Hiroharu Yamashita

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BACKGROUND A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2

Adiponectin, a circulating peptide hormone produced in adipose tissue, has been shown to be reduced in the plasma of patients with cancer, suggesting that this adipokine may be mechanically involved in the pathogenesis of adiposity‐related carcinogenesis. In this study, we examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) and assessed the function of adiponectin in gastric cancer. All of the six gastric cancer cell lines significantly expressed mRNA and protein of both receptors with variable levels. Addition of 30 µg/mL adiponectin potently induced apoptosis and inhibited the proliferation of AZ521 and HCG27. Down‐regulation of either AdipoR1 or AdipoR2 by specific siRNA significantly suppressed the growth inhibitory effects of adiponectin in both cell lines. Moreover, a local injection of adiponectin markedly inhibited the growth of AZ521 inoculated subcutaneously in nude mice. Similarly, the continuous intraperitoneal infusion of adiponectin effectively suppressed the development of peritoneal metastasis of AZ521. Adiponectin negatively regulates the progression of gastric cancer cells possibly through both AdipoR1 and AdipoR2. Although adiponectin was already reported to have antiangiogenic effects, our results suggest that the antitumor effect of adiponectin was, at least partially, dependent on the direct effects on tumor cells. (Cancer Sci 2007; 98: 1120–1127)

Prospective Randomized Trial Comparing Billroth I and Roux-en-Y Procedures after Distal Gastrectomy for Gastric Carcinoma

To determine the clinical efficacy of Roux-en-Y reconstruction (RY) after distal gastrectomy, we compared postoperative outcomes of patients who underwent RY or conventional Billroth I reconstruction (B-I). A total of 50 patients were prospectively randomized to either B-I or RY reconstruction, and complications, postoperative course, and nutritional status were compared. Bile reflux and inflammation in the remnant stomach and lower esophagus were evaluated by postoperative follow-up endoscopy at 6 months. Operative time and blood loss as well as postoperative nutrition did not show significant differences between the two groups. As anticipated, 5 of 24 patients with RY reconstruction developed gastrojejunal stasis in the early postoperative period, which led to a longer postoperative hospital stay as compared with the B-I group (mean ± S.D; B-I; 19.0 ± 6.2, RY; 31.8 ± 21.7 days) (P < 0.05). Endoscopic examination revealed that the frequency of bile reflux (P < 0.01) and degree of inflammation in the remnant stomach (P < 0.05) were less in the RY group than in the B-I group. However, inflammatory findings in the lower esophagus were observed in 7 (27%) of B-I, and 8 (35%) of the RY group, suggesting that late phase esophagitis was not improved in the RY group. Roux-en-Y reconstruction was effective in preventing duodenogastric reflux and resulting gastritis, but it did not prevent esophagitis. Because RY reconstruction induces the frequent complication of Roux-en-Y stasis, causing longer postoperative hospital stay, this method has limited advantages over B-I anastomosis after distal gastrectomy.

Efficacy of the 5-HT1A Agonist Tandospirone Citrate in Improving Symptoms of Patients With Functional Dyspepsia: A Randomized Controlled Trial

OBJECTIVES:Functional dyspepsia (FD) is a common condition in the general population; however, its treatment remains a challenge. The aim of this study was to examine the efficacy of tandospirone citrate, a new partial agonist of the 5-hydroxytryptamine 1A (5-HT1A) receptor, in improving the symptoms of patients with FD.METHODS:In this double-blind, placebo-controlled, multicenter study, FD patients were randomized to treatment with 10 mg t.i.d. tandospirone citrate or to placebo for 4 weeks. The primary end point was change in abdominal symptom scores. The difference in the proportion of responders (a total abdominal symptom score of 0 or 1) was also assessed. The quality-of-life questionnaire, the SF-8, and a psychological test questionnaire, the State-Trait Anxiety Inventory (STAI), were completed at baseline and at weekly intervals.RESULTS:Data were available for 144 patients: 73 for tandospirone and 71 for placebo. Improvements in total abdominal scores were significantly larger with tandospirone than placebo at weeks 1, 2, and 4. Significantly greater improvements in the tandospirone group were observed in upper abdominal pain (P=0.02) and discomfort (P=0.002) at week 4. The proportion of responders was significantly greater in the active treatment arm at weeks 3 (P=0.017) and 4 (P=0.0016). Significant improvements in STAI (P<0.0001) were reported in both arms, as well as in the majority of questions in the SF-8 (P=0.04). No serious adverse events were reported, with similar rates in both study arms.CONCLUSIONS:Despite a considerable placebo effect, the benefits of tandospirone were shown in terms of improvement in abdominal symptom scores.

Hyperfibrinogenemia is associated with lymphatic as well as hematogenous metastasis and worse clinical outcome in T2 gastric cancer

BackgroundAbnormal hemostasis in cancer patients has previously been described, however the correlation between the plasma fibrinogen level and cancer metastasis and prognosis has not been reported in a large-scale clinical study.MethodsPreoperative plasma fibrinogen levels were retrospectively examined in 405 patients who underwent surgery for advanced gastric cancer. The association of fibrinogen levels with clinical/pathological findings and clinical outcome was evaluated.ResultsThere was a positive correlation between plasma fibrinogen levels and the depth of invasion (p < 0.05). Hyperfibrinogenemia (>310 mg/dl) was independently associated with lymph node (Odds Ratio; 2.342, P = 0.0032) and liver (Odds Ratio; 2.933, P = 0.0147) metastasis, not with peritoneal metastasis in this series. Patients with hyperfibrinogenemia showed worse clinical outcome in T2 gastric cancer, however, there was no correlation of plasma fibrinogen level with prognosis in T3/T4 gastric cancer.ConclusionOur results might support the idea that hyperfibrinogenemia can augment lymphatic and hematogeneous metastasis of advanced gastric cancer, which is major determinant of the prognosis in T2 gastric cancer. Therefore, in the situation without peritoneal involvement, hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome in T2 gastric cancer.

