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A 67-year-old man visited our hospital for epigastric pain. Esophagogastroduodenoscopy(EGD)revealed type 2 gastric cancer from the cardia to the gastric angle, and histopathological examination revealed papillary adenocarcinoma(pap), HER2-positive. Contrast-enhanced CT showed wall thickening mainly in the posterior wall of the gastric body, enlarged lymph nodes that were lumped together with the main lesion, and 8 low-absorption areas with ring shaped contrast effects in both lobes of the liver. The patient was diagnosed as gastric cancer cT4aN(+)M1[HEP], clinical Stage ⅣB. Six courses of capecitabine plus cisplatin plus trastuzumab(XP plus Tmab)therapy and 17 courses of capecitabine plus trastuzumab(X plus Tmab)therapy were performed. After chemotherapy, liver and lymph node metastases disappeared on CT and MRI. EGD showed residual gastric cancer, and the policy was to resect the primary tumor. Laparoscopic total gastrectomy with D2 lymph node dissection was performed. Pathological results showed T1b(SM)depth, no lymph node metastasis, and histologic response was Grade 2a. Six courses of X plus Tmab were administered as postoperative adjuvant chemotherapy, but were discontinued at the patient's request. Currently, 5 years have passed since the first chemotherapy and 3.5 years have passed since the surgery, and the patient is alive without recurrence, suggesting that the conversion surgery may have contributed to the prolonged survival.

A 72-year-old man visited his local doctor for gastric discomfort. Esophagogastroduodenoscopy revealed a type 3 tumor on the gastric antrum, and histopathological examination revealed a moderately differentiated adenocarcinoma(tub2). The patient was referred to our hospital and CT scan revealed wall thickening with contrast effect in the gastric angle but no enlarged lymph nodes in the region. The patient was diagnosed as cT3N0M0, Stage ⅡB gastric cancer and underwent open distal gastrectomy and D2 lymph node dissection. No peritoneal dissemination was observed, but intraoperative laparoscopic cytology showed Class Ⅴ. The patient was diagnosed as CY1 Stage Ⅳ gastric cancer, and treated with S-1 plus Tmab therapy starting 1 month after surgery. One year postoperative follow-up CT revealed recurrence of peritoneal disseminations, and the patient was treated with nab-PTX as a second-line therapy. Tumor shrinkage was achieved steadily, and the peritoneal disseminations disappeared at the CT after 12 courses, resulting in cCR. Thereafter, cCR continued and treatment was terminated at the 17th course. Seven years have passed since the end of chemotherapy, and the patient is still alive without recurrence.

Background: Omentectomy is considered an essential part of curative gastrectomy for locally advanced gastric cancer (GC), albeit without solid evidence. We conducted a randomized phase II trial (the TOP-G trial) comparing omentectomy and omentum preservation for gastric cancer. This report describes the short-term findings regarding the trial's secondary endpoints., Methods: The trial protocol was submitted to the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ : UMIN000005421). The key eligibility criteria were histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. Short-term surgical outcomes, including morbidity and mortality, were compared between the omentectomy group (group A, control arm) and the omentum-preserving surgery group (group B, test arm). All procedures were performed via an open approach. Based on a non-inferiority margin of 7%, statistical power of 0.7, and type I error of 0.2, the sample size was set to 250 patients., Results: A total of 251 patients were eligible and randomized (group A: 125 patients, group B: 126 patients) between April 2011 and October 2018. After excluding patients who had peritoneal metastasis or laparotomy history, safety outcomes were analyzed for 247 patients. Group A had a significantly longer median operation time (225 min vs. 204 min, p = 0.022) and tended to have greater median blood loss (260 mL vs. 210 mL p = 0.073). The incidences of morbidity were similar and < 10% in both groups (8% vs. 9%, p = 1.000). There was no mortality in either group., Conclusions: Operative risk was generally similar between omentectomy and omentum-preserving surgery for locally advanced gastric cancer.

