The application of an institutional clinical data warehouse to the assessment of adverse drug reactions (ADRs). Evaluation of aminoglycoside and cephalosporin associated nephrotoxicity.

OBJECTIVES: To apply an institutional clinical data warehouse (CDW) to the assessment of adverse drug reactions (ADRs) and demonstrate its utility through a specific example. METHODS: We modeled the process for assessing ADRs through retrospective cohort design by using CDW at the Osaka University Hospital as follows: 1) We defined a drug X, an adverse drug reaction (ADR) Y, and a laboratory measurement Z to assess Y during a given study period; 2) we excluded those whose Z value exceeded the defined criteria or were not available at the inception of the cohort; 3) we divided the patients into two groups based on exposure or non-exposure to X; 4) we matched the patient characteristics between the two groups through stratification and randomization; and 5) we compared the frequency of patients who presented Y during the study period between the two groups. Aminoglycoside and Cephalosporin associated nephrotoxicity in pediatric inpatients was used as an example to demonstrate the usefulness of this approach. RESULTS: Our evaluation indicates that there is an increased risk of nephrotoxicity for pediatric inpatients who were prescribed cephalosporin either alone or in combination with aminoglycoside; further, aminoglycoside tends to increase the cephalosporin-associated nephrotoxicity. CONCLUSIONS: Our findings are consistent with those drawn from other studies, indicating that the method of applying an institutional CDW is useful for assessing ADRs.

A novel split liver protocol using the subnormothermic oxygenated circuit system in a porcine model of a marginal donor procedure.

BACKGROUND: A merit of subnormothermic perfusion has been reported to preserve grafts from ischemic injury in animal models. The split liver technique is commonly performed to solve the shortage of liver grafts. However, there has been no study showing the effect of a split liver graft on subnormothermic perfusion. We herein investigated the split liver protocol using a subnormothermic oxygenated circuit system (SOCS). METHODS: Auxiliary liver transplantation was performed in a porcine marginal donor model by using a SOCS. In the SOCS group, the portal vein and hepatic artery of the graft were cannulated, and the graft was perfused by SOCS. In the cold storage (CS) group, the graft was placed in cold preservation solution. In the preservation phase, the graft was split. RESULTS: There were no significant differences in the biochemical markers between the SOCS and CS groups. In terms of the histology, the sinusoidal spaces were widened in the CS group 12 hours after implantation. CONCLUSION: We have demonstrated a possibility to use SOCS with the split liver protocol by using a porcine model. This split liver protocol using SOCS will extend the split liver criteria and rescue more patients from hepatic failure, including pediatric patients.

S100A9 expression in invasive ductal carcinoma of the breast: S100A9 expression in adenocarcinoma is closely associated with poor tumour differentiation.

S100A9 is associated with myelomonocytic cell differentiation and is also expressed in some epithelia. However, there have been few studies on S100A9 in adenocarcinoma (AC) because the expression in normal epithelia is limited to squamous epithelia. Our previous studies on pulmonary AC and liver carcinomas suggested that S100A9 expression in carcinomas of glandular cell origin is related to poor tumour differentiation. In this study, we examined S100A9 expression in invasive breast carcinoma and evaluated the relation of the expression to the tumour differentiation in 70 cases of invasive ductal carcinoma (IDC) of the breast. S100A9 gene and protein expression was detected in MCF-7 breast carcinoma cells. The rate of S100A9 immunopositivity in IDC showed a higher correlation with poor tumour differentiation, especially in nuclear pleomorphism (P=0.0002) and mitotic activity (P=0.0001). Furthermore, transcriptional expression of S100A9 in sections of IDC could be detected in cases with a high S100A9 immunopositivity. No significant differences in the number of myelomonocytic cells expressing S100A9 were found among cases. There was no correlation between S100A9 immunopositivity and lymph node metastasis (P=0.32). S100A9 immunopositivity in non-invasive ductal carcinoma was also associated with poor tumour differentiation. No immunopositive reaction was observed in invasive lobular carcinomas with a classic cytological appearance and non-neoplastic duct cells. We conclude that S100A9 in glandular epithelial cells is newly expressed under cancerous conditions and is over-expressed in poorly differentiated AC.

