[Robot-assisted general surgery].
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Digestive System Diseases↗
Biomedical subjects
Masaki Kitajima
Publications and source records attributed to Masaki Kitajima.
[A randomized phase II clinical trial of tailored CPT-11 + TS-1 vs TS-1 in patients with advanced or recurrent gastric carcinoma as the first-line chemotherapy (JFMC31-0301)].
The Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) has designed and initiated a randomized Phase II clinical trial planned as a first-line of chemotherapy for advanced or recurrent gastric cancer. The trial focuses on two groups and selecting the better of two regimens. The first group was given tailored CPT-11, adjusting individual optimal dosage using toxicity-based grading as an index in combination with TS-1, and the second group was given standard TS-1 treatment. The aim of this tailored dosage regimen for each individual patient is to continue chemotherapy as long as possible, and eventually, to prolong survival. In this trial, subsidiary pharmacokinetics analysis for the tailored arm is also proposed. We would like to introduce the significance and theory of tailored dosage chemotherapy in this paper.
Antineoplastic Combined Chemotherapy Protocols↗
Living donor liver transplantation with special reference to ABO-incompatible grafts and small-for-size grafts.
Living donor liver transplantation (LDLT) has developed on the basis of increased safety of conventional liver surgery and the need for expanding donor sources, especially in children. Indications for LDLT were soon extended to adult patients in Japan, where cadaveric donation was limited. The right liver is now routinely transplanted to adults to avoid small-for-size graft syndrome, even though the right liver graft has the disadvantages of less remaining donor liver and the question of donor safety. Assessing the suitable size or quality of the graft, as well as of the remnant donor liver, is one of the most important problems in adult LDLT. Although several tactics have been proposed to manage the small-for-size syndrome, their efficacy remains a question. We suggest that small-for-size syndrome is preventable by engaging in careful donor selection or using effective agents for hepatic microcirculatory disturbance control. Sometimes for LDLT only ABO-incompatible grafts are available from relatives, but they must be transplanted despite the expected poor outcome in adults and older children. To overcome the problems in this situation, we developed a novel protocol including intraportal infusion therapy with methylprednisolone, prostaglandin E1, and gabexate mesylate. Two adult patients undergoing ABO-incompatible LDLT have now survived 53 and 35 months after transplantation with good liver function. However, the other two patients suffered thrombotic microangiopathy postoperatively and died owing to cerebral hemorrhage or multiple organ failure, respectively. Further investigation is needed to improve the outcome of liver transplantation across the ABO blood group barrier.
ABO Blood-Group System↗
Induction of operational tolerance and generation of regulatory cells after intratracheal delivery of alloantigen combined with nondepleting anti-CD4 monoclonal antibody.
BACKGROUND: We previously showed that intratracheal delivery of alloantigen induced prolonged survival of fully allogeneic cardiac grafts in mice. Here, this treatment protocol was combined with nondepleting anti-CD4 monoclonal antibody (mAb) to induce operational tolerance. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of whole splenocytes from C57BL/10 (H-2b) mice or a 15-mer Kb peptide, with or without intraperitoneal administration of nondepleting anti-CD4 mAb (YTS177). Seven days later, C57BL/10 hearts were transplanted into the pretreated CBA mice. In addition, some naive CBA mice underwent adoptive transfer of splenocytes from pretreated CBA mice and transplantation of a C57BL/10 heart on the same day. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time, 12 days). Mice given intratracheal delivery of whole splenocytes or Kb peptide demonstrated prolonged graft survival (median survival time, 84 and 76 days, respectively). Concurrent administration of YTS177 and intratracheal delivery of splenocytes or Kb peptide resulted in indefinite graft survival. Mice with long-surviving C57BL/10 cardiac grafts showed acceptance of skin grafts from C57BL/10 mice but not BALB/c mice, demonstrating that operational tolerance had been induced. Adoptive transfer of splenocytes from mice pretreated with intratracheal delivery of splenocytes or Kb peptide plus YTS177 induced indefinite survival of cardiac grafts in secondary recipients, indicating that regulatory cells had been generated. CONCLUSION: In a murine model, intratracheal delivery of donor splenocytes or Kb peptide combined with YTS177 induced operational tolerance and generated regulatory cells.
Adoptive Transfer↗
CD27/CD70, CD134/CD134 ligand, and CD30/CD153 pathways are independently essential for generation of regulatory cells after intratracheal delivery of alloantigen.
