Biomedical subjects
Publications and source records attributed to M Kitajima.
Recent clinical trials with experimental immunotherapeutic agents for sepsis have not proven their overall benefit yet although some studies suggested significant effect of these antisepsis therapies. This review article summarizes the results of these trials, their analysis, lessons learned from past failure, and future perspectives for immunotherapies as anti-sepsis treatments.
In gastric cancer, the process of carcinogenesis is thought to occur as a stepwise accumulation of genetic abnormalities. However, the mechanisms of the process of multistage carcinogenesis is still unknown for gastric cancer. Gene abnormalities seen in gastric cancer, including ras, myc, c-erbB-2, met, K-sam and cript are summarized herein. Abnormalities of cancer suppressor genes, including p53, RB and APC are also described. In our studies, the biological malignancy of patients with c-erbB-2 amplification was higher than that of patients without amplification. Moreover, the cases with amplification of c-erbB-2 were found to be highly correlated with distant organ metastasis. However, very little is currently known of the molecular abnormalities leading to gastric cancer. In order to clarify the multiple gene abnormalities in gastric cancer, we used the method of restriction landmark genomic scanning (RLGS). RLGS provides a useful method for genomic analysis of gastric cancer. In the future, new analytical methods that will permit screening of all gene abnormalities at once promise to improve our understanding of the mechanisms of gastric cancer.
Following the successful introduction of laparoscopic cholecystectomy, many reports confirming the feasibility of using laparoscopy for bowel resection and predicting that it would be advantageous in terms of its minimal invasiveness have been published. In the context of cancer treatment, however, the feasibility of lymphadenectomy, the risk of recurrence, and survival have emerged as major concerns. Even though mucosal cancer (Tis) can be treated by endoscopic resection (ER), when this is not possible open surgery (OS) must be performed. In patients with T1 cancer, tumors showing slight submucosal layer invasion (sm 1) can be treated in the same way as Tis (in cancer) cancers. But 5% to 10% of patients with T1 cancer have massive submucosal layer invasion (sm 2-3) with paracolic lymph node metastasis. At least partial bowel resection with paracolic lymphadenectomy is considered necessary for T1 (sm 2-3) cancers in principle. In summary, laparoscopic local excision of Tis cancers that are endoscopically unresectable and laparoscopically assisted partial resection with paracolic lymphadenectomy for T1 cancers have become accepted because local excision and partial resection with paracolic lymphnedectomy are fairly simple to perform laparoscopically. Therefore as a strategy for the treatment of early colorectal cancer (CRC), minimally invasive laparoscopic bowel resection (LBR) has been positioned between endoscopic resection (ER) and open surgery (OS). While the difficulty of performing radical lymphadenectomy is considered one of the greatest obstacles to the introduction of laparoscopic bowel resection (LBR) for the treatment of advanced colorectal cancer (CRC), early colon cancer is a good indication for laparoscopic bowel resection.
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We present the first report of laparoscopic resection for colorectal mucosa-associated lymphoid tissue (MALT) lymphoma. A 76-year-old man was found to have MALT lymphoma of the cecum during colonoscopy. He underwent a laparoscopically assisted ileocecal resection after admission and was discharged 9 days postoperatively without any complications. Colorectal MALT lymphoma is a rare neoplasm that responds favorably to locally directed therapy, because it tends to remain localized for prolonged periods. Laparoscopic surgery for colorectal MALT lymphoma is considered feasible because it is minimally invasive, making it suitable for treatment of low-grade malignancies, such as MALT lymphoma, which cannot be removed endoscopically.
We used a novel cDNA cloning method based on the cadherin-beta-catenin protein interaction and identified a new human classic-type cadherin, which we named cadherin-15, from adult brain and skeletal muscle cDNA libraries. Sequence analysis revealed that this cadherin was closely related to mouse muscle cadherin and seemed to be its human counterpart. However, its deduced amino acid sequence differed from that of mouse muscle cadherin in that it had an extra 31-amino acid sequence at its C terminus that has been found neither in mouse muscle cadherin nor in any other known classic cadherin. Analysis of cadherin-15 protein expressed in L fibroblasts showed that it was cleaved proteolytically, expressed on the cell surfaces as a mature form of about 124-kDa, and functioned as a cell-cell adhesion molecule in a homophilic and specific manner, but Ca2+ did not protect it against degradation by trypsin. Our findings also suggest that cadherin-15 mediates cell-cell adhesion with a binding strength comparable to that of E-cadherin.
