutely impossible to reduce the mortality of breast cancer. To achieve this, the administration and clinicians will be required to cooperate with each other to increase the spread and cover rate of high-quality mammographic screening.