BACKGROUND: We investigated whether blockade of tumor necrosis factor receptor-ligand pathways could generate regulatory cells induced by intratracheal delivery of alloantigen. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of splenocytes (1x10(7)) from C57BL/10 (H-2b) mice and intraperitoneal administration of monoclonal antibody (mAb) specific for CD70, CD134 ligand (CD134L), CD153, or CD137L. Seven days later, C57BL/10 hearts were transplanted into pretreated CBA mice. Some naive CBA mice underwent adoptive transfer of splenocytes (5x10(7)) from pretreated CBA mice and transplantation of a C57BL/10 heart on the same day. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST] 12 days). Pretreatment with intratracheal delivery of C57BL/10 donor splenocytes prolonged graft survival significantly (MST 84 days). Mice given intratracheal delivery of alloantigen plus anti-CD70, anti-CD134L, or anti-CD153 mAb, but not those given intratracheal delivery of alloantigen plus anti-CD137L mAb, rejected their graft acutely (MST 16, 14, 10, and 65 days, respectively). Adoptive transfer of splenocytes from mice pretreated with intratracheal delivery of alloantigen plus anti-CD70, CD134L, or CD153 mAb did not prolong survival of C57BL/10 cardiac grafts in naive secondary CBA recipients (MST 14, 11, and 11 days, respectively), whereas adoptive transfer of splenocytes from mice given intratracheal delivery of alloantigen plus anti-CD137L mAb did (MST 75 days). CONCLUSION: The CD27/CD70, CD134/CD134L, and CD30/CD153 pathways are independently required for generation of regulatory cells in our model.
Adoptive Transfer↗
Lewis type 1 antigen synthase (beta3Gal-T5) is transcriptionally regulated by homeoproteins.
The type 1 carbohydrate chain, Galbeta1-3GlcNAc, is synthesized by UDP-galactose:beta-N-acetylglucosamine beta1,3-galactosyltransferase (beta3Gal-T). Among six beta3Gal-Ts cloned to date, beta3Gal-T5 is an essential enzyme for the synthesis of type 1 chain in epithelium of digestive tracts or pancreatic tissue. It forms the type 1 structure on glycoproteins produced from such tissues. In the present study, we found that the transcriptional regulation of the beta3Gal-T5 gene is controlled by homeoproteins, i.e. members of caudal-related homeobox protein (Cdx) and hepatocyte nuclear factor (HNF) families. We found an important region (-151 to -121 from the transcription initiation site), named the beta3Gal-T5 control element (GCE), for the promoter activity. GCE contained the consensus sequences for members of the Cdx and HNF families. Mutations introduced into this sequence abolished the transcriptional activity. Four factors, Cdx1, Cdx2, HNF1alpha, and HNF1beta, could bind to GCE and transcriptionally activate the beta3Gal-T5 gene. Transcriptional regulation of the beta3Gal-T5 gene was consistent with that of members of the Cdx and HNF1 families in two in vivo systems. 1) During in vitro differentiation of Caco-2 cells, transcriptional up-regulation of beta3Gal-T5 was observed in correlation with the increase in transcripts for Cdx2 and HNF1alpha. 2) Both transcript and protein levels of beta3Gal-T5 were determined to be significantly reduced in colon cancer. This down-regulation was correlated with the decrease of Cdx1 and HNF1beta expression in cancer tissue. This is the first finding that a glycosyltransferase gene is transcriptionally regulated under the control of homeoproteins in a tissue-specific manner. beta3Gal-T5, controlled by the intestinal homeoproteins, may play an important role in the specific function of intestinal cells by modifying the carbohydrate structure of glycoproteins.
Amino Acid Motifs↗
Induction of indefinite survival of fully allogeneic cardiac grafts and generation of regulatory cells by intratracheal delivery of alloantigens under blockade of the CD40 pathway.
