Yoshimi Akamo

Alteration of integrins by interleukin-1α in human pancreatic cancer cells

Introduction Adhesion of tumor cells to extracellular matrix (ECM) proteins plays an important role in tumor invasion and metastasis. Aims To investigate the expression of integrins in human pancreatic cancer cell lines and its alteration by interleukin (IL)-1&agr; to examine the mechanism of adhesion of metastatic human pancreatic cancer cells to ECM proteins. Methodology The expression of integrin subunits and their alteration by IL-1&agr; were examined by flow-cytometric analysis and cellular enzyme-linked immunosorbent assay in three metastatic human pancreatic cancer cell lines (AsPC-1, BxPC-3, and SW1990) and two nonmetastatic cancer cell lines (PaCa-2 and PANC-1). In addition, assays of cancer cell adhesion to ECM proteins were performed to investigate if increased integrin expression actually affected the adhesive interaction between cancer cells and the putative integrin ECM ligands. Results The &agr; 6 subunit expressed in metastatic cancer cells was enhanced by IL-1&agr;. Metastatic cancer cells also showed preferential adherence to laminin compared with nonmetastatic cancer cells, and this was enhanced by IL-1&agr;. Conclusion In pancreatic cancer, the enhancement of &agr; 6 &bgr; 1 integrin by IL-1&agr; through IL-1 receptor type I, as well as the expression of &agr; 6 &bgr; 1 integrin, plays an important role in metastasis formation.

Phosphoinositide 3‐kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo

In order to block peritoneal metastasis of pancreatic cancer cells, we have attempted to block the signal transduction pathway involving hyaluronan (HA), Src, phosphoinositide 3‐kinase (PI3K) and Akt. We examined the effects of Src, PI3K and Akt inhibitors on pancreatic cancer cell motility, invasion and metastasis. The pancreatic cancer cell line SW1990, known to cause peritoneal metastasis efficiently in nude mice, was used in this study. SW1990 cells were stimulated by HA to induce Akt phosphorylation. Then, the inhibitory effects of PI3K and Src kinase inhibitors were examined. Cell motility and cell migration assays were adopted to assess the cancer cell motility and its migration capability. We also examined the therapeutic efficacies of PI3K inhibitor wortmannin on peritoneal metastasis of SW1990 cells in the nude mouse model. Stimulation of SW1990 cells by HA markedly induced the Src‐PI3K‐Akt signaling, thus enhancing cancer cell motility and its migration. Significantly, we found that wortmannin could exert marked inhibition of the peritoneal metastasis of SW1990 in nude mice in vivo. These findings indicate that the PI3K‐Akt signaling pathway plays an essential role in peritoneal metastasis and PI3K inhibitors such as wortmannin can be novel modalities to prevent peritoneal metastasis of invasive cancers such as pancreatic cancer. (Cancer Sci 2009; 100: 770–777)

Chemotherapy Targeting Regional Lymph Nodes by Gastric Submucosal Injection of Liposomal Adriamycin in Patients with Gastric Carcinoma

We investigated the delivery of adriamycin (ADR) to the regional lymph nodes of the stomach following the gastric submucosal injection of liposomal adriamycin (Lipo‐ADR) in 34 gastric carcinoma patients, as well as following intravenous administration of free ADR (F‐ADR) in another 18 patients. Prior to radical gastrectomy, Lipo‐ADR was endoscopically injected into the gastric submucosa adjacent to the primary tumor via a needle‐tipped catheter. After Lipo‐ADR injection, the ADR concentration in the primary and secondary drainage lymph nodes was higher than in the other regional lymph nodes. Thus, the regional nodes more susceptible to metastasis showed higher levels of ADR. In contrast, the intravenous administration of F‐ADR produced a similar and far lower ADR concentration in all the nodes. Delivery of ADR to the primary drainage lymph nodes following injection of 5 ml of Lipo‐ADR was compared with delivery to the left gastric artery lymph nodes after intravenous administration of an equal dose of F‐ADR. The ADR levels (μg/g) after gastric submucosal injection were 15.1±8.30 on day 1 (n = 4); and 11.9±4.80 on day 4 (n = 6). Those after intravenous administration were 0.29±0.10 on day 1 (n = 4); and 0.36±0.0 on day 4 (n = 2). The differences between the two groups were significant (P<0.05). The ADR levels after the gastric submucosal injection were far higher than those after intravenous administration. These findings indicate that the gastric submucosal injection of Lipo‐ADR can specifically deliver ADR to the regional lymph nodes at high concentrations. Such preoperative adjuvant chemotherapy targeting the regional lymph nodes may be useful for preventing the lymph node recurrence of gastric carcinoma.

