[A case of primary unknown cancer responding to CDGP/S-1].

A 77-year-old woman visited our hospital with the chief complaint of left supraclavicular lymph node redness and swelling. Needle biopsy revealed metastatic, epithelial, undifferentiated carcinoma. However, the primary tumor remained unknown despite further thorough examinations, FDG-PET showed abnormal FDG accumulation at the lymph nodes of para-aortic and left external iliac artery area in addition to left supraclavicular lymph node. However, CT and MRI showed no lymph node swelling in the peritoneal cavity. Nedaplatin (CDGP) combined with S-1 therapy was carried out for this primary unknown cancer with lymph node metastases. Three months after CDGP/S-1 therapy was begun, the swollen left supraclavicular lymph node was obviously reduced by 42.5%. Moreover, abnormal FDG accumulation at left supraclavicular and para-aortic lymph nodes dramatically decreased and that at the left external iliac artery area disappeared. The anti-tumor effect was evaluated as a partial response by use of Response Evaluation Criteria in Solid Tumors (RECIST). Standard treatment for primary unknown cancer was not established, because it includes various carcinomas. Here we report a case of primary unknown cancer successfully treated with CDGP/S-1. This combined therapy was considered to be one of the promising strategies for a primary unknown cancer.

Chloride ions control the G1/S cell-cycle checkpoint by regulating the expression of p21 through a p53-independent pathway in human gastric cancer cells.

The aim of the present study is to investigate whether the chloride affects cell growth and cell-cycle progression of cancer cells. In human gastric cancer MKN28 cells, the culture in the Cl(-)-replaced medium (replacement of Cl(-) by NO(3)(-)) decreased the intracellular chloride concentration ([Cl(-)](i)) and inhibited cell growth. The inhibition of cell growth was due to cell-cycle arrest at the G(0)/G(1) phase caused by diminution of CDK2 and phosphorylated Rb. The culture of cells in the Cl(-)-replaced medium significantly increased expressions of p21 mRNA and protein without any effects on p53. These observations indicate that chloride ions play important roles in cell-cycle progression by regulating the expression of p21 through a p53-independent pathway in human gastric cancer cells, leading to a novel, unique therapeutic strategy for gastric cancer treatment via control of [Cl(-)](i).

Intraoperative pathological investigation of recurrent nerve nodal metastasis can guide the decision whether to perform cervical lymph node dissection in thoracic esophageal cancer.

Three-field lymph node dissection has been widely used to treat thoracic esophageal cancer, but is very invasive and can cause serious complications. Whether cervical lymph node dissection should be performed in all patients with thoracic esophageal cancer remains controversial. We pathologically examined the recurrent nerve lymph nodes during surgery in patients with thoracic esophageal cancer to determine the presence or absence of lymph node involvement. In patients without recurrent nerve nodal involvement, cervical lymph node dissection was not performed. Treatment outcomes were analyzed to evaluate whether intraoperative pathological investigation was a useful procedure. Among 71 patients with thoracic esophageal cancer who underwent 3-field lymph node dissection, the rate of cervical lymph node metastasis was 40.9% in patients with recurrent nerve nodal metastasis on intraoperative pathological investigation, as compared with 10.2% in patients without recurrent nerve nodal metastasis (p=0.007). Multiple logistic-regression analysis showed that recurrent nerve nodal metastasis was a strong predictor of cervical lymph node metastasis (odds ratio, 2.98; 95% confidence interval, 1.139-7.775; p=0.03). Among 41 patients who underwent intraoperative pathological investigation, 10 had recurrent nerve nodal metastasis and underwent cervical lymph node dissection. Two of these patients had histological evidence of cervical lymph node metastasis. The remaining 31 patients had no recurrent nerve nodal metastasis on intraoperative pathological examination and therefore did not receive cervical lymph node dissection. None of these patients had cervical lymph node recurrence on follow-up. We compared patients who underwent intraoperative pathological investigation with those who underwent conventional 3-field lymph node dissection (without performing intraoperative pathological investigation). The rates of cervical lymph node recurrence were similar among the groups (2.6% vs. 6.7%), but the 3-year survival rate was significantly higher in the patients who underwent intraoperative pathological dissection (83.3%) than in those who underwent 3-field dissection (57.2%; p<0.05). Although this was a retrospective study, our results suggest that outcomes of patients undergoing cervical lymph node dissection according to the results of intraoperative pathological investigation are at least as good as those in patients undergoing 3-field lymph node dissection. We conclude that intraoperative pathological investigation of recurrent nerve nodal metastasis is useful for determining whether cervical lymph node dissection should be performed in patients with thoracic esophageal cancer.