A highly specific and effective magnetic resonance imaging (MRI) contrast agent was prepared by coating super-paramagnetite particles with monoclonal antibodies (MAbs) directed against epidermal growth factor receptors (EGFRs), which are over-expressed in esophageal squamous cell carcinoma. The preparation maintained both the immunoreactivity of the MAbs and the full relaxing capability of the magnetite particles. The particles of this EGFR-specific contrast agent are 13.2 +/- 1.9 nm in size, and thus, it is assumed that they are smaller than capillary pores and, hence, able to escape scavenging by reticulo-endothelial system cells. The EGFR-specific T2-relaxing ability of this contrast agent was ascertained first in vitro, using the EGFR-expressing cell line TE8 and the EGFR-deficient cell line H69. The results in athymic rats bearing TE8 or H69 tumors revealed that the agent has EGFR-specific MRI contrast capacity in vivo. The electron-microscopic findings in TE8 tumor-bearing rats revealed that the magnetite particles had been taken up by their lysosomes. In conclusion, immuno-specific MRI using magnetite particles coated with MAbs against EGFR appears to be useful in the diagnosis of squamous cell carcinoma of the esophagus.
BACKGROUND AND OBJECTIVES: 1-Ethyl-2-¿[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-+ ++oxothiazolidin-2-ylidenemethyl¿pyridium chloride (MKT-077, formerly known as FJ776), a delocalized lipophilic cation, is known to accumulate in the mitochondria, according to the negative potential inside the mitochondria, and exert its cytotoxicity. METHODS: The single-cell suspensions of human cancer cell lines, human spleen cells, and fresh cancer specimens obtained from patients with gastric carcinoma were used for the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. RESULTS: The antitumor activity of MKT-077 was dose and concentration related, and 50% inhibitory concentrations (IC50) ranged from 1.7 to 14.3 microg/ml, with a mean +/- standard deviation (SD) of 8.4 +/- 4.6 microg/ml. The IC50 of fresh surgical spleen-cell specimens ranged from 0.34 microg/ml to >100 microg/ml in a 48 h incubation, with a mean +/- SD of 66.5 +/- 37.7 microg/ml. When the antitumor activity of MKT-077 was compared between gastric cancer cells and spleen cells obtained from the same patient, the concentration-dependent antitumor activity of this agent was obvious in the cancer cells, while no significant cytotoxicity was observed in the spleen cells. The fresh surgical specimens of gastric cancer showed higher sensitivity to MKT-077 than did spleen cells at a concentration of 30 microg/ml, with a statistically significant difference at P < 0.05. CONCLUSIONS: The selective antitumor activity of MKT-077 was confirmed using fresh surgical specimens and warrants further investigation.
Although discontinuous total parenteral nutrition (d-TPN) has recently been favored for clinical use over continuous total parenteral nutrition (c-TPN) to ameliorate liver dysfunction, mechanisms for the protection against postoperative liver dysfunction remain unknown. This study aimed to examine differences in mitochondrial function in d-TPN- and c-TPN-pretreated livers during ischemia-reperfusion. Rat livers pretreated with d-TPN or c-TPN were perfused with Krebs-Ringer buffer and were exposed to 25% low-flow hypoxia followed by reperfusion. Intrahepatic mitochondrial membrane potential (triangle up) and cell viability were assessed by dual-color digital microfluorography using rhodamine 123 (Rh123) and propidium iodide (PI), respectively. In response to hypoxia, livers pretreated with c-TPN, d-TPN, and an ordinary chow diet exhibited a significant triangle up reduction among the entire lobules. Upon reperfusion, the regional triangle up values further decreased in the c-TPN liver, whereas those in the d-TPN-treated or chow-treated livers displayed a rapid recovery toward the control levels. The severity of cell injury did not differ among the groups, showing that the reperfusion-induced triangle up drop in the c-TPN-pretreated liver is not a consequence of cell injury. Differences in the triangle up drop among the groups appear to occur irrespective of those in the glycogen storage, because the livers undergoing d-TPN display a marked triangle up recovery even when reperfused at the end of a fasted state. These results indicate that c-TPN, but not d-TPN, jeopardizes mitochondrial re-energization and suggest that a circadian pattern of the TPN serves as a potentially beneficial strategy to reduce the risk of postischemic mitochondrial dysfunction in the liver.
