Katsuyuki Kunieda

Large solitary fibrous tumor of the retroperitoneum: report of a case.

We report an unusual case of a large solitary fibrous tumor (SFT) in the retroperitoneum. A 53-year-old man was referred to our hospital for surgical treatment of a swelling in the right flank with dull pain. Abdominal computed tomography (CT) and echograms showed a large encapsulated tumor compressing the right kidney and liver. At laparotomy, the tumor was found to be encapsulated but fixed to the capsule of the right kidney within a small area. Therefore, complete removal was achieved. The resected specimen was an encapsulated elastic hard tumor, 14 × 13 × 10 cm in size. Immunohistochemical studies revealed reactivity for CD34 and vimentin, but no staining for keratin, S-100, or Α-smooth muscle actin, confirming a diagnosis of SFT. Although SFT is usually associated with a favorable prognosis, close follow-up is recommended because of the limited information on its long-term behavior.

Antitumor Effects Induced by the Combination of TNP-470 as an Angiogenesis Inhibitor and Lentinan as a Biological Response Modifier in a Rabbit Spontaneous Liver Metastasis Model

Purpose:An angiogenesis inhibitor, TNP-470 (TNP), has shown promising results in tumor dormancy therapy, and we have been studying its antitumor effects using a rabbit spontaneous liver metastasis model. However, because inhibition was observed only at the step of micrometastasis, we examined the effects of combining TNP in the same model with a nonspecific immunopotentiator, lentinan (LNT), as a biological response modifier.Methods:The model was established by the inoculation of VX-2 tumors into the colon, and colectomy was subsequently performed, including the primary tumor. Combination (TNP + LNT) effects were evaluated in terms of the number and volume of metastatic nodules, microvessel density (MVD), expression of proliferating cell nuclear antigen (PCNA), and apoptosis, using immunohistochemical staining with anti-CD31, anti-PCNA monoclonal antibody, and the TUNEL (in situ nick end-labeling) method, respectively.Results:Angiogenesis was significantly inhibited in the TNP + LNT group, and the apoptotic index was also significantly higher than in the TNP or LNT groups. The positive expression of PCNA in the VX2 cells was reduced in the LNT alone and TNP + LNT groups, but not in the TNP alone group.Conclusion:These findings indicate that TNP-470 and lentinan could prove useful for preventing the development of metachronous liver metastases from colorectal cancers after curative resection.

Impact of splenectomy and immunochemotherapy on survival following gastrectomy for carcinoma: Covariate interaction with immunosuppressive acidic protein, a serum marker for the host immune system

The role of the spleen in tumor immunology is still controversial in that it can either enhance or suppress the antitumor immune response depending on the tumor-bearing host. To clarify this biphasic effect of the spleen, a clinical evaluation of splenectomy in conjunction with immunotherapy and the host immune status was performed in gastric cancer patients. The effect of splenectomy and immunotherapy in 253 gastric cancer patients enrolled in a prospective randomized trial (SIP) was analyzed using the Cox’s proportional hazards model in terms of the covariate interaction of the preoperative immunosuppressive acidic protein (IAP) level. In patients with high IAP levels (>580 μg/ml) with predicted negative antitumor immune reactions splenectomy improved the prognosis. In patients with lower IAP values, conversely, the preservation of the spleen and immunotherapy demonstrated a significant benefit to survival. The spleen was shown to have a biphasic activity in terms of its antitumor immune response depending on the IAP level of the patient. The effect of immunotherapy is significantly influenced by the activity of spleen cells. The preoperative IAP level is therefore considered to be a possible indicator for the effectiveness of splenectomy and immunotherapy in curatively resected gastric cancer patients.