Limiting vein puncture to three needle passes in subclavian vein catheterization by the infraclavicular approach.

PurposeWith central venous catheterization, each additional vein puncture raises the risk of complications. We assessed the rate of failure and complications using a limiting rule whereby the number of needle passes for subclavian vein catheterization was restricted to three.MethodsA prospective clinical trial was conducted between September 2001 and December 2003 in a university hospital surgical department. Two hundred and thirty-two adult patients were enrolled to undergo subclavian vein catheterization under non-emergency conditions. The patients were subjected to right subclavian vein catheterization by the infraclavicular approach. Vein puncture failure was defined as such if venipuncture was not accomplished after three attempts. Any arterial puncture was judged to be a failure immediately.ResultsVein puncture failure occurred in nine patients (3.9%), and included two arterial punctures (0.9%). No other complications, such as pneumothorax, hemothorax, plexus lesion, mediastinal hematoma or bleeding, or air embolism, were observed. In multivariate analyses, a close to average body mass index (weight in kilograms divided by the square of the height in meters, odds ratio 0.74; 95% confidence interval 0.56–0.97; P = 0.028) was associated with a low risk of failure.ConclusionLimiting the number of needle passes to three may therefore prevent mechanical complications. A low body mass index was predictive of vein puncture failure.

Granulocyte-colony stimulating factor producing rectal cancer

BackgroundGranulocyte-colony stimulating factor (G-CSF)-producing cancer has been reported to occur in various organs, especially the lung. However, G-CSF-producing colorectal cancer (CRC) has never been reported in the English literature.Case presentationA 57-year-old man was admitted for the surgical removal of a rectal cancer. Some hepatic tumors in the liver were revealed concurrently, and their appearance suggested multiple liver metastases. Low anterior resection was performed. with the help of histopathological examination and immunohistochemical studies, we diagnosed this case to be an undifferentiated carcinoma of the rectum. After the operation, the white blood cell (WBC) count increased gradually to 81,000 cells/μL. Modified-FOLFOX6 therapy was initiated to treat the liver metastases, but there was no effect, and peritoneal dissemination had also occurred. The serum level of G-CSF was elevated to 840 pg/mL (normal range, <18.1 pg/mL). Furthermore, immunohistochemistry with a specific monoclonal antibody against G-CSF was positive; therefore, we diagnosed this tumor as a G-CSF-producing cancer. The patient died from rapid growth of the liver metastases and peritoneal dissemination 2 months after surgery.ConclusionThis is the first case of G-CSF-producing rectal cancer, and its prognosis was very poor.

Successful paclitaxel-based chemotherapy for an alpha-fetoprotein-producing gastric cancer patient with multiple liver metastases.

BackgroundAlpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis.Case presentationA 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date.ConclusionWe consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases.