BACKGROUND: The authors previously showed that intratracheal delivery (ITD) of donor splenocytes induced prolonged survival of fully allogeneic cardiac grafts in mice. In this study, this treatment protocol was combined with blockade of the CD40 pathway in an attempt to induce operational tolerance. METHODS: CBA mice were given donor splenocytes (1x107) or Kb peptide (100 microg) by ITD with or without antibody specific for mouse CD40 ligand (MR1, 200 microg) 7 days before transplantation of a C57BL/10 heart. Also, splenocyte (5 x 107) from primary recipient CBA mice given ITD of donor splenocytes or Kb peptide plus MR1 were adoptively transferred into naive CBA secondary recipients 7 days after the pretreatment and C57BL/10 hearts were transplanted into those recipients the same day. RESULTS: ITD of donor splenocytes and Kb peptide induced prolonged survival of cardiac grafts (median survival time [MST], 74 and 56 days, respectively), whereas naive control mice and mice pretreated with syngeneic splenocytes had acute graft rejection (MST in both groups, 7 days). When MR1 was included, all grafts survived indefinitely (>200 days), but mice pretreated with MR1 alone had graft rejection (MST, 54 days). Mice bearing cardiac grafts had acceptance of skin grafts from C57BL/10 but not BALB/c mice, demonstrating that operational tolerance was induced. Secondary recipients given adoptive transfer of splenocytes from primary recipients of the combined treatment had acceptance of C57BL/10 grafts, suggesting that regulatory cells were generated within 7 days of pretreatment. CONCLUSIONS: ITD of donor splenocytes or Kb peptide under blockade of the CD40 pathway induced operational tolerance and generated regulatory cells.
Adoptive Transfer↗
High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells.
BACKGROUND: The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens. METHODS: CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed. RESULTS: Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2. CONCLUSION: AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.
Animals↗
Emerging patterns of practice in the implementation and application of sentinel lymph node biopsy in breast cancer patients in Japan.
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Breast Neoplasms↗
Chemosensitivity testing--present and future in Japan.
Radical surgery with extended lymph node dissection is the first and only curative treatment of gastrointestinal cancer. Although the combined cancer chemotherapy has achieved 30%-50% response rates, a controversy still remains over the significance of the adjuvant cancer chemotherapy after surgery. To break through this limitation, we have introduced the chemosensitivity test to evaluate the appropriate adjuvant cancer chemotherapy for advanced gastrointestinal cancer. Our plural studies indicated that the chemosensitivity test would be useful in evaluating the appropriated adjuvant chemotherapy by increasing survival in the sensitive group. Recently, the molecular targets have been clarified for the conventionally available antitumor agents, e.g., thymidylate synthetase for 5-fluorouracil, ATP-binding cassette transporters for anthracyclines, glutathione-related detoxification for platins, and topoisomerase I for CPT-11, which will be applied for dinical use in evaluating the appropriate cancer chemotherapy. The chemosensitivity test is approved as "advanced clinical medicine" by the Japanese Ministry of Health, Welfare, and Labor in five institutes at present. Because complete dissection and chemosensitivity test-guided adjuvant chemotherapy will result in a survival benefit for patients with advanced gastrointestinal cancer, this test should be approved as "social insurance" for further wide clinical application.
Antineoplastic Agents↗
Combined antitumor activity of 7-hydroxystaurosporine (UCN-01) and tamoxifen against human breast carcinoma in vitro and in vivo.
BACKGROUND: 7-Hydroxystaurosporine (UCN-01) was originally isolated as a protein kinase C inhibitor and has shown antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to the S phase and is associated with inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor p21, leading to dephosphorylation of retinoblastoma (Rb) protein. Tamoxifen (TAM) traps cancer cells in the G1 phase, suggesting that the mechanism of action of TAM is similar to that of UCN-01. The present study was conducted to assess the antitumor activity of UCN-01 combined with TAM against human breast carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: MCF-7 cells were treated with UCN-01, TAM, or UCN-01 combined with TAM at various concentrations in vitro. The antitumor effect was evaluated as the inhibition rate (I.R.%) by MTT assay. Two human breast carcinoma xenografts in nude mice, MCF-7 and Br-10, were treated with UCN-01, TAM or both agents together. The expression of p21 and the phosphorylation status of Rb protein in MCF-7 cells were detected by Western blotting. RESULTS: UCN-01 or TAM alone inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. Combined treatment with UCN-01 followed by TAM inhibited the growth of MCF-7 cells synergistically and no significant differences in cytotoxicity were observed between the different sequences of UCN-01/TAM and TAM/UCN-01. Combination treatment with UCN-01 and TAM against MCF-7 and Br-10 in vivo exhibited superior antitumor effects compared with either agent treatment alone. Although 0.1 microg UCN-01 per ml (I.R.: 48.1%) or 2 microM TAM (I.R.: 31%) induced p21 expression, phosphorylation of Rb protein was not inhibited. However, combination treatment with UCN-01 and TAM at the same concentrations resulted in an I.R. of 67% and dephosphorylation of Rb protein. CONCLUSION: The present study suggests that combining UCN-01 and TAM could result in augmented cytotoxicity because of their similar mechanism of action. This combination may have potential clinical applications for breast cancer treatment, by reducing the toxicity of UCN-01.
