Akihiko Kobayashi

Aggressive surgical treatment for T4 gastric cancer

Surgical treatment for locally advanced gastric cancer remains controversial, and many still question the benefits of extended resection. The aim of this study was to evaluate the effectiveness of combined resection of the involved organs with regard to survival in patients with gastric cancer. Between 1993 and 2000, among the 1638 patients with gastric cancer who underwent gastrectomy, 82 were found to have evidence of adjacent organ spread at laparotomy. A retrospective analysis of these patients was performed. Curative resections were carried out in 50 patients, whereas noncurative resections were performed in 32 patients. The 5-year survival rate in the group undergoing curative resection was 36.9%. The survival rate in the R0 group was significantly higher than the survival rate for patients undergoing noncurative resections. There was no significant difference in survival rates between patients with pT3 cancer and those with pT4 cancer. Seventy-one patients were pathologically proved to have lymph node metastasis, and the survival rate for patients with a lymph node ratio greater than 0.2 was lower than that in other groups. In multivariate analysis, peritoneal dissemination, lymph node ratio, and histologic findings were the predictors of survival. Patients with T4 gastric carcinoma, even with lymph node metastasis, might have benefited from aggressive surgery with curative intent.

Histological and prognostic importance of CD44+/CD24+/EpCAM+ expression in clinical pancreatic cancer

CD44+/CD24+/EpCAM+ cells have been reported to be cancer stem cells in pancreatic cancer; however, the histological and clinical importance of these cells has not yet been investigated. Here we clarified the characteristics of CD44+/CD24+/EpCAM+ cells in clinical specimens of pancreatic cancer using immunohistochemical assay. We used surgical specimens of pancreatic ductal adenocarcinoma from 101 patients. In view of tumor heterogeneity, we randomly selected 10 high‐power fields per case, and triple‐positive CD44+/CD24+/EpCAM+ expression was identified using our scoring system. The distribution, histological characteristics, and prognostic importance of CD44+/CD24+/EpCAM+ cells were then analyzed. As a result, the distribution of CD44+/CD24+/EpCAM+ cells varied widely among the 101 cases examined, and CD44+/CD24+/EpCAM+ expression was correlated with poor glandular differentiation and high proliferation. Survival analysis showed that CD44+/CD24+/EpCAM+ expression was not correlated with patient outcome; however, CD44+/CD24+ expression appeared to be correlated with poor prognosis. In conclusion, CD44+/CD24+/EpCAM+ expression overlapped with poorly differentiated cells and possessed high proliferative potential in clinical pancreatic cancer. In particular, the presence of double‐positive CD44+/CD24+ expression seemed to have clinical relevance, associating with poor prognosis.

Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including colorectal cancer (CRC), and we have investigated the potential use of FAS inhibitors for chemoprevention of liver metastasis of CRC in mice. Expression of FAS was evaluated in murine CRC cell lines Colon 26 and CMT 93. Cerulenin, a natural inhibitor of FAS, induced apoptosis in these cell lines. The ability of cerulenin to prevent development of liver metastatic lesions in Colon 26 was evaluated. The numbers and sizes of liver metastatic CRC tumors were significantly reduced by treating mice with cerulenin. Cerulenin treatment was associated with reduced levels of phosphorylated Akt in Colon 26 cells, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventive activity of this compound. Based on studies in mouse models, inhibiting FAS would be an effective strategy to prevent and retard growth of liver metastatic tumors of CRC that have high expression of this enzyme. (Cancer Sci 2010; 00: 000–000)