To investigate the influence of the liver on differentiation of hematopoietic stem cells/pro-T cells, TN-NWP-BMC (athymic nude bone marrow cells that were treated with anti-TCRbeta, anti-CD4, and anti-CD8 Abs plus complement and then passed through a nylon wool column) were cultured on parenchymal liver cells. After culture for 2.5 days, CD3-4-8-TCRbeta+ cells and CD3-CD4+/CD8+TCRbeta- cells were developed from TN-NWP-BMC. TCRVbeta8+ cells comprised 19.9% of CD3-4-8-TCRbeta+ cells, and Vbeta8 mRNA was detected in the CD3-4-8-TCRbeta+ cells by reverse transcriptase-polymerase chain reaction. The CD3-CD4+/CD8+TCRbeta- cells contained not only single-positive cells but also CD4+8+ double-positive cells. The CD8 protein consisted of 88.9% CD8alpha+beta-, 10.1% CD8alpha+beta+, and 1% CD8alpha-beta+ molecules. From these results and the finding of co-expressed antigens, CD3-4-8-TCRbeta+ cells and CD3-CD4+/CD8+TCRbeta- cells appear to be immature cells not committed to a certain cell lineage.
The chemosensitivity of breast cancer is important for its management, but it is difficult to evaluate preoperatively. Tc-99m hexakis-2-methoxyisobutylisonitrile (MIBI) scintimammography has been reported to indicate the expression of P-glycoprotein, which is one factor concerned with multidrug resistance. We developed a chemosensitivity assay by using surgical specimens to investigate whether 99mTc-MIBI scintimammography findings before the operation are related to chemosensitivity according to our assay. Fifteen patients with primary breast cancer were enrolled into the study. Early and delayed images were obtained at 10 and 120 minutes after intravenous injection of 99mTc-MIBI, respectively. Regions of interest were placed on the tumors and the contralateral healthy breasts in each patient to estimate 99mTc-MIBI uptake in the tumor, and retention indices were then calculated to assess the washout of 99mTc-MIBI. Chemosensitivity assay was performed by incubating surgical specimens with anticancer agents such as doxorubicin, epirubicin, pinorubicin, mitomycin C, cisplatin and 5-fluorouracil. 99mTc-MIBI washout on scintimammography was successfully related to inhibition ratios on chemosensitivity tests when compared with 99mTc-MIBI uptake by the tumor. In particular, high correlation coefficients were obtained between the retention index of 99mTc-MIBI and the inhibition ratios of doxorubicin (r = 0.75), epirubicin (r = 0.60) and pinorubicin (r = 0.62), but poor correlation was found for mitomycin C (r = 0.44) and cisplatin (r = 0.31). Our results indicate that the retention index of 99mTc-MIBI is closely correlated to chemosensitivity to anthracyclines, suggesting that double-phase scintimammography allows preoperative prediction of chemosensitivity of breast cancer.
We reviewed the MRI studies of 25 patients with occipital lobe infarcts to clarify the distribution of infarcts in the posterior cerebral arterial territory, focussing on their relationship to the striate cortex. Visual field defects and MRI findings were also correlated in 16 patients. On coronal and/or sagittal images, the distribution of the infarct and its relationship to the striate cortex were classified. Involvement of the cortex of both upper and lower lips of the calcarine fissure was observed in 10 patients, and involvement of the lower lip alone in 15. The upper cortical lesions were always accompanied by lower cortical lesions. The visual field defects were complete hemianopia in nine patients, superior quadrantanopia in six and hemianopia with a preserved temporal crescent in one. All patients with superior quadrantanopia had involvement of the lower cortex alone; there were no cases of inferior quadrantanopia. The characteristic vascular anatomy, and poor development of the collateral circulation in the lower cortical area, may explain the vulnerability of this area to infarcts.
