Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer.

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study).

BACKGROUND: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer. PATIENTS AND METHODS: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS). RESULTS: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66). CONCLUSION: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN. TRIAL IDENTIFIER: UMIN000012535.

[Liver Herniation through a Diaphragmatic Defect Mimicking Pleural Tumor;Report of a Case].

Liver herniation is rare and sometimes difficult to differentiate from pleural or diaphragmatic tumor. A 64-year-old woman was admitted due to a mass-like shadow in the right lower lung field. Computed tomography, coronal view, showed a well-defined mass forming an acute angle with the right diaphragm, mimicking pleural tumor. Video-assisted thoracic surgery was performed, revealing herniated liver through one of the multiple diaphragmatic defects, which was repositioned into the abdominal cavity, and the diaphragmatic defect was repaired. The patient recovered well and was discharged on postoperative day 5.

Multi-institutional prospective feasibility study to explore tolerability and efficacy of oral nutritional supplements for patients with gastric cancer undergoing gastrectomy (CCOG1301).

BACKGROUND: Postoperative malnutrition after gastrectomy is deemed inevitable, which could have prejudicial influence on survival for gastric cancer patients. A prospective feasibility study was conducted to evaluate the efficacy of postoperative oral nutritional supplements. METHODS: Stage I-III gastric cancer patients who underwent distal or total gastrectomy received oral administration of Racol® NF (Otsuka Pharmaceutical Factory, Japan), a liquid enteral nutritional formula, as a supplement to regular meals. Racol® NF administration at a recommended dosage of 400 kcal/400 ml per day was started within 7 days postoperatively and was continued for 3 months postoperatively. The primary end point was ratio of the weight loss at 3 months postoperatively to the preoperative body weight (body weight loss ratio). Secondary end points were the adherence to Racol® NF therapy and changes in body composition. RESULTS: One hundred eighteen patients were registered before surgery, 82 of whom were eligible for efficacy analyses. The average rate of body weight loss after 3 months postoperatively was 8.3%. The mean daily intake of Racol® NF was 211 ml. There was a significant correlation between adherence to Racol® NF therapy and body weight loss ratio (P < 0.001). Adherence to Racol® NF therapy was the only factor that correlated with the body weight loss ratio among all clinical characteristics by the multiple linear regression analysis (P = 0.007). CONCLUSIONS: Oral nutritional supplementation with Racol® NF led to a significant reduction in body weight loss for gastrectomized patients who tolerated more than 200 ml of the nutrient per day compared with those who could not tolerate this amount.

Influence of Food Intake on the Healing Process of Postoperative Pancreatic Fistula After Pancreatoduodenectomy: A Multi-institutional Randomized Controlled Trial.

BACKGROUND: The usefulness of enteral nutrition via a nasointestinal tube for patients who develop postoperative pancreatic fistula (POPF) after miscellaneous pancreatectomy procedures has been reported. However, no clear evidence regarding whether oral intake is possible during management of POPF after pancreatoduodenectomy (PD) is currently available. We investigated the effects of oral food intake on the healing process of POPF after PD by a multi-institutional randomized controlled trial. METHODS: Patients who developed POPF were randomly assigned to the dietary intake (DI) group (n = 30) or the fasted group [no dietary intake (NDI) group] (n = 29). The primary endpoint was the length of drain placement. RESULTS: No significant differences were found in the length of drain placement between the DI and NDI groups [27 (7-80) vs. 26 (7-70) days, respectively; p = .8858]. POPF progressed to a clinically relevant status (grade B/C) in 20 patients in the DI group and 19 patients in the NDI group (p = .9257). POPF-related intra-abdominal hemorrhage was found in 2 patients in the NDI group, but in no patients in the DI group (p = .1434). There were no significant differences in POPF-related intra-abdominal hemorrhage, the incidence of other complications, or the length of the postoperative hospital stay between the 2 groups. CONCLUSION: Food intake did not aggravate POPF and did not prolong the length of drain placement or hospital stay after PD. There may be no need to avoid oral dietary intake in patients with POPF.

A randomized phase III trial exploring the prognostic value of extensive intraoperative peritoneal lavage in addition to standard treatment for resectable advanced gastric cancer: CCOG 1102 study.

A randomized controlled trial has started in Japan to evaluate the efficacy of extensive intraoperative peritoneal lavage in the treatment of resectable advanced gastric cancer. Patients with T3 or deeper carcinoma of the stomach are intraoperatively randomized to either extensive intraoperative peritoneal lavage + arm or extensive intraoperative peritoneal lavage- arm. A total of 300 patients will be accrued from 20 institutions. The primary endpoint is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events.