A malignant granular cell tumor of the stomach: Report of a case

We report herein what to our knowledge is the first documented case of a malignant granular cell tumor of the stomach. A 64-year-old woman was admitted to our hospital for investigation of gastric submucosal tumor. Endoscopy disclosed a large hemispherical mass located on the lesser curvature at the gastric antrum with a normal mucosal surface, and computed tomography (CT) revealed a solid tumor about 7 cm in diameter with clear margins. A laparotomy was carried out under the preoperative diagnosis of leiomyosarcoma of the stomach. A tumor was found in the gastric antrum, with extragastric extension to the hepatic hilum, and a distal partial gastrectomy was performed. However, a follow-up CT scan performed 21 months postoperatively revealed a solid tumor of about 10 cm in diameter with clear margins, situated between the liver and the transverse colon. This was subsequently diagnosed as local recurrence and a resection was carried out. Microscopic examination of both the first and second specimens showed that the tumor cells were large and polygonal, with medullary proliferation and finely granular eosinophilic cytoplasm. Mitotic figures were also present. Thus, the lesion was diagnosed as a malignant granular cell tumor of the stomach from the clinical and pathological findings.

Local interferon-α gene therapy elicits systemic immunity in a syngeneic pancreatic cancer model in hamster

The interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis and immunomodulation. We previously examined the two antitumor mechanisms, taking advantage of the fact that IFN‐α did not show cross‐species activity in its in vivo effect. In a nude mouse subcutaneous xenograft model using human pancreatic cancer cells, the expression of human IFN‐α effectively induced cell death of human pancreatic cancer cells, whereas mouse IFN‐α augmented antitumor immunity by stimulation of natural killer cells. Here, we extended our investigation to a syngeneic pancreatic cancer model, so that the integrated antitumor activity of local IFN‐α gene therapy, including the antiproliferative, proapoptotic, antiangiogeneic and immunomodulatory effects, can be evaluated rigorously. When a recombinant hamster IFN‐α adenovirus was injected into syngeneic subcutaneous tumors of hamster pancreatic cancer (PGHAM‐1) cells in Syrian hamster, tumor growth was significantly suppressed due to cell death and T cell‐ and natural killer cell‐mediated antitumor immunity. Moreover, in this case, tumor regression was observed not only for the injected subcutaneous tumors but also for the untreated tumors both in the peritoneal cavity and at distant sites. No significant systemic toxicity was observed in the treated hamsters. Moreover, the subcutaneous rechallenge of PGHAM‐1 cells was rejected in three of four cured hamsters from the initial tumor challenge. This study further demonstrated that local IFN‐α gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its multiple mechanisms of antitumor activity and its lack of significant toxicity. (Cancer Sci 2007; 98: 455–463))

Effective delivery of chemotherapeutic nanoparticles by depleting host Kupffer cells

Although chemotherapeutic nanoparticles would confer various advantages, the majority of administrated nanoparticles are known to be spoiled by the reticuloendothelial system (RES). Intending to more effectively deliver therapeutic nanoparticles to target regions in vivo, host RES, especially Kupffer cells in the liver, have been depleted ahead of drug administration. To demonstrate this hypothesis, clodronate liposomes were preinjected into BALB/c nude mice for depletion of Kupffer cells 2 days before, and pegylated liposomal doxorubicin (Doxil) at the doses of 1.25, 2.5 and 5.0 mg/kg was administered. As a result, doxorubicin accumulation in the liver was decreased from 36 to 26% injected dose/organ by the Kupffer cells depletion, and consequently, the plasma concentration of doxorubicin was significantly enhanced threefold (from 11 to 33 μg/mL) on day 1 at 1.25 mg/kg‐dose group. Doxorubicin accumulation in the tumor was increased from 0.78 to 3.0 μg/g‐tissue on day 3, and tumor growth inhibition by Doxil was significantly boosted (tumor volumes from 751 to 482 mm3 on day 24) by the Kupffer cells depletion. In conclusion, Kupffer cells depletion by clodronate liposomes enhanced the plasma concentration and antitumor effects of Doxil, and would be widely applicable for various clinical cancer chemotherapies using nanoparticles.

