[The efficacy of neoadjuvant chemotherapy with S-1/CDDP (SP) to the patients with large type 3 and type 4 gastric cancer].

Here, I examined the efficacy of neoadjuvant chemotherapy( NAC) with S-1/CDDP( SP) in my hospital. The subjects were 8 patients with advanced gastric cancer who had undergone NAC since 2007 (7 men and 1 woman; median age, 70 years). The staging before the treatment was Stage II A: 1 patient, II B: 2 patients, III B: 3 patients, III C: 1 patient, and IV: 1 patient. The macroscopic type of 3 and 5 patients was large type 3 and type 4, respectively. Gastrectomy was performed following the NAC with SP. The NAC response rate was 62.5%. In the histological response criteria, 1 patient was grade 0, 2 patients were grade 1a, 2 patients were grade 1b, and 3 patients were grade 2. Adverse events following the NAC were in the acceptable range. We noted that the presence of Stage IV or grade 0 histological response criteria to NAC indicated poor prognosis. Thus, I believe that preoperative surgery after NAC in Stage III gastric cancer should be considered to be curative.

[A case that showed an improved quality of life for rectal gastrointestinal stromal tumor patient treated with cytoreductive surgery].

A 49-year-old man was admitted to another hospital with the complaint of difficulty in defecating. He underwent laparotomy, and investigation of the biopsy revealed a huge intraperitoneal tumor. He began to take imatinib in April 2008 following a diagnosis of gastrointestinal stromal tumor (GIST), but the tumor increased in size. He was referred to our hospital for oral administration of sunitinib to reduce the tumor size. The tumor was 30 cm in diameter, and there were several peritoneal metastases around the liver. He began to take sunitinib in February 2009. The tumor increased in size from August 2010 but a partial remission was noted. We performed cytoreductive surgery in April 2011 as palliative care, but the tumor size increased again in October. We performed cytoreductive surgery again, but he died in December 2011. Although cytoreductive surgery for GIST is a potential treatment option, we suggest supportive care.

[A case of liver metastases from gastric cancer treated with stereotactic body radiation therapy].

A 69-year-old man underwent distal gastrectomy in September 2007 for type 2 gastric cancer with liver metastasis (S5) in LM area (p-T2N3aM1, Stage IV). After the operation, we performed chemotherapy. But the liver metastasis was enlarged, so we performed a partial hepatectomy in July 2008. After hepatectomy, liver metastases appeared on S6 and S7 in February 2009. So we performed the fifth-line chemotherapy with paclitaxel. The effect of paclitaxel was not so good. Therefore, SBRT was performed for the liver metastases (S6/7 and S7) in December 2009 and February 2010. After SBRT, he had no recurrent tumor. SBRT was one of the effective treatments for liver metastases from gastric cancer.

[More than 20 years of long-term survival case of intraabdominal GIST by combined therapies with frequent surgeries].

A jejunum partial resection was performed on a 49-year-old female for jejunum leiomyosarcoma of 7 cm in 1990. She was resected four times for recurrent tumors from 1993 to 2004. We started an internal use of imatinib in 2003, because we could get a diagnosis of GIST. After the surgery of 2004, she stopped taking the internal use of imatinib, but an intraabdominal recurrence occurred in 2006 and she restarted taking the internal use of imatinib.

[A long-term survival case of hepatic metastases after curative gastrectomy by combined therapies].

A 74-year-old female was performed distal gastrectomy (f-T3N0H0P0CY0M0, Stage II) for gastric cancer in 2003. After 14 months, CT scan showed a metastasis in S7 segment of the liver. We performed chemotherapies until seventh-line and radio-frequency ablation (RFA). It finally got a long-term survival of 36 months postoperatively. RFA may be one of the useful therapies of liver metastasis from gastric cancer.

[A case report of long-term survival of advanced gastric cancer (P1CY1) after gastrectomy].

A-57-year-old male was performed a total gastrectomy (f-T3N2H0P1CY1M0, Stage IV) for gastric cancer in 2004. We kept performing chemotherapies until the seventh-line, and the patient at last had a long-term survival of 46 months after surgery. If we recognized a tumor that had a tendency to be progressive, the long-term survival may be obtained by changing a regimen as early as possible.

Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines.

Vitamin K2 (VK2) has a growth inhibitory effect on various types of cancer cells in vitro, and its efficacy has been demonstrated in clinical applications in a number of patients with leukemia and hepatocellular carcinoma. In this study, the effect of cell growth inhibition and apoptosis induction and the concomitant use of an anticancer agent by VK2 (menaquinone: MK4), on gastric cancer cell lines were examined. When 4 kinds of gastric cancer cells (KATO III, MKN7, MKN74 and FU97) were exposed to MK4, the cell growth was inhibited in an MK4 dose-dependent manner. Morphologically, apoptosis induced by MK4 was recognized in FU97, but only a slight number of apoptotic images was recognized in other cell lines. On the contrary, in all the cell lines, the percentage of APO2.7 positive cells increased significantly in the MK4-treated group as compared to the controls. Caspase-3 activity increased significantly in KATO III and FU97 as compared to the controls, while no significant differences were noted in MKN7 or MKN74. Moreover, in all the cell lines, the percentage of G0/G1-phase cells ( approximately 70% in KATO III and FU97, and > or =80% in MKN7 and MKN74) increased in comparison to the controls, suggesting that cell-cycle arrest had occurred. All of the gastric cancer cell lines were given MK4 in different concentrations and two kinds of anticancer agent, with the result that cell growth was inhibited by the anticancer agent in a dose-dependent manner when it was given with MK4 in concentrations of up to 10 microM. In conclusion, our results demonstrate that the effect of MK4 on apoptosis and cell-cycle arrest differs in differentiated (MKN7, MKN74) and undifferentiated (KATO III, FU97) gastric cancer cell lines, and that MK4 alone or with anticancer agents has an antitumor effect on gastric cancer cell lines.

[Biomarkers for neoplasmas in digestive organs].

This review is concerned with the usefulness and the problem of biomarkers for cancer of digestive organs. Carcinoembryonic antigen (CEA) is a most popular and useful tumor marker for cancer of digestive organs. Squamous cell carcinoma (SCC) antigen and CYFRA have been reported as a useful tumor marker for esophageal cancer. CEA and CA 19-9 are a good prognostic factor in gastric cancer patients. The post-operative increase of serum CEA can be a predictive marker for the patients of colorectal cancer. Development of a radioimmunoassay for highly sensitive detection of tumor markers, they are considered to be useful for monitoring after treatment. But are not useful for the early diagnosis. The diagnosis of hepatocellular carcinoma (HCC) is based mainly on serological markers, such as alpha-fetoprotein and PIVKA-II. The two are useful complementary markers of HCC because they do not correlate with each other. But the problem of the false-positive rate for the patients with chronic hepatitis or liver cirrhosis is still remained. A typical marker of pancreatic and bile duct cancer is carbohydrate antigen, but the sensitivity of these markers is only 50%. Recent molecular biological analysis may be used as effective biomarkers in the diagnosis, prognosis, therapy, and risk assessment of digestive cancer.

[A case of liver metastases from gastric cancer successfully treated with induced hypertensive chemotherapy].

We report a 77-year-old patient with gastric cancer who has survived 5 years after multidisciplinary treatment for both liver and brain recurrences. He underwent a D2 distal gastrectomy for macroscopically type 2 cancer at the lower third of the stomach on May 1997. The histopathological findings were as follows: O-IIc (SM2), poorly differentiated adenocarcinoma, pN2, ly2, v2, stage II. One year after surgery, a follow-up abdominal CT scan revealed multiple liver metastases. He received both hepatectomy and prophylactic hepatic arterial infusion of mitomycin C with induced hypertensive chemotherapy (IHC), a drug delivery system using the difference in blood flow between normal and tumor vessels by intravenously injected angiotensin-II. IHC was carried out monthly and the total dose of MMC was 74 mg (6 courses). Although he was disease-free for about 2 years, brain metastases were found on December 2000. He then underwent excision of the brain metastases and consecutive radiation by X-knife. Although he had a relapse of liver metastases on April 2002, he is still alive now. We consider multidisciplinary treatment including complete surgical resection as effective, even for recurrent or highly malignant gastric cancer.