Cystic lymphangioma of the gallbladder: report of a case.

Abdominal lymphangioma is usually diagnosed within the first 2 years of life and is extremely rare in adults. The most common location of abdominal lymphangioma is the mesentery, but there are sporadic reports of its development in the gallbladder. A 66-year-old woman was found to have a cystic lesion near the gallbladder. Preoperative studies, including endoscopic ultrasonography, computed tomography, and magnetic resonance imaging, showed a tumor with multilocular cystic structure, originating in the gallbladder fossa. The patient underwent exploratory laparotomy, and the mass was resected en bloc with the gallbladder, as there was no evidence of malignancy on intraoperative ultrasonography. Macroscopically, the tumor was a multilocular cystic mass, 6 x 3 x 2 cm in size, with a rough, sponge-like appearance. Histologically, the cystic tumor was diagnosed as a lymphangioma, originating in the gallbladder. To our knowledge, only three other cases of a cystic lymphangioma originating in the gallbladder have been reported in the medical literature of the world.

Aberrant methylation of the CHFR gene in digestive tract cancer.

BACKGROUND: Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. The methylation status of the CHFR gene was examined in primary esophageal and gastric carcinomas. MATERIALS AND METHODS: The methylation status of the CHFR promoter region and mRNA expression in cancer cell lines were examined first. The methylation status of the CHFR gene in 38 esophageal and 53 gastric cancers was subsequently examined and the correlation between CHFR methylation and the clinicopathological findings was investigated. RESULTS: Aberrant methylation of the CHFR gene was detected in 9 out of 38 (24%) primary esophageal and 16 out of 53 (30%) primary gastric cancers. After methylation analysis of all the samples, the clinicopathological data were correlated with these results. There was a significant difference according to gender (p = 0.0404), indicating that female esophageal cancers were more frequently methylated than male. On the other hand, abnormal methylation was found in esophageal and gastric cancer patients at all clinical stages. CONCLUSION: Aberrant methylation of the CHFR gene was frequently shown in esophageal and gastric cancers. In addition, abnormal methylation was found in these cancer patients at all clinical stages, suggesting that this cancer could be methylated at an early stage.

Aberrant methylation of the CHFR gene is frequently detected in non-invasive colorectal cancer.

BACKGROUND: Aberrant methylation of the CHFR gene associated with gene silencing has been reported in several primary tumors. In order to define the role of CHFR in the tumorigenic pathway of the colorectum, the methylation of CHFR was examined in tumors from colorectal cancer patients. MATERIALS AND METHODS: Ninety-eight colorectal cancer patients were examined using a methylation-specific PCR (MSP) for CHFR CpG island in primary tumors. RESULTS: An aberrant methylation of the CHFR gene was detected in 25 out of 98 (26%) primary colorectal cancers. No methylation was detected in the corresponding normal tissue specimens. This finding suggested that an aberrant methylation of the CHFR gene occurs frequently in colorectal cancers. After a methylation analysis of all samples, the clinicopathological data were correlated with these results. A significant difference was found in the tumor (p = 0.035), thus, indicating that in early colorectal cancer the CHFR gene was more frequently methylated than in advanced cases. CONCLUSION: These findings suggest that CHFR might act as a tumor suppressor in at least some colorectal cancers and that CHFR methylation might, therefore, be a particular phenomenon of early colorectal cancer.

Aberrant methylation of the CHFR gene in advanced hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. We examined the methylation status of the CHFR gene in primary hepatocellular carcinomas (HCCs) and evaluated the correlation between the methylation status and the malignancy of HCC. METHODOLOGY: We first examined the methylation status of the CHFR promoter region and mRNA expression in cancer cell lines. Next, we examined the methylation status of the CHFR gene in 62 primary HCCs and then investigated the correlation between CHFR methylation and the clinicopathological findings. RESULTS: The cell line with CHFR promoter methylation showed a loss of CHFR expression that was restored after 5-aza-2'-deoxycytidine (5-aza-dC) treatment, suggesting that aberrant methylation of the CHFR gene was associated with gene silencing. CHFR methylation was detected in 22 of 62 (35%) primary HCCs, whereas no methylation was detected in noncancerous liver tissues. Furthermore, CHFR methylation was significantly associated with an infiltrative growth pattern (p=0.047) and an advanced stage (p=0.037). CONCLUSIONS: Aberrant methylation of the CHFR gene is significantly correlated with the progression of HCC, suggesting that CHFR methylation might be a novel molecular marker to estimate the malignancy of this disease.