Neural plasticity detected in short- and long-term cochlear implant users using PET.

The interaction of listening to words and watching sign language in short-term and long-term cochlear implant (CI) users who have learned sign language after becoming deaf was measured using PET. In short-term CI users the auditory cortex was inactive while in long-term CI users it was fully activated with the simultaneous presentation of auditory and visual input. The result suggests the possibility that the interference of rival modalities may be diminished with experience and the preference switchover from the visual input to the auditory input could be accomplished by means of the neural plasticity persisting in the mature human auditory cortex.

Primary ovarian pregnancy in a cystic teratoma.

Hemoperitoneum was identified by culdocentesis in a 26-year-old woman suffering acute abdominal pain. A pregnancy test was positive. Operation indicated a ruptured ovarian pregnancy, and histologic examination revealed primary intrafollicular ovarian pregnancy in a cystic teratoma. Ovarian pregnancy in an ovarian tumor is exceedingly rare.

Hepatocellular carcinoma depicted as hypoattenuation on CT hepatic arteriography (CTA) and hyperattenuation on CT during arterial portography (CTAP).

We report a 68-year-old man with three nodules of hepatocellular carcinoma (HCC) in a cirrhotic liver; the largest nodule was 3.0cm in diameter. The nodules showed hypoattenuation on computed tomography (CT) hepatic arteriography (CTA) and hyperattenuation on CT during arterial portography (CTAP), indicating that the dominant vascularity of the HCC nodules may have been the portal vein. A biopsy specimen obtained from the nodules showed well differentiated HCC (Edmondson-Steiner grade I). The imaging findings of the nodules on both CTA and CTAP are unusual, in spite of the rather large size, so this seemed suggestive of the hemodynamic properties of relatively large nodules of well differentiated HCC.

Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation.

S100 protein A9 is associated with myeloid cell differentiation and is also expressed in some epithelia. However, there have been few studies on S100A9 in specific types of carcinomas, except for squamous cell carcinoma (SCC) because the expression in normal epithelia is limited to squamous epithelia. Recently, S100A9 gene expression has been detected in cultured human adenocarcinoma (AC) cells derived from various organs. In this study, we also detected S100A9 gene expression in human pulmonary AC cell lines by reverse transcription-polymerase chain reaction. Furthermore, using the monoclonal antibody against S100A9, we carried out an immunohistochemical evaluation of S100A9 protein expression in 70 cases of resected pulmonary AC and examined the relation of S100A9 expression to tumor differentiation. S100A9 immunopositivity was 0/21 (0%) in well differentiated ACs, 12/30 (40%) in moderately differentiated ACs and 19/19 (100%) in poorly differentiated ACs, and the poorly differentiated ACs showed a significantly greater positive reaction. The immunopositivity in the moderately differentiated ACs was marked in specific cytologic subtypes. In the controls, conspicuous S100A9 immunopositivity was observed in pulmonary SCCs, regardless of the degree of differentiation, but not in adenomatous hyperplasia or normal surface epithelia. These above results suggest that the S100A9 protein is also expressed in pulmonary AC and that the expression rate in pulmonary AC shows higher correlation in poorly differentiated carcinomas, in agreement with our recent results regarding liver carcinoma. We believe S100A9 is also closely related to the differentiation of carcinomas of glandular cell origin.

Early detection of haemobilia associated with percutaneous ethanol injection for hepatocellular carcinoma.