Evaluation of Treatment for Synchronous Hepatic Metastases from Gastric Cancer with Special Reference to Long-Term Survivors

Abstract.Abstract.Purpose: The purpose of this study was to determine the most effective means of treating liver metastases from gastric cancer.Methods: We retrospectively examined 43 patients with liver metastases, but without peritoneal dissemination, who had received different forms of treatment.Results: The crude 5-year survival rates of patients who underwent gastrectomy with complete hepatectomy (curative gastrectomy), noncurative gastrectomy, and no gastrectomy were 33.3%, 3.7%, and 0%, respectively. The curative gastrectomy group showed the highest survival rate (not significant). The median survival of patients given hepatic artery infusion (HAI), systemic chemotherapy, and no chemotherapy were 353, 189, and 61 days, respectively. The patients given chemotherapy survived significantly longer than those not given chemotherapy. Three patients survived for more than 5 years without any signs of recurrence. The long-term survivors all had primary lesions without serosal invasion (T2) and no other noncurative factors. Two patients underwent curative gastrectomy and one underwent noncurative gastrectomy. All were given postoperative chemotherapy; as HAI in two cases, and as systemic chemotherapy in one case.Conclusion: These findings suggest that curative gastrectomy combined with HAI or systemic chemotherapy should be attempted for patients with primary tumors without serosal invasion or any other noncurative factors.

Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study (JFMC39-0902)

Objective This exploratory trial was performed to determine whether Daikenchuto accelerates recovery of gastrointestinal function in patients undergoing open colectomy for colon cancer. Methods A total of 386 patients undergoing colectomy at 1 of the 51 clinical trial sites in Japan from January 2009 to June 2011 were registered for the study (JFMC39-0902). Patients received either placebo or Daikenchuto (15.0 g/day, t.i.d) between post-operative day 2 and post-operative day 8. Primary end-points included time to first bowel movement, frequency of bowel movement and stool form. The incidence of intestinal obstruction was evaluated post-operatively. The safety profile of Daikenchuto until post-operative day 8 was also evaluated. Results The results for 336 patients (Daikenchuto, n = 174; placebo, n = 162) were available for statistical analysis. The time to first bowel movement did not differ significantly between the two groups. All patients reported having diarrhea or soft stools immediately after surgery, and the time until stool normalization (50th percentile) in the Daikenchuto and placebo groups was 6 days and 7 days, respectively. The placebo group had a significantly greater number of hard stools at post-operative day 8 (P = 0.016), and bowel movement frequency continued to increase until post-operative day 8 as well. In contrast, bowel movement frequency in the Daikenchuto group increased until post-operative day 6, however decreased from post-operative day 7 and was significantly lower at post-operative day 8 compared with the placebo group (P = 0.024). Conclusion The moderate effects of Daikenchuto were observed ∼1 week after the operation. Although Daikenchuto had an effect on gastrointestinal function after open surgery in patients with colon cancer, this study did not show its clinical benefits adequately.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study

EAGLE was a randomized, multicenter phase III study which evaluated the superiority of bevacizumab 10 mg/kg plus FOLFIRI compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC previously treated with first-line bevacizumab plus an oxaliplatin-based regimen. The results suggest that the higher 10 mg/kg dose offers no clear clinical benefit compared with bevacizumab 5 mg/kg in this setting.

Significance of Apoptosis Induced by Tumor Necrosis Factor-α and/or Interferon-γ Against Human Gastric Cancer Cell Lines and the Role of the p53 Gene

AbstractPurpose. The expression of the p53 gene in target cells plays an important role in the induction of apoptosis by tumor necrosis factor (TNF)-Α and interferon (IFN)-Γ. We herein present a study suggesting the existence of a caspase-independent pathway from p53 via insulin-like growth factor binding protein 3 (IGF-BP3) which acts as an apoptosis induction mechanism. Methods. MKN-45 (wild-type p53) or MKN-28 (mutant-type p53) was cultured with TNF-Α or IFN-Γ either alone or together. After 24 and 48 h, the apoptotic index (AI) was determined by Hoechst staining and then compared. To clarify whether the mechanism of apoptosis is induced by TNF-Α and/or IFN-Γ, apoptosis-related genes were examined by a cDNA on microarray analysis and a Western blot analysis. Results. (1) The AI for MKN-45 increased at 48 h in the presence of TNF-Α or IFN-Γ alone. (2) In the case of combination treatment using TNF-Α and IFN-Γ, the AI for MKN-45 was higher than those in the groups with a single treatment. (3) A cDNA microarray analysis showed that IGF-BP3, the TNF superfamily, and caspase 1 were all upregulated after treatment with the combination of TNF-Α and IFN-Γ. (4) A Western blot analysis of MKN-45 showed a reaction with an anti-IGF-BP3 antibody. Conclusions. These results suggest that the induction mechanism underlying apoptosis induced by TNF-Α and IFN-Γ might therefore involve the caspase-independent pathway via IGF-BP3.