Para-aortic lymph node metastasis in carcinoma of the head of the pancreas.

BACKGROUND: Metastasis to para-aortic lymph nodes often occurs in pancreatic head cancer, but factors that predict it are not well known. METHODS: Using histopathologic data of 178 patients who underwent extended lymph node dissection for pancreatic head cancer, we analyzed the distribution of metastases to lymph node groups classified in detail and attempted to identify the lymph node groups that have a strong relation with metastasis to para-aortic lymph nodes. RESULTS: A high incidence of lymph node metastasis was found in para-aortic lymph nodes (No. 16, 19%) as well as in regional lymph nodes, such as those on the posterior aspect of the pancreas head (No. 13, 47%), on the anterior surface of the pancreas head (No. 17, 29%), along the superior mesenteric artery (No. 14, 28%), and along the hepatoduodenal ligament (No. 12, 19%). Statistical analysis showed that metastases to para-aortic lymph nodes had a strong correlation with metastases to Nos. 12, 13, 14, and 17 lymph nodes. Para-aortic lymph node metastases were seldom observed among the patients who had no metastases to Nos.13, 14, and 17 lymph nodes. CONCLUSIONS: Examination of Nos. 13, 14, and 17 lymph nodes may be useful to predict the involvement of para-aortic lymph nodes.

Transhepatic portal venous angioplasty with stenting for bleeding jejunal varices.

A 54-year-old woman, who had undergone pancreatoduodenectomy with resection of the portal vein and intraoperative radiation therapy for cancer of the lower bile duct 16 months before, visited our institution complaining of melena. To identify the cause of bleeding and severe anemia, we performed gastrointestinal endoscopy but could detect no obvious source. The portal phase of the superior mesenteric arteriography and percutaneous transhepatic portography revealed severe stenosis of the extrahepatic portal vein, which corresponded to the end-to-end anastomosis of the portal vein, and hepatofugal collaterals. Extravasations into the afferent loop of the jejunum were detected only with portography. These findings suggested that portal hypertension due to extrahepatic portal obstruction led to bleeding varices. Subsequent to percutaneous transhepatic portography, we dilated the stenosis of the extrahepatic portal vein using a balloon catheter and placed an expandable metallic stent there. Portography after the treatment revealed the disappearance of the hepatofugal flow to collaterals and extravasations, and the patient has had no further episodes of gastrointestinal bleeding since. In conclusion, for patients with bleeding varices due to extrahepatic portal obstruction, especially after abdominal surgery, percutaneous transhepatic angioplasty is considered to be the treatment of choice because of its efficiency and minimal invasiveness.

Decreased expression and frequent allelic inactivation of the RUNX3 gene at 1p36 in human hepatocellular carcinoma.

BACKGROUND/AIMS: Alteration in transforming growth factor-beta signaling pathway is one of the main causes of hepatocellular carcinoma (HCC). The human runt-related transcription factor 3 gene (RUNX3) is an important component of this pathway. RUNX3 locus 1p36 is commonly deleted in a variety of human cancers, including HCC. Therefore, we examined genetic and epigenetic alterations of RUNX3 in human HCC. METHODS: Five HCC cell lines and 41 patients with HCC were investigated in this study. We examined the expression of RUNX3 mRNA, methylation status of RUNX3 promoter region, loss of heterozygosity (LOH) at 1p36, and mutation analysis. These results were compared with clinicopathological data. RESULTS: Promoter hypermethylation was detected in four (80%) of five HCC cell lines and 31 (75.6%) of 41 HCC tissues, confirmed by sequence of bisulfite-treated DNA. LOH was detected in 14 (37.8%) of 37 HCC. By comparison with clinicopathological data, hypermethylation was more common in hepatitis C virus antibody and formation of capsule-positive cases, and decrease of expression was correlated strongly with advanced stage and LOH-detected cases. CONCLUSION: Hypermethylation and LOH appear to be common mechanisms for inactivation of RUNX3 in HCC. Therefore, RUNX3 may be an important tumor suppressor gene related to hepatocarcinogenesis.

Frequent promoter methylation and gene silencing of CDH13 in pancreatic cancer.