[Two patients with metastatic ovarian tumor (Krukenberg's tumor) of gastric origin who underwent oophorectomy with paraaortic and intrapelvic lymph node dissection].

We report 2 patients with metastatic ovarian tumors of gastric origin who underwent oophorectomy with paraaortic and intrapelvic lymph node dissection, and showed a relatively good outcome. Case 1 A 40-year-old female with gastric cancer located in the MULE area underwent total gastrectomy with D3 lymph node dissection on June 2, 1989. Pathological Stage was IIIB and curability was B according to the JGCA classification. In month 56 after surgery, a left ovarian tumor was detected, and bilateral oophorectomy with paraaortic and intrapelvic lymph node dissection was performed. Signet ring cell carcinoma from the stomach was confirmed in both left ovary and lymph node around the left external iliac artery. In month 51 after the oophorectomy, the patient died from carcinomatous peritonitis. Case 2 A 23-year-old female with gastric cancer located in the M area underwent distal gastrectomy with D3 lymph node dissection on November 1, 2000. Pathological Stage was IV and curability was B according to the JGCA classification. In month 19 after surgery, a left ovarian tumor was detected, and left oophorectomy with paraaortic and intrapelvic lymph node dissection was performed. Poorly differentiated adenocarcinoma from the stomach was confirmed in both left ovary and paraaortic lymph nodes. Chemoradiation therapy was performed for the bone metastasis in lumbar vertebra, which was detected in month 4 after the oophorectomy, and partial response was achieved. As of June 2003, no other malignant lesion has been detected.

Measurement of serum thymidine phosphorylase levels by highly sensitive enzyme-linked immunosorbent assay in gastric cancer.

Thymidine phosphorylase (TP) is an enzyme that converts 5'-DFUR to 5-FU and also acts as an angiogenic factor. Measurement of serum TP levels has recently become possible by highly sensitive enzyme-linked immunosorbent assay (ELISA). We examined 38 patients with gastric adenocarcinoma to measure serum TP levels by highly sensitive ELISA method and tissue TP levels by conventional ELISA. In addition, immunohistochemical staining of normal and cancer tissues was also performed. Serum TP levels in patients with stages III and IV and inoperable or recurrent cancer were significantly higher than those in healthy controls. A high correlation was found between serum TP levels and tumor TP levels (r=0.65, p<0.0001). Moreover, serum TP levels were about 1/2500 of tumor TP levels. Tissue TP values in tumor were significantly higher than those in normal tissue. On the other hand, no significant differences among the cancer stages were found in either serum or tumor tissue. In conclusion, we demonstrate that serum TP levels strongly reflect tumor TP levels, and it may predict clinicopathological factors, prognosis, or sensitivity of anti-cancer drugs.

Effect of survivin on cell proliferation and apoptosis in gastric cancer.

We investigated the effect of expression of survivin, an apoptosis inhibiting protein, on cellular proliferation and apoptosis in gastric cancer and assessed its relation to the pathological characteristics of gastric cancer. Resected gastric cancer specimens from 42 patients (intestinal type; 21 cases and diffuse type; 21 cases) were evaluated. There were no significant differences in the clinicopathologic factors between the two groups. Survivin mRNA expression was measured using real-time reverse transcription-polymerase chain reaction, and survivin protein expression was evaluated by immunohistochemical staining. The Ki-67 index was adopted for cell proliferation scoring, and the ss-DNA positive rate as an apoptotic index. The survivin mRNA expression inversely correlated with the apoptotic index (p<0.05). Survivin mRNA expression (p<0.001) and survivin protein expression (p<0.001) were significantly higher in the diffuse type than the intestinal type. In conclusion, gastric cancer avoids cellular death by survivin expression and this tendency was more conspicuous in diffuse type gastric cancer.