OBJECTIVE: Haemobilia often results from iatrogenic injury caused by therapeutic procedures. The objective of this study was to evaluate the efficacy of early diagnosis of haemobilia based on ultrasonography in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection. PATIENTS AND METHODS: A combination retrospective and prospective study on the early detection of haemobilia caused by percutaneous ethanol injection was conducted on 365 patients in 1995-1996. The retrospective study reviewed the clinical, laboratory and imaging data of 172 patients who had undergone ethanol injection therapy in 1995. The results showed that ultrasonographic changes in the gallbladder, namely the rapid appearance of echogenic material in the gallbladder lumen, are a useful early sign of haemobilia. Based on the results of the retrospective study, a prospective study on the early detection of haemobilia was carried out in 1996. In the prospective study, percutaneous ethanol injection was halted as soon as haemobilia was detected. RESULTS: The incidence of haemobilia in the prospective group (3.6%) was not different from that in the retrospective group (4.7%). However, the mean duration between percutaneous ethanol injection and diagnosis of haemobilia was only 0.3 +/- 0.2 days in the prospective group, compared with 2.8 +/- 2.1 days in the retrospective group (P < 0.001), and the mean duration of jaundice in the prospective group (4.3 days) was significantly shorter than in the retrospective group (40.0 days) (P< 0.05). CONCLUSION: Early diagnosis of haemobilia based on ultrasonographic findings of the gallbladder lumen effectively reduces the severity of haemobilia-related complications due to immediate interruption of the interventional procedure.

[Essential thrombocythemia in pregnancy].

A 30-year-old woman was admitted to our hospital because of thrombocythemia during pregnancy. Her leukocyte count was 10,000/microliters, Hb was 11.7 g/dl, and platelet count 181.9 x 10(4)/microliter. Bone marrow aspirate showed an increase in megakaryocytes (255/microliters). Both Ph1 chromosome and bcr rearrangement were negative. She was diagnosed as having essential thrombocythemia (ET) with pregnancy, and was treated with aspirin (150 mg/day). Her pregnancy was uneventful, but she was readmitted because of overterm pregnancy. A caesarean section was performed, and a healthy male infant weighing 3,672 g was delivered, with a platelet count of 25.5 x 10(4)/microliter. However, the uterine was atonic, and atonic hemorrhage occurred. Supravaginal hysterectomy was performed. Subsequently, intrabdominal gross hemorrhage occurred, but the bleeding was halved by platelet transfusion. Microscopic examination showed uterine infarction. We suggest that platelet count should be reduced by means of plateletpheresis or interferon-alpha throughout pregnancy with ET.

[Percutaneous ethanol injection therapy for small hepatocellular carcinoma].

Hepatocellular carcinoma is different from other solid tumors. Because of concomitant cirrhosis or multiple lesions, most hepatocellular carcinoma is unresectable. Still worse, hepatocellular carcinoma frequently recurs after surgical resection; the 5-year cumulative recurrence rate is 70-90% even after curative hepatectomy. The situation is similar in small hepatocellular carcinoma 2 cm or less in diameter. Thus, non-surgical treatment plays an important role. At present, we think that percutaneous ethanol injection therapy (PEIT) is best for the treatment of hepatocellular carcinoma because of its local curativity, minimal adverse effect on liver function, and the easy feasibility of repeated treatment for recurrence. We have recently treated about 85% of hepatocellular carcinoma cases by PEIT and have achieved satisfactory long-term results. Here we describe our results in PEIT for small hepatocellular carcinoma. By the end of December 1995, we performed PEIT on 410 patients with hepatocellular carcinoma. Among them, 140 patients were diagnosed as having small hepatocellular carcinoma 2 cm or less in diameter. The 1-, 3-, 5-, 7-, and 10-year survival rates of the 140 patients were 93%, 73%, 55%, 51%, and 32%, respectively. Furthermore, in 83 patients who had a single, small hepatocellular carcinoma 2 cm or less in diameter, the 1-, 3-, 5-, 7-, and 10-year survival rates were 92%, 82%, 72%, 66%, and 66%, respectively. Thus PEIT achieved satisfactory long-term survival rates in the treatment of small hepatocellular carcinoma.