Primary hepatic leiomyosarcoma in a woman after renal transplantation: Report of a case

In contrast to malignant lymphomas or skin cancer, smooth muscle tumors including leiomyosarcoma are rarely associated with transplant recipients. We herein present a 33-year-old woman with end-stage renal disease who received a transplant at 27 years of age. Four years after the transplantation, at age 31, she underwent a mastectomy because of primary right breast cancer, which was found to be a 5-mm-sized mucinous carcinoma with no regional lymph node metastasis. Six years after the transplantation, a liver tumor was unexpectedly discovered. An explorative laparotomy revealed a well-encapsulated tumor occupying the posterior portion of the right lobe of the liver. The patient underwent a posterior segmentectomy. Histologically, the tumor possessed intermingling fascicles of spindle cells with eosinophilic cytoplasm and elongated nuclei. Based on an immunohistochemical examination, the tumor cells were positive for the muscle-associated antibody. In addition, RNA probes for Epstein-Barr virus were negative based on in situ hybridization. The histologic, immunohistochemical findings were considered to be diagnostic for leiomyosarcoma, which is a low-grade malignancy. Two years after surgery, the patient is doing well with no recurrence of liver tumors or breast cancer.

Massive hemorrhage in a patient with intestinal Behçet's disease: report of a case.

Abstract Major gastrointestinal bleeding is a rare manifestation of intestinal Behçets disease. We report herein the case of a 64-year-old man with intestinal Behçets disease complicated by myelodysplastic syndrome who suffered massive hemorrhage. Colonoscopy demonstrated ulceration of the entire colon from the cecum to the rectum, characterized by punched-out ulcers. Angiography demonstrated apparent extravasation of contrast material in the terminal ileum, and embolization was not successful. Continued and massive bleeding necessitated surgical resection of the involved segment of ileum; however, massive bleeding recurred. Re-endoscopy showed oozing hemorrhage from the multiple colon ulcerations. Intra-arterial prednisolone injection therapy was given, following which the melena gradually subsided and completely stopped within a few days.

MR Imaging of Reactive Lymphoid Hyperplasia of the Liver

IntroductionReactive lymphoid hyperplasia, also known as pseudolymphoma or nodular lymphoid lesion of the liver, is a rare benign lesion. It is mainly detected in the lung, stomach, small intestine, orbit, pancreas, skin, and breast. It remains difficult to distinguish reactive lymphoid hyperplasia from malignant disease clinically when it develops in the liver.Case Report We have recently encountered a patient with liver reactive lymphoid hyperplasia who had undergone colon cancer surgery.ConclusionPreoperative MR imaging showed some useful findings indicating reactive lymphoid hyperplasia.

Allogeneic MHC Gene Transfer Enhances an Effective Antitumor Immunity in the Early Period of Autologous Hematopoietic Stem Cell Transplantation

Purpose: In autologous hematopoietic stem cell transplantation (HSCT), lymphopenia-induced homeostatic proliferation of T cells is driven by the recognition of self-antigens, and there is an opportunity to skew the T-cell repertoire during the T-cell recovery by engaging tumor-associated antigens, leading to a break of tolerance against tumors. However, the homeostatic proliferation–driven antitumor responses seem to decline rapidly in association with tumor growth. We hypothesized that a tumor-specific immune response induced by an immune gene therapy could enhance and sustain homeostatic proliferation–induced antitumor immunity. Experimental Design: The antitumor effect of allogeneic MHC (alloMHC) gene transfer was examined at the early phase of the immune reconstitution after syngeneic HSCT. Results: Syngeneic HSCT showed significant tumor growth inhibition of syngeneic colon cancer cells within a period of 30 days; however, the tumor then resumed rapid growth and the survival of the mice was not prolonged. In contrast, when the alloMHC plasmid was intratumorally injected at the early phase after syngeneic HSCT, the established tumors were markedly regressed and the survival of recipient mice was prolonged without significant toxicities, whereas no survival advantage was recognized in recipient mice injected with a control plasmid. This tumor suppression was evident even in the other tumors that were not injected with the alloMHC plasmid. The antitumor response was characterized by the development of tumor-specific T cell– and natural killer cell–mediated cytotoxicities. Conclusion: The results suggest the efficacy and safety of integrating intratumoral alloMHC gene transfer with an autologous HSCT for the treatment of solid cancers.