Furosemide, a blocker of Na+/K+/2Cl- cotransporter, diminishes proliferation of poorly differentiated human gastric cancer cells by affecting G0/G1 state.

Furosemide, a blocker of Na(+)/K(+)/2Cl(-) cotransporter (NKCC), is often used as a diuretic to improve edema, ascites, and pleural effusion of patients with cancers. The aim of the present study was to investigate whether an NKCC blocker affects cancer cell growth. If so, we would clarify the mechanism of this action. We found that poorly differentiated gastric adenocarcinoma cells (MKN45) expressed the mRNA of NKCC1 three times higher than moderately differentiated ones (MKN28) and that the NKCC in MKN45 showed higher activity than that in MKN28. A cell proliferation assay indicates that furosemide significantly inhibited cell growth in MKN45 cells, but not in MKN28 cells. Using flow cytometrical analysis, we found that the exposure to furosemide brought MKN45 cells to spend more time at the G(0)/G(1) phase, but not MKN28 cells. Based on these observations, we indicate that furosemide diminishes cell growth by delaying the G(1)-S phase progression in poorly differentiated gastric adenocarcinoma cells, which show high expression and activity of NKCC, but not in moderately differentiated gastric adenocarcinoma cells with low expression and NKCC activity.

The range of tumor extension should have precedence over the location of the deepest tumor center in determining the regional lymph node grouping for widely extending esophageal carcinomas.

BACKGROUND: The Japanese Guide Lines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus (9th edn) give precedence to the location of the deepest tumor center rather than the range of tumor extension when determining regional lymph node grouping. We evaluated the validity of this recommendation. METHODS: The subjects were 49 patients with carcinomas of the distal thoracic esophagus and cardia who had undergone esophagectomy with three-field lymph node dissection. We measured variables defining tumor location, such as the distance from the esophagogastric junction (EGJ) to the proximal margin of the tumor (DJP), the distance from the EGJ to the distal margin of the tumor (DJD), and the distance from the EGJ to the deepest tumor center (DJC). To examine the relation of tumor location to lymph node metastasis in the proximal direction, the patients were divided into two groups according to the presence (14 patients) or absence (35 patients) of middle-upper mediastinal and/or cervical lymph node metastases. These two groups were compared with respect to the above variables. To analyze lymph node metastasis in the distal direction, the patients were also divided into two groups according to the presence (12 patients) or absence (37 patients) of distant abdominal lymph node metastases. These two groups were similarly compared with respect to the above variables. RESULTS: DJP was significantly longer in the patients with middle-upper mediastinal and/or cervical lymph node metastases than in those without such metastases. Multiple logistic regression analysis showed that the DJP was a better predictor of middle-upper mediastinal and/or cervical lymph node metastases than was the DJC. The DJD was significantly longer in the patients with distant abdominal lymph node metastases. Multiple logistic regression analysis also showed that the DJD was a better predictor of distant abdominal lymph node metastases than was the DJC. CONCLUSIONS: The range of tumor extension is a more reliable predictor of the risk of distant lymph node metastases than is the location of the deepest tumor center in esophageal carcinoma.

The extending range of the tumor is a more suitable predictive risk factor for lymph node metastases than the location of the deepest tumor invasion in distal thoracic esophageal and cardiac cancer.

In the regional lymph node grouping of esophageal cancer by the Japanese Guide Line (the 9th edition), the location of the deepest tumor invasion has precedence in determination. In this study, we investigated the extending range of the tumor and the location of the deepest tumor invasion to ascertain which was the more important factor in predicting lymph node metastases. We examined 52 patients with distal thoracic esophageal and cardiac cancer who had undergone esophagectomy with three-field lymph node dis-section. Among the 52 patients, 16 were found to be positive and 36 negative, for middle-upper mediastinum and cervical lymph node metastases, and the two groups were compared in terms of detailed parameters of the tumor's location. In the result, the distance from the esophagogastric junction (EGJ) to the proximal margin of the tumor was significantly longer in the metastatic group (p=0.005). In univariate logistic regression with this parameter as the independent variable, we obtained a statistically significant result (p=0.0115, odds ratio=1.041, 95% confidence interval=1.009-1.073, R2=0.1169). On the other hand, when the distance from the EGJ to the deepest portion of the tumor was used as the independent variable, p=0.0742, odds ratio=1.045, 95% confidence interval=0.996-1.096 and R2=0.0577. Multiple logistic regression was performed with these two parameters, and the distance from the EGJ to the proximal margin of the tumor was a more important factor than the distance from the EGJ to the deepest portion of the tumor (p=0.0553 vs. 0.9161). We concluded that the extending range of the tumor was a more suitable predictive risk factor of lymph node metastases than the location of the deepest tumor invasion in distal thoracic esophageal and cardiac cancer. We should seriously consider the extending range of the tumor in the regional lymph node grouping of the Japanese Guide Line.