Animals↗
Elevated expression of caveolin-1 at protein and mRNA level in human cirrhotic liver: relation with nitric oxide.
BACKGROUND: Caveolin, the principal structural protein of caveolae, binds with endothelial nitric oxide synthase (eNOS) leading to enzyme inhibition. This study examined the expression of caveolin and eNOS at the protein and mRNA levels in patients with hepatocellular carcinoma and hepatitis C-related cirrhosis, and in control noncirrhotic liver specimens obtained from patients with metastatic liver carcinoma. METHODS: Anti-eNOS, anti-caveolin-1, and anti-calmodulin antibodies were used for Western blotting. For in situ hybridization (ISH), human eNOS and caveolin-1 peptide nucleic acid probes were used with a catalyzed signal amplification system. RESULTS: Western blotting showed marked overexpression of caveolin-1 protein in cirrhotic liver, while caveolin-1 was almost undetectable in control liver tissue. Endothelial NOS was expressed at a slightly higher level in cirrhotic liver than in control liver tissue. Calmodulin was expressed abundantly in control liver tissue and at a low level in cirrhotic liver tissue. By ISH, eNOS mRNA was localized on portal vein and hepatic lining cells, and caveolin-1 mRNA was almost undetectable in normal liver tissue. In cirrhotic liver tissue, caveolin-1 mRNA was overexpressed on hepatic sinusoidal lining cells, while eNOS mRNA expression was similar to that in normal liver. CONCLUSIONS: Enhanced caveolin-1 expression may be associated with a significant reduction in NO catalytic activity in cirrhosis.
Aged↗
Spindle cell carcinoma of the intrahepatic bile duct in a patient with primary sclerosing cholangitis.
We present a case of spindle cell carcinoma of the intrahepatic bile duct that developed in a 34-year-old man with primary sclerosing cholangitis. At the time of presentation, the patient had a 10-year history of primary sclerosing cholangitis. A mass was found in the hepatic hilus and was resected surgically. The tumor was composed predominantly of spindle cells, and a small portion of the tumor appeared to be adenocarcinomatous by histology. Histological and immunohistochemical findings suggested that the spindle cells were epithelial in origin; thus, this tumor was identified as a spindle cell carcinoma. Spindle cell carcinomas arising in the bile duct are extremely rare. Furthermore, the coexistence of spindle cell carcinoma and primary sclerosing cholangitis has not been reported thus far. We were able to follow up the entire course of this rare case. In this case report, we describe the clinicopathological findings of this case and review the literature concerning this type of tumor.
Adult↗
Diffuse cavernous hemangioma of the rectum: report of a case.
Cavernous hemangioma of the rectum (CHR) is an uncommon benign vascular lesion, which mainly affects young adults. The rectosigmoid area is the most common site of cavernous hemangioma in the gastrointestinal tract. CHR is often misdiagnosed due to a lack of knowledge of the clinical features. We report a case of CHR, focusing on the clinical features, diagnostic procedures used, and treatments given. This patient was finally treated effectively with abdominoperineal resection. Thorough preoperative imaging is necessary to confirm the diagnosis and evaluate both the site and extent of the hemangioma. Magnetic resonance imaging (MRI) provides information about the dimensions of the tumor and involvement of the adjacent structures with its high resolution and multiplanar capability, without the use of contrast medium. Moreover, endorectal surface coil MRI depicts the five separate layers of the bowel wall and internal and external sphincter more clearly than the conventional body coil MRI.
Female↗
Complete response of a highly advanced gastric carcinoma to preoperative chemoradiotherapy with S-1 and low-dose cisplatin.
S-1 has been developed as a new oral anticancer drug, based on the biological modulation of 5-fluorouracil. We report a patient with highly advanced gastric carcinoma who was treated successfully with a new combination chemoradiotherapy using S-1 and cisplatin (CDDP). The patient was a 37-year-old man who was diagnosed with advanced gastric carcinoma (T4N3M0) that had invaded the diaphragm and the paraaortic tissues. Remarkable tumor reduction was observed in the primary tumor and metastatic lymph nodes around the stomach after three cycles of the therapy. Radiological examination before surgery determined that a partial response (PR) had been achieved by the initial therapy. Adverse effects included only a gastrointestinal disorder that was limited to grade 2 when low-dose CDDP was utilized in the regimen, while an initial high dose of CDDP resulted in grade 3 toxicity, due to myelosuppression. The patient underwent curative surgery, including total gastrectomy, D2 lymph node dissection, and splenectomy, after completion of the radiochemotherapy regimen. No surgical complication was observed. No tumor cells were detected by pathological evaluation of the resected stomach and all the regional lymph nodes, confirming a pathological complete response (CR; grade 3). This regimen is a potent treatment for advanced gastric carcinoma, especially when used as preoperative chemotherapy to control cancer cells.