It has recently been reported that CDH13 expression is silenced by aberrant methylation of the promoter region in several cancers. We examined the methylation status of the CDH13 gene in pancreatic cancer using methylation-specific PCR (MSP), and detected aberrant methylation of CDH13 in all 6 pancreatic cancer cell lines examined. To confirm the status of the CDH13 gene in relation to the methylation pattern, we next examined CDH13 expression in these cell lines using reverse transcription (RT)-PCR. As expected, no CDH13 expression was detected in any of the 6 pancreatic cancer cell lines. Moreover, 5-aza-2'-deoxycytidine (5-aza-dC) treatment of CDH13-methylated cell lines led to restoration of CDH13 expression. Among primary pancreatic cancers, 19 of 33 (58%) cases exhibited CDH13 methylation, while no cases exhibited it in corresponding normal pancreatic tissues. CDH13 methylation was detected even in relatively early pancreatic cancers, such as stage II cancers and cancers less than 2 cm in diameter. Our results suggest that the aberrant methylation of CDH13 occurs frequently in pancreatic cancer, even at a relatively early stage.

Extended radical resection versus standard resection for pancreatic cancer: the rationale for extended radical resection.

OBJECTIVES: This clinical study was carried out to clarify the indications for extended radical resection for pancreatic carcinoma. METHODS: From July 1981 to September 2003, 250 of 391 (63.9%) patients with pancreatic carcinoma underwent tumor resection in our department. Portal vein resection was performed in 171 of these 250 (68.4%) resected cases. The postoperative survival rate was studied using the operative and histologic findings. RESULTS: Most of the patients who survived for 2 or 3 years were in the carcinoma-free surgical margins group. CONCLUSION: The most important indication for an extended radical resection combined with portal vein resection for pancreatic cancer is the ability to obtain surgical cancer-free margins. There is no indication for an extended resection in patients in whom the surgical margins will become cancer positive if such an operation is employed.

Mesenteric pseudocyst of the sigmoid colon.

A 31-year-old woman with right lower abdominal pain was hospitalized. Palpation revealed both tenderness and rebound tenderness in the right lower quadrant of her abdomen. Abdominal ultrasonography (US) indicated a multilocular cystic mass on the right side of the pelvic area, and a computed tomography (CT) scan showed a low-density mass measuring 7 cm in diameter. Torsion of the pedicle of a right ovarian cyst was suspected, and emergency laparotomy was performed. At operation, however, the uterus and both ovaries appeared normal, and exploration revealed a yellow-reddish cystic mass, approximately 10 cm in size, in the subserosa of the sigmoid colon. The mass was excised together with a 10-cm segment of the sigmoid colon. Macroscopically, it was a multilocular cyst, measuring 10 x 10 cm in size, and it contained white gelatinous fluid. Histological examination showed the cyst wall to be composed of neutrophils, lymphocytes, fibrin, and fibroblasts, but neither a specific endothelial lining nor proliferating lining was detected. The final pathological diagnosis was a mesenteric pseudocyst. Mesenteric pseudocysts are rare, and only 14 cases have been reported previously in the Japanese literature. Emergency operation was performed in 3 patients, including our own. The etiology of these three pseudocysts (manifested by acute abdomen) was unknown. We suspect that inflammation spread and injured lymph vessels, causing lymph to leak out and pool under the subserosal layer.

Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis.

PURPOSE: Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of Janus kinase and signal transducer and activation of transcription pathway. Recently, it was demonstrated that SOCS-1 gene was silenced frequently by methylation of CpG island in human hepatocellular carcinoma (HCC). We examined the methylation-mediated silencing of SOCS-1 in tumors of HCC patients. EXPERIMENTAL DESIGN: Fifty patients with HCC were investigated in this study. We examined the methylation status of the SOCS-1 promoter region by methylation-specific PCR and then confirmed the methylation-mediated silencing of SOCS-1 by Northern blot analysis. Furthermore, this methylation status was compared with clinicopathological findings. RESULTS: Aberrant methylation of the SOCS-1 gene was detected in 30 of 50 (60%) HCC specimens. No corresponding nontumorous liver tissues showed SOCS-1 methylation. Subsequent Northern analysis proved that methylation of the SOCS-1 promoter inactivated translation and diminished expression of SOCS-1 mRNA. We then analyzed the correlation between the clinicopathological data and SOCS-1 aberrant methylation and found that HCC derived from liver cirrhosis had a significant relationship with SOCS-1 methylation (P = 0.0207). CONCLUSIONS: SOCS-1 may be a novel tumor suppressor, and its aberrant methylation may be a key event for HCC transformation of cirrhotic nodules.