Antitumor effect of liposome-entrapped adriamycin administered via the portal vein

We examined the distribution in tissues and antitumor effect of freeze‐dried liposome‐entrapped adriamycin (Lipo‐ADM) administered via the portal vein to rabbits bearing VX2 tumors. Liposomes composed of egg phosphatidylcholine (cholesterol 50 mol%) were used as drug carriers. The liver concentration of ADM increased after delivery and cardiac uptake decreased compared with free drug treatment. The in vivo antitumor effect of Lipo‐ADM was determined in rabbits inoculated with VX2 tumor. Repeated injections of free ADM via the portal vein prolonged the life span of tumor‐bearing rabbits. The life span was further prolonged by Lipo‐ADM treatment compared with the control group and the free ADM group. Histological examination revealed that the damage to the liver caused by Lipo‐ADM administered via the portal vein did not differ from that observed in animals treated with free ADM. These results indicate that portal vein administration of Lipo‐ADM may be more effective in dealing with liver metastases than treatment with free ADM and may be therapeutically useful without toxic side effects.

Delivery of Lymph Node‐targeted Adriamycin by Gastric Submucosal Liposomal Injection in Rabbits

We investigated the feasibility of specifically delivering adriamycin (ADR) to the regional lymph nodes via gastric submucosal injection of liposomal adriamycin (Lipo‐ADR) in a rabbit model. We determined the tissue distribution of ADR for up to 7 days after the gastric submucosal injection of Lipo‐ADR (0.4 nag/kg of ADR potency) and i.v. administration of an equal dose of free adriamycin (F‐ADR). The area under the ADR concentration‐time curve (AUC) of the regional lymph nodes was 85.4 μg‐day/g after gastric submucosal injection of Lipo‐ADR and 8.44 μg‐day/g after i.v. administration of F‐ADR. The targeting index of the regional lymph nodes, defined as the ratio of the AUC after gastric submucosal injection of Lipo‐ADR to the AUC after i.v. administration of F‐ADR, was 10.1. Gastric submucosal injection of Lipo‐ADR enhanced lymph node‐specific delivery of ADR compared with i.v. administration of F‐ADR. The targeting index was 0.47 for the heart, 0.25 for the bone marrow, and 0.41 for the spleen, indicating that gastric submucosal injection of Lipo‐ADR reduced delivery of ADR to these organs, as compared with i.v. administration of F‐ADR. These data demonstrate that gastric submucosal injection of Lipo‐ADR is well suited for specific delivery of ADR to the regional lymph nodes, suggesting that this method of administration may be useful in delivering preoperative adjuvant chemotherapy for preventing gastric cancer recurrence.

Solitary Intraperitoneal Recurrence of α-Fetoprotein-Producing Gastric Carcinoma : Report of a Case

AbstactA solitary recurrence of gastric carcinoma in the peritoneal cavity is extremely rare. We herein present a case of solitary intraperitoneal recurrence in a patient with α-fetoprotein (AFP)-producing gastric carcinoma. As far as we can determine, this is the first report of such a form of recurrence in a patient with gastric carcinoma who underwent a successful resection. A review of our eight patients who had AFP-producing gastric carcinoma showed a frequent association with hepatic metastasis and a poor prognosis as has been reported previously. Our patient received intra-arterial chemotherapy with low-dose cisplatin and 5-fluorouracil to prevent hepatic recurrence, but eventually developed multiple hepatic metastases after ceasing this therapy. Therefore, adjuvant intra-arterial chemotherapy may have altered the site of first recurrence in this patient.

Palliative Percutaneous Jejunal Stent for Patients with Short Bowel Syndrome

Gastrointestinal obstruction is a common preterminal event in patients with gastric and pancreatic cancer who often undergo palliative bypass surgery. Although endoscopic palliation with self-expandable metallic stents has emerged as a safe and effective alternative to surgery, experience with this technique remains limited. In particular, a proximal jejunal obstruction requires more technical expertise than a duodenal obstruction. Palliative treatment modalities include both surgical and nonsurgical approaches. In this report, we describe the successful placement of self-expandable metallic stents at the proximal jejunum using a combination of percutaneous endoscopic, intraoperative, and transstomal stenting. Usually endoscopy is not indicated in cases of proximal jejunal obstruction, but some cases may require palliative endoscopy instead of bypass operation.