A case of Castleman's disease arising from the lesser omentum.

A 29-year-old female presented with upper abdominal pain. An upper gastrointestinal radiograph and endoscopy revealed an extra compression in the lesser curvature of the body of the stomach. A computed tomography scan and magnetic resonance imaging revealed a tumor located between the left lobe of the liver and the lesser omentum of the stomach. F-18 fluorodeoxyglucose positron emission tomography revealed high uptake at the tumor in the upper abdomen. In an angiogram, a large hypervascular mass had a prominent vascular supply from the left gastric artery; venous pooling and an enlarged feeding vessel were also apparent. From these results, we suspected that the patient had Castleman's disease arising from the lesser omentum. The patient underwent hand-assisted laparoscopic tumor resection. The resected tumor was an encapsulated mass, the surface of which was smooth and the dimensions of which were 77 x 51 x 43 mm. Based on microscopic findings, we diagnosed hyaline vascular type Castleman's disease. Since surgical intervention, the patient has remained asymptomatic, with no pathologic clinical or laboratory findings. Castleman's disease that occurs in the lesser omentum is extremely rare, and the preoperative diagnosis is very difficult. For the localized type of Castleman's disease, clinical findings are usually improved by complete surgical resection.

Long-term administration of low-dose cisplatin plus 5-fluorouracil prolongs the postoperative survival of patients with esophageal cancer.

To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.

[A case of unresectable multiple liver metastases from colon cancer successfully treated by hepatic arterial infusion chemotherapy and systemic immunotherapy (IFNANK) followed by hepatic resection].

The patient was a 76-year-old man, diagnosed with sigmoid colon cancer with unresectable multible liver metastases. After sigmoidectomy with D2 regional lymphnode dissection on June 21, 2002 (moderately differentiated adenocarcinoma, ss, n(-), H3, P0, M(-), Stage IV), intermittent hepatic arterial infusion chemotherapy using 5-FU (1,250 mg/body/3 hr) and CDDP (10 mg/body/30 min) was performed weekly for 23 times, and then biweekly for 15 times. The total dosages of 5-FU were 47.5 g. During the regional chemotherapy, IFNANK therapy was performed biweekly as systemic immunotherapy. As a result, serum levels of tumor markers were remarkably decreased, and the metastatic liver tumors had disappeared in the CT finding in July 2003. Thereafter, IFNANK therapy was continued without the chemotherapy. However, CT and PET detected the recurrent liver tumors in December 2003, and the tumors were curatively resected on January 28, 2004.

S-1-induced, prolonged complete regression of lung metastasis from gastric cancer refractory to 5'-DFUR: a case report with pharmacokinetic study.

S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5'-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5'-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.

Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen-derived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with metastatic gastrointestinal or lung adenocarcinomas.

We conducted a clinical study of cancer vaccine therapy with dendritic cells (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to assess the feasibility and efficacy of such therapy. Eighteen patients with CEA-expressing metastatic gastrointestinal or lung adenocarcinomas who were positive for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the patients' autologous monocyte-enriched fractions of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. The generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide (CEA652) and injected into the patients intradermally and subcutaneously every 2 weeks. Toxicity and clinical and immunological responses were closely monitored in each patient. No severe toxicity directly attributable to the treatment was observed, and the vaccine was well tolerated. Although no definite tumor shrinkage occurred in any patient, long-term stable disease or marked decreases in the serum CEA level were observed in some patients after therapy. Most of the patients in whom treatment was clinically effective showed a positive skin response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a positive in vitro CTL response to CEA652 peptide after therapy. We conclude that active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible treatment that is clinically effective in some patients with metastatic gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage further refinement and development of DC-based immunotherapy with HLA-A24-restricted CEA-derived peptide for refractory solid cancers that express CEA.