Optimal extent of lymph node dissection for Siewert type II esophagogastric junction carcinoma.

Objective: To determine the optimal extent of lymph node dissection for carcinomas of the true cardia, otherwise called Siewert type II esophagogastric junction (EGJ) carcinomas. Background: In patients with cancer of the EGJ, comparable outcomes have been obtained with extended esophagectomy and total gastrectomy. The issue of the optimal surgical approach for EGJ tumors has been under debate. Nodal involvement is a strong predictor of survival, however, the optimal extent of prophylactic lymphadenectomy for Siewert type II tumors remains to be elucidated. Methods: We retrospectively evaluated the distributions of the metastatic nodes, the recurrence pattern, and the oncological outcomes in a single-center large cohort of 225 patients with Siewert type II tumors. To assess the therapeutic outcomes of respective node dissection, we applied an index calculated by multiplication of the incidence of metastasis by the 5-year survival rate of patients with metastasis in the respective node stations. Results: The incidence of nodal metastasis was high in the right paracardial (38.2%), lesser curve (35.1%) and left paracardial (23.1%) nodes, and also the nodes along the left gastric artery (20.9%). Involvement of the suprapancreatic nodes along the celiac artery, splenic artery and common hepatic artery was found in 23, 25, and 14 patients, respectively. According to the index of estimated benefit from lymph node dissection, dissection of the paracardial and lesser curve nodes yielded the highest therapeutic benefit. The number of metastatic nodes in these areas was as predictive of the disease-free and overall survivals as the TNM pN category. The 5-year overall survival rates in patients with no or 1–2 metastatic nodes were 76.6% and 62.3%, respectively, whereas the 5-year survival rate in those with 3 or more positive nodes was only 22.4%, comparable with the rate of 17.4% in patients with TNM pN3 tumors. Conclusions: Clear anatomic distinction of EGJ tumors is likely to provide insight into the appropriate extent of lymphadenectomy. Dissection of the paracardial and lesser curve nodes is essential for staging as well as for obtaining therapeutic benefit in surgery for in EGJ carcinomas (Siewert type II).

Leptin augments proliferation of breast cancer cells via transactivation of HER2.

Excessive fat mass is a risk factor for postmenopausal breast cancer. Leptin, a fat cell-derived peptide hormone, elicits a growth-stimulating effect in breast cancer cells with leptin receptor expression, although the leptin-induced signal in malignant cells is not fully understood. Here, we found that exogenous leptin induced tyrosine phosphorylation of HER2 in SKBR3 cells, which showed marked overexpression of HER2. Phosphorylation of HER2 was detected at 2 min and continued up to 120 min after the start of stimulation. Leptin-induced HER2 phosphorylation was partially reduced by an epidermal growth factor receptor inhibitor, AG1478, or a Janus-activated kinase inhibitor, AG490. Leptin also induced phosphorylation of extracellular signal-regulated kinase 1/2, which was mostly abrogated by a HER2 tyrosine kinase inhibitor, AG825. In a proliferation assay, addition of 500 ng/mL leptin increased the proliferation of SKBR3, which was totally inhibited by AG825. Collectively, our data suggest that leptin can transactivate HER2 through both epidermal growth factor receptor and Janus-activated kinase 2 activation, which can cause the growth of breast cancer cells with HER2 overexpression.

Sphingosine 1-phosphate transactivates c-Met as well as epidermal growth factor receptor (EGFR) in human gastric cancer cells.

Receptor tyrosine kinases (RTKs) are transactivated by the stimulation of G protein‐coupled receptors (GPCRs). Sphingosine 1‐phosphate (S1P), a ligand of GPCR, is known as a tumor‐promoting lipid, but its signaling pathways are not fully understood. We here demonstrated that S1P induces rapid and transient tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and c‐Met in gastric cancer cells, both of which have been proposed as prognostic markers of gastric cancers. The pathway of S1P‐induced c‐Met transactivation is Gi‐independent and matrix metalloproteinase‐independent, which differs from that of EGFR transactivation. Our results indicate that S1P acts upstream of various RTKs and thus may act as a potent stimulator of gastric cancer.

Phase I Pharmacokinetic Study of Weekly Intravenous and Intraperitoneal Paclitaxel Combined with S-1 for Advanced Gastric Cancer

Objectives: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Patients and Methods: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m2, and intraperitoneally with an initial dose of 20 mg/m2, stepped up to 30 or 40 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m2, as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m2. The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.

A phase 2 trial of intravenous and intraperitoneal paclitaxel combined with S‐1 for treatment of gastric cancer with macroscopic peritoneal metastasis

The prognosis of patients with gastric cancer with peritoneal metastasis is extremely poor. This phase 2 study evaluated the benefits and tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) treatment combined with oral S‐1 in patients with gastric cancer who had macroscopic peritoneal metastasis.