[Percutaneous tumor ablation therapy for the advanced stage of HCC].

We have performed percutaneous tumor ablation (PTA) including percutaneous ethanol injection therapy (PEIT) for 90% of the patients with hepatocellular carcinoma. Until December 1998, the 793 patients received PTA, 5 years survival rate reached 39.8%. Excluding the patients with Child C whose hepatic function were extremely low, 5 years survival rate reached to the level of 41.2%. Since 5 years survival rate in stage IV-A reached 24.4%, the patients of stage IV-A may be considered to have an indication for PTA. We have confirmed the effectiveness of the local treatment including radiotherapy for advanced hepatocellular carcinoma with portal vein invasion. We are attempting to perform PTA for the extra-hepatic lesions that had no indication of other treatment. However the indication of PTA is limited by the presence of diffuse nodules, exacerbation of the hepatic function, or tumor invasion to portal vein, bile duct, inferior vena cava.

Evaluation of liver preservation solutions by using rats transgenic for luciferase.

INTRODUCTION: The solution in which graft tissue is stored (that is, preservation solution) is an important component of liver transplantation technology. Its protective effect is induced by substances in the solution, including radical scavengers, buffers, and energy-giving substances. New preservation solutions have proven to be effective in preventing organ damage during cold ischemia and in extending the time limits for storage. AIM: This study determined the relationship between luminescence intensity and content of adenosine triphosphate (ATP) in liver tissue and proposes a new ex vivo screening system that uses Lewis rats transgenic for luciferase for evaluating the effectiveness of preservation solutions. METHODS: Samples (diameter, 2 mm) of liver were obtained from transgenic rats. The viability of these tissues after storage for as long as 6 hours in University of Wisconsin (UW) solution, extracellular trehalose solution of Kyoto, Euro-Collins (EC) solution, histidine-tryptophan-ketoflutarate solution, low potassium dextran solution, or normal saline was assessed by determining ATP content and luminescence intensity. RESULTS: Luminescence had a linear relationship (R = 0.88) with ATP levels. Regardless of the preservation solution used, the luminescence intensities of the liver tissue chips decreased linearly with time especially through a short span of time (0 to 2 hours; R(2) = 0.58-1.0). The luminescence of liver chip tissues maintained long term (2 to 6 hours) in UW solution tended to be higher than those of tissues stored in other solutions (P < .05; 6 hours). On the basis of luminescence intensity, EC might be preferable to the other solutions tested for ultra-short-term storage (0.5 to 2 hours). CONCLUSION: Our model, which combines the use of the bioimaging system and Lewis rats transgenic for luciferase, effectively assessed the viability of liver tissue samples. We believe that this ex vivo screening system will be an effective tool for evaluating preservation solutions for liver grafts.

Impact of ex vivo administration of mesenchymal stem cells on the function of kidney grafts from cardiac death donors in rat.