Adult↗
Gastric carcinoid tumors with aggressive lymphovascular invasion and lymph node metastasis.
We report a patient with multiple gastric carcinoid tumors without hypergastrinemia. An abdominal computed tomography (CT) scan was performed in a 66-year-old Japanese man who had abdominal discomfort. An abnormal, round, 2.5 cm mass close to the lesser curvature of the stomach was detected. Multiple small gastric carcinoid tumors were also detected by endoscopy. A total gastrectomy with lymph node dissection was performed after it was determined that the round mass was a lymph node metastasis of carcinoid tumor. Further pathological investigation of the surgical specimen revealed multiple gastric carcinoid tumors with severe lymphovascular invasion. The carcinoid tumors in the present patient were not related to hypergastrinemia. These lesions could not be grouped as any of the three types of gastric carcinoid tumors in the recent classification. Furthermore, as a simple distal gastrectomy is the standard treatment for multiple carcinoid tumors of the stomach, we recommend that a precise histopathological evaluation should be performed before an appropriate curative surgical treatment is selected.
Abdominal Pain↗
Colorectal motility induction by sacral nerve electrostimulation in a canine model: implications for colonic pacing.
PURPOSE: This study investigated the role of the sacral nerves in the mechanism of defecation using adult mongrel dogs. The possibility of designing a colonic pacemaker as a new therapeutic device to treat defecation disturbances, such as fecal incontinence and severe constipation, is also discussed. METHODS: Colorectal motility during spontaneous defecation was monitored with force strain-gauge transducers implanted in the proximal, distal, and sigmoid colon, rectum, and internal anal sphincter. Under general anesthesia, the sacral nerve was stimulated electrically, and the colorectal motility response was examined. RESULTS: During spontaneous defecation, three characteristic motility patterns were observed: 1) giant migrating contractions of the colon were propagated to the rectum or anus; 2) the rectum relaxed before the giant migrating contractions were propagated; and 3) the internal anal sphincter was relaxed during the propagation of the giant migrating contraction. Sacral nerve stimulation elicited the following three unique responses: 1) contractile movements were propagated from the distal colon to the rectum; 2) a relaxation response was noted in the rectum; and 3) the internal anal sphincter exhibited a relaxation response. The duration and propagation velocity of the contractile responses and the duration of relaxation responses elicited by electrical stimulation of the sacral nerve were similar to those that occurred during spontaneous defecation, but their amplitudes were smaller. CONCLUSION: The coordinated processes of the colon and anorectum during defecation were affected by the sacral nerves. This suggests that it is possible to design a colonic pacemaker to control lower colonic and rectal movements.
Animals↗
A role of cytokines in OK-432 injection therapy for cystic lymphangioma: an approach to the mechanism.
PURPOSE: This study examines cytokine levels of aspirates from cystic lymphangiomas after injection of OK-432 and over the course of several weeks to better understand the process of tumor regression. METHODS: Fluids aspirated from lymphangioma cysts of 3 patients were collected sequentially before and after OK-432 injection. Mononuclear cells (MNCs) were separated and cultured with or without OK-432. Vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR1), sVEGFR2, transforming growth factor beta-1 (TGF-beta1), interleukin (IL)-6, IL-8, IL-12+p40, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels in the supernatants of the aspirates and the culture supernatants of MNCs were then measured by ELISA. RESULTS: The aspirates exhibited a marked elevation in IL-6, IL-8, VEGF, and TGF-beta1 levels for a few weeks after the OK-432 injection. IL-6, IL-8, IL-12+p40, TNF-alpha, and IFN-gamma levels were elevated in the culture supernatants of the MNC cultured with OK-432 for up to 9 days. All the tumors regressed significantly, with sclerotic change, within 3 months after OK-432 injection. CONCLUSIONS: Cytokine production is maintained for a few weeks after OK-432 injection. Fibrotic changes may be another main mechanism in tumor regression in addition to cytotoxic effects on lymphangioma cells. A close relationship between cytokines from intracystic cells and lymphangioma cells is suggested.
Child, Preschool↗