Therapeutic effect of TNP-470 on spontaneous liver metastasis of colon tumors in the rabbit.

Abstract Even though angiogenesis inhibitor is thought to be one of the promising agents in tumor dormancy therapy, its optimal administration is still unknown. Therefore, the efficient protocol using TNP-470 was examined regarding its treatment affect against spontaneous liver metastases of colon tumors in the rabbit. A spontaneous liver metastases model was established in the rabbit by the inoculation of VX-2 tumors into the subserosal space of the colon. The therapeutic effect of TNP-470 was then investigated by monitoring both the number of metastatic nodules in the liver and the microvessel density (MVD) in the tumor by immuno-histochemical staining using anti-CD31 monoclonal antibody. TNP-470 did not show any effect on the primary tumor. It was able to reduce the metastatic spread to liver when it was administered at the microscopic metastatic stage. Treatment at this stage, however, was not able to sufficiently control the disease. These results indicated that TNP-470 could efficiently cause the tumor to enter into a dormant state by inhibiting angiogenesis when it was used at the initial stage of the metastatic process in the liver. Regarding its clinical application, TNP-470 might be useful for preventing the metachronous liver metastases of colorectal cancer when it is administered as adjuvant therapy after curative surgery.

Mediastinal lipoma: Report of a case

We experienced a case of mediastinal lipoma, which is considered to be a relatively rare disease. A 3-year-old girl was referred to Gifu University hospital because of fever and an abnormal shadow on her chest X-ray. The chest X-ray clearly showed a well-delineated tumor shadow which seemed to oppress the diaphragm and the right atrium in the right lower lung area. A computed tomogram (CT) of the chest showed a homogeneous mass localized on the right diaphragm and adjoining the right anterior chest wall and heart. The mass showed a fat density measuring about-100 HU. Magnetic resonance imaging (MRI) showed a high-intensity mass which was almost the same level as the subcutaneous fat on both the T1-weighted and T2-weighted images. Thoracotomy was performed and a fatty tumor was found. It arose from the right side of the pericardium and adjoined the diaphragm, the anterior chest wall, and the thymus. There was no adhesion between the tumor and the surrounding organs. It was resected easily and its contents were yellowish and homogeneous. The patient made an uneventful recovery and was discharged 10 days after the operation. Light microscopy showed a lipoma consisting of mature adipose tissue and no malignancy was found.

Evaluation of carcinoembryonic antigen mRNA in living, necrotic, and apoptotic gastric cancer cells by reverse transcriptase-polymerase chain reaction

AbstractPurpose. Positive mRNA expression of carcinoembryonic antigen (CEA) is often found in histologically negative lymph nodes, even in early gastric cancer. Therefore, we examined the differences in mRNA expression in MKN45 gastric cancer cells obtained under various cell conditions, namely, living cells, necrosis, and apoptosis, and assessed the possibility of detecting micrometastasis from these results. Methods. MKN45 cells were cultured with low-dose anticancer drugs (5-fluorouracil (5FU) + cisplatin (CDDP)) or cytokines (tumor necrosis factor alpha (TNFΑ) + interferon gamma (INFΓ)) to induce apoptosis, or subjected to freezing–thawing to induce necrosis. All the treated cells were stained with propidium iodide and Hoechst and the numbers of living, apoptotic, and necrotic cells were counted. CEA mRNA expression was examined by reverse transcriptase–polymerase chain reaction (RT-PCR) and DNA fragmentation was confirmed. Results. mRNA expression of CEA and CEA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) tended to decrease as the apoptotic index (AI) increased in the 5FU + CDDP group. On the other hand, almost no change was seen, even when the AI increased, in the TNFΑ + IFNΓ group. mRNA expression in the necrotic cells was the almost same as that in the living cells. Conclusion. Positive CEA mRNA expression by RT-PCR could suggest the existence of living cancer cells.