BACKGROUND: Mesenchymal stem cells (MSCs) have been applied to the treatment of various diseases, and MSC administration in marginal donor grafts may help avoid the ischemia-reperfusion injury associated with solid organ transplants. Given the reports of side effects after intravenous MSC administration, local MSC administration to the target organ might be a better approach. We administered adipose tissue-derived MSCs (AT-MSCs) ex vivo to donor rat kidneys obtained after cardiac death (CD). METHODS: Using male Lewis rats (8-10 weeks), and a marginal transplant model of 1hr CD plus 1hr sub-normothermic ET-Kyoto solution preservation were conducted. AT-MSCs obtained from double-reporter (luciferase-LacZ) transgenic Lewis rats were injected either systemically (1.0 × 10(6) cells/0.5 mL) to bilaterally nephrectomized recipient rats that had received a marginal kidney graft (n = 6), or locally via the renal artery (500 µL ET-Kyoto solution containing the same number of AT-MSCs) to marginal kidney grafts, which were then preserved (1 hour; 22°C) before being transplanted into bilaterally nephrectomized recipient rats (n = 8). Serum was collected to assess the therapeutic effects of AT-MSC administration, and the recipients of rats surviving to Day 14 were separately evaluated histopathologically. Follow-up was by in vivo imaging and histological LacZ staining, and tumor formation was evaluated in MSC-injected rats at 3 months. RESULTS: Systemic injection of MSC did not improve recipient survival. In vivo imaging showed MSCs trapped in the lung that later became undetectable. Ex vivo injection of MSCs did show a benefit without adverse effects. At Day 14 after RTx, 75% of the rats in the AT-MSC-injected group (MSC[+]) had survived, whereas 50% of the rats in the AT-MSC-non-injected group (MSC[-]) had died. Renal function in the MSC(+) group was improved compared with that in the MSC(-) group at Day 4. LacZ staining revealed AT-MSCs attached to the renal tubules at 24 hours after RTx that later became undetectable. Histopathologic examination showed little difference in fibrosis between the groups at Day 14. No teratomas or other abnormalities were seen at 3 months.

Luminescence-based assay to screen preservation solutions for optimal ability to maintain viability of rat intestinal grafts.

BACKGROUND: Segmental intestinal transplantations from living, genetically related donors provide advantages compared with those from cadaveric subjects. However, successful preservation during ischemic cold storage is critical for living donor grafts. Thus, the development of preservation solutions that maintain graft viability is essential for success. Herein we have reported application of a cell-based viability assay in multiwell plates to assess the effectiveness of various solutions to preserve intestinal grafts. METHODS: Freshly isolated intestinal chips from luciferase transgenic rats were placed in 96-well tissue culture plates for incubation at 4°C for 24 hours in various preservation solutions: ET-Kyoto (ET-K), University of Wisconsin (UW) solution, Euro-Collins (EC) solution, histidine-tryptophan-ketoglutarate (HTK) solution, lactated Ringer's (LR) solution, or saline. RESULTS: As indicated by a higher level of luminescence, intestinal chips preserved in UW, HTK, or ET-K solution contained more viable cells, than those preserved in EC, LR, or saline solution. After exposure to the preservation solutions for 1 hour, the mucosal layer chips showed lower cell viability than the muscle layer chips. CONCLUSION: Our data demonstrated that ET-K and UW solutions used together with intestinal chips of Luciferase transgenic rat and in vivo imaging provided optimal viability during ischemic cold storage prior to transplantation. Further development of preservation conditions to minimize the loss of viability of intestinal grafts before clinical transplantation is essential to improve outcomes.

Artificial ascites technique for percutaneous radiofrequency ablation of liver cancer adjacent to the gastrointestinal tract.

BACKGROUND: Percutaneous radiofrequency ablation (RFA) of liver tumours adjacent to the gastrointestinal tract is controversial. This study assessed the value of an intraperitoneal water infusion (artificial ascites) technique for percutaneous RFA of such tumours. METHODS: Before ablation in 52 patients (55 treatments, 58 tumours), between 250 and 3000 (mean 681) ml 5 per cent glucose solution was infused into the abdominal cavity using a 14-G needle, with the aim of preventing thermal injury by separating the liver from the gastrointestinal tract. RESULTS: There were no adverse events associated with the artificial ascites technique. In 43 (78 per cent) of the 55 treatments, the liver and gastrointestinal tract were separated successfully. In the other 12 treatments, in which the separation was not confirmed by real-time ultrasonography, there was one case of perforation of the ascending colon after RFA; adhesion of the liver and colon resulting from previous laparotomy may have been related to the injury. CONCLUSION: Production of artificial ascites can be undertaken safely, making RFA safe and effective for hepatic tumours adjacent to the gastrointestinal tract. In patients with possible postoperative adhesions, confirmation of separation of the liver from surrounding organs is mandatory to avoid thermal injury.