Poor prognostic factors of hepatectomy in patients with resectable small hepatocellular carcinoma and cirrhosis.

PURPOSE: Some patients with hepatocellular carcinoma (HCC) at an early stage cannot attain long-term survival after hepatectomy. The aim of the present study was to investigate the poor prognostic factors for hepatectomy in patients with resectable small HCC with cirrhosis. METHODS: We studied 95 patients with cirrhosis with HCC, which consisted of a single tumor 5 cm or smaller or two or three tumor nodules each 3 cm or less; an absence of extrahepatic metastasis; and an absence of radiological evidence of macroscopic portal vein or hepatic vein invasion. We used Cox's proportional hazard model to identify risk factors associated with prognosis to determine the contra-indications for hepatectomy in patients with resectable small HCC. RESULTS: Preoperative risk factors were: (1) serum AFP concentration of more than 400 ng/ml; (2) infiltrative-, massive-, or multinodular-type (multiple) HCC; and (3) the presence of intrahepatic metastasis. Patients who had had more than one of the three preoperative risk factors were poor candidates for hepatic resection, with a 4-year survival of 16.3%. CONCLUSION: If patients with resectable small HCC are diagnosed as having more than one of three preoperative risk factors, they should not receive hepatectomy or should be considered for primary liver transplantation as a therapeutic option for HCC.

[Intratumoral administration of methotrexate bound to activated carbon particles (MTX-CH) inducing antitumor effect in vivo].

Methotrexate is one of the anticancer drugs that can be safely administered subcutaneously, but locally injected MTX in aqueous solution form does not function in the administration site for very long. We developed a new dosage formulation: methotrexate bound to activated carbon particles (MTX-CH), and can report that it controlled tumor growth through its long-acting effect at the administration site. In this study, we investigated the effect of local administration of MTX-CH compared with MTX aqueous solution in tumors from transplanted human colon cancer cells (LoVo) into the back of nude mice. MTX-CH is superior to MTX aqueous solution in terms of its long-acting effect at the administration site and antitumor effect. We suggest that intratumoral injection therapy of MTX-CH is useful for patients in poor condition and with high surgical risk due to cardiac disease or old age, and patients who are diagnosed positive for cancer after endoscopic mucosal resection of early colorectal cancer.

[Endoscopic local injection of anticancer drugs bound to carbon particles for treatment of advanced rectal cancer, when surgical treatment was contraindicated].

Generally, patients with advanced rectal cancer in whom surgical treatment is contraindicated receive radiation or chemotherapy. In such patients, we have administered local injection of methotrexate and mitomycin C bound to activated carbon particles. Four patients received intratumoral injection of the dosage formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C) under colonofiberscope. After the treatment, bleeding and pain were lessened in all 4 patients. In two patients, the tumor markedly decreased in size and there was no regrowth prior to death 12-14 months after the treatment. In another patient, bleeding and pain disappeared until the patient died of pulmonary and liver metastases. The fourth patient is alive without regrowth 5 months after treatment. Side effects were not severe.

Subtotal gastrectomy for cancer located in the greater curvature of the middle stomach with prevention of the left gastric artery.

BACKGROUND: A novel distal subtotal gastrectomy was performed in 5 patients with macroscopically node-positive gastric cancer located in the greater curvature of the middle stomach. In these patients, total gastrectomy or standard distal subtotal gastrectomy has been typically performed. In these typical gastrectomies, the hepatic and the coeliac branches of the vagi are removed en bloc with the left gastric artery and the whole of the lesser omentum because the lymphatics along the left gastric artery are in the lower stream-regions of lymph flow from the cancer and metastases exist potentially. METHODS: During novel distal subtotal gastrectomy the activated carbon method confirmed that the lymphatics along the ascending branch of the left gastric artery were not in the lower stream-region of lymph flow from the cancer. Then, we preserved the hepatic and coeliac branches of the vagi as well as the ascending branch of the left gastric artery and the upper part of the lesser omentum. The other arteries feeding the stomach were removed with the surrounding lymphatics. In novel distal subtotal gastrectomy the remnant stomach was fed only by the ascending branch of the left gastric artery, while in standard distal subtotal gastrectomy the remnant stomach was fed by the short gastric arteries. CONCLUSIONS: Although further examinations are necessary, novel distal subtotal gastrectomy may have superior merit such as good function of gallbladder because of the preservation of the vagal nerve system, compared with total gastrectomy or standard distal subtotal gastrectomy.