The reestablishment of anal function by transposition of the gracilis muscle, combined with the implantation of electrodes and a neuromuscular stimulator (dynamic graciloplasty), has recently been developed. With this method, the transposed muscle maintains contraction by electrical stimulation to maintain neoanal pressure without fatigue. It is necessary to convert the fatigue-prone gracilis muscle to fatigue-resistant muscle by long-term electrical stimulation (conditioning). In most patients receiving dynamic graciloplasty, the conditioning is accomplished after the transposition. However, conditioning before graciloplasty should reduce the risk of ischemia in the transposed muscle after the graciloplasty and improve the outcome. This new sequence of procedures is described, in combination with J-pouch construction, in a patient who required abdominoperineal excision of the rectum for lower rectal cancer. The graciloplasty was performed after conditioning of the gracilis muscle in situ; the conditioning did not cause the patient discomfort and resulted in good anal function.
BACKGROUND/PURPOSE: This report describes a technique devised for two children with megaduodenum consisting of subtotal duodenal resection with the proximal jejunum used as an onlay patch. METHODS: A 2-year-old boy presented after unsuccessful surgical repairs for duodenal stenosis with web. Another 8-year-old boy returned from the United States after several surgical procedures for complicated congenital left diaphragmatic hernia with gastric outlet obstruction. Both boys manifested postprandial right upper abdominal fullness, occasional vomiting, abdominal pain, and failure to thrive. Upper gastrointestinal contrast study findings showed massively dilated duodenums in both patients that were larger than the stomach. During the operative procedures, about 95% of the duodenal wall was resected, leaving the basal portion that was unified with the pancreatic head and the ampulla of Vater as linguiform flap, which was covered with the proximal jejunum as an onlay patch so as to form the anterior wall of the duodenal bulb. RESULTS: The patients showed markedly improved quality of life and catch-up growth after the operations. The duodenal bulbs were of adequate size in follow-up gastrointestinal series. CONCLUSION: This technique will be useful in cases of functional duodenal obstruction with megaduodenum secondary to congenital duodenal malformations leading to blind loop syndrome.
BACKGROUND/PURPOSE: The mucosectomy of the aganglionic rectal mucosa has been performed transabdominally in the Soave procedure. Recently, mucosectomy with transanal approach was reported both in the laparoscopic and the open surgical procedure. However, the operative view and working field are restricted because the dissection has to be done in the anal canal. The authors report an innovative approach, an extra-anal mucosectomy, to perform mucosectomy in the Soave procedure for Hirschspung's disease in combination with the laparoscopic-assisted prolapsing technique. METHODS: Four patients underwent laparoscopic surgery for Hirschsprung's disease with extra-anal mucosectomy between 1995 and 1997. One 10-mm and 5-mm ports were used throughout the operation. The rectum was pulled out through the anal canal to create a rectal prolapse and was divided outside the anal canal. The mucosectomy was performed in the everted rectal mucosa outside the anal canal to the level of dentate line. The colon was sutured to the anal mucosa 2 mm above the dentate line. Mean operative time was 3 hours. RESULTS: The present technique made the whole mucosectomy possible under direct observation. CONCLUSION: The extra-anal mucosectomy in conjunction with a laparoscopic-assisted prolapsing technique seems to be a safe and reliable modality in the surgical treatment of Hirschsprung's disease.
A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6-49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6-100) days to onset of and median duration of response was 125 (36-305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1-3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1-3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.
BACKGROUND: A clinicopathological study of early gastric cancer with submucosal invasion was carried out in relation to lymph node metastasis. METHODS: A retrospective study was conducted of 245 patients with submucosal gastric cancer treated by gastrectomy combined with D2 lymph node resection between 1985 and 1994 in a university hospital. RESULTS: Lymph node metastasis was observed in 34 patients (14 per cent). The mortality rate due to recurrence in patients with lymph node metastasis (three of 34) was significantly higher than in those without lymph node metastasis (five (2 per cent) of 211) (chi2 = 3.95, 1 d.f., P < 0.05). Tumour size, depth of invasion, lymphatic involvement of cancer cells and preoperative diagnosis of advanced cancer correlated significantly with the presence of lymph node metastasis. When the submucosal carcinomas were classified into three categories according to depth of invasion by dividing the submucosal (sm) layer into three equal parts, sm1, sm2 and sm3, the incidence of lymph node metastasis increased from 2 per cent to 12 and 20 per cent respectively. CONCLUSION: When the pathological report reveals sm1 invasion after laparoscopic or endoscopic surgery, reoperation should not be necessary because sm1-carcinomas with diameters of less than 2 cm do not usually metastasize to the lymph nodes.