Background: A multi-institutional phase II study was conducted to evaluate the efficacy and safety of preoperative docetaxel, cisplatin and S-1 therapy in marginally resectable advanced gastric cancer., Methods: Patients with macroscopic type 4, large macroscopic type 3 and bulky lymph node metastasis received two cycles of preoperative docetaxel, cisplatin and S-1 therapy (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 80 mg/m2 for 14 days, every 4 weeks). The primary endpoint was the pathological response rate, with an expected value of 65%., Results: Thirty-one patients were enrolled in this study. The pathological response rate was 54.8%, and it was higher than the threshold value but lower than the expected rate. The R0 resection rate was 93.5%. The frequencies of grade 3-4 toxicities during docetaxel, cisplatin and S-1 therapy were 41.9% for neutropenia, 6.5% for febrile neutropenia and 32.3% for nausea/vomiting. Grade 2 and 3 surgical morbidities occurred in 23.3 and 6.7% of the patients, respectively., Conclusions: Preoperative docetaxel, cisplatin and S-1 therapy was feasible in terms of chemotherapy-related toxicities and surgical morbidity, but the effect did not achieve the expected value. The association between the pathological response rate and survival will be evaluated in the final analysis of this clinical trial., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer., Methods: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m 2 ) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting., Findings: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort., Interpretation: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure., Funding: Taiho Pharmaceutical and Eli Lilly., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Spheroid colony formation is a useful method to identify cancer stem cells (CSCs). The aim of this study was to identify a novel prognostic marker or therapeutic target for GC using a method to identify CSCs. We analyzed the microarray data in spheroid body-forming and parental cells and focused on the CLSPN gene because it is overexpressed in the spheroid body-forming cells in both the GC cell lines MKN-45 and MKN-74. Quantitative reverse-transcription polymerase chain reaction analysis revealed that CLSPN messenger RNA expression was up-regulated in GC cell lines MKN-45, MKN-74, and TMK-1. Immunohistochemistry of claspin showed that 94 (47%) of 203 GC cases were positive. Claspin-positive GC cases were associated with higher T and N grades, tumor stage, lymphatic invasion, and poor prognosis. In addition, claspin expression was coexpressed with CD44, human epidermal growth factor receptor type 2, and p53. CLSPN small interfering RNA treatment decreased GC cell proliferation and invasion. These results indicate that the expression of claspin might be a key regulator in the progression of GC and might play an important role in CSCs of GC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A 72-year-old man underwent total gastrectomy for gastric cancer (por2, T3, N2, Stage IIIA). Eleven courses of postoperative chemotherapy with TS-1 (tegafur/gimeracil/oteracil) were administered. Five months after surgery, the serum carcinoembryonic antigen value was slightly elevated. However, computed tomography did not reveal any metastatic lesions in other organs. Two years after surgery, the patient felt a mass in the left mammary. A 2-cm tumor was palpable in the central portion of the breast. Ultrasonography revealed a hypoechoic tumor, which was Class 3 on aspiration biopsy cytological examination. No mass was detected on positron emission tomography-computed tomography. The mammary gland tumor increased in size to 3 cm, and a core needle biopsy procedure was performed. Histological examination findings revealed breast metastasis of gastric cancer. No other recurrence was found, and radical mastectomy was performed 2 years and 5 months after gastrectomy. Immunohistological analysis of the resected material confirmed breast metastasis of the gastric cancer. Two courses of TS-1 + cisplatin were administered, but this treatment was subsequently terminated because the patient experienced Grade 3 diarrhea and neutropenia. Three years and 1 month after the gastrectomy, the tumor recurred in the pelvic area. Chemotherapy and radiation therapy were performed, but the patient's overall condition became progressively worse, and he died 3 years and 9 months after gastrectomy.

Objective: Spheroid colony formation is a useful method of cancer stem cell (CSC) characterization. We previously showed that the IQ motif containing the GTPase-activating protein 3 gene (IQGAP3) is upregulated in spheroid body-forming gastric cancer (GC) cells compared with parental cells. We investigated IQGAP3 expression in GC., Methods: IQGAP3 protein expression was analyzed by immunohistochemistry in 165 GC cases. RNA interference was used to inhibit IQGAP3 expression in GC cell lines., Results: In non neoplastic gastric mucosa, weak staining of IQGAP3 was observed in the foveolar epithelium, while GC tissue showed stronger, more extensive staining. Of the 165 GC cases, 34 (21%) were positive for IQGAP3 expression. GC cases positive for IQGAP3 were found more frequently in stage II/III/IV cases than in stage I cases. Univariate and multivariate analyses demonstrated that IQGAP3 expression is an independent prognostic classifier of GC patients. Both the number and size of the spheres formed by MKN-74 cells were significantly reduced by knockdown of IQGAP3. The phosphorylation of Akt and Erk1/2 was inhibited by knockdown of IQGAP3., Conclusion: These results suggest that IQGAP3 plays an important role in gastric CSCs. The location of IQGAP3 on the cell membrane makes it a potential therapeutic target for GC., (© 2017 S. Karger AG, Basel.)

Background: Elderly patients usually have concurrent ailments, and the safety and effectiveness of laparoscopy-assisted distal gastrectomy (LADG) for these patients have been controversial. This study aimed to evaluate whether laparoscopy-assisted distal gastrectomy is safe and effective for elderly patients aged 80 years and over, as well as to clarify their long-term prognosis., Methods: A total of 31 patients aged 80 years and over who underwent LADG in our hospital were retrospectively reviewed. Peri- and postoperative data were compared with those of 38 patients aged 65 years and younger. The median follow-up period of the elderly and younger group was 56.0 and 63.0 months, respectively, and their prognosis was examined., Results: There were significant differences between the two groups in preoperative respiratory and renal functions, hemoglobin, and nutritional index. Significant differences in postoperative complications were seen only in pneumonia and delirium. There were no hospital deaths, but the 3-year and 5-year overall survival rates were significantly lower in the elderly group than in the non-elderly group. However, in the elderly group, only one patient died of gastric cancer recurrence, whereas four died of cardiovascular disease and three died of pneumonia during follow-up. Therefore, the recurrence-free survival rate was not significantly different between the groups., Conclusions: LADG seems to be safe and effective even for elderly patients, and their prognosis was satisfactory. However, careful monitoring for cardiovascular and pulmonary disease should be observed during the follow-up period.

Esophageal squamous cell carcinoma (ESCC) is one of the most common human cancers. We previously reported that KIFC1 is involved in gastric cancer pathogenesis and that KIFC1 plays an important role in gastric cancer spheroid colony formation. However, the significance of KIFC1 in ESCC has not been examined. In the present study, we analyzed the expression and distribution of KIFC1 in 132 ESCC cases by immunohistochemistry. In contrast to weak or no staining of KIFC1 in non-neoplastic mucosa, ESCC tissue showed stronger, more extensive KIFC1 staining. In total, 95 (72%) of 132 ESCC cases were positive for KIFC1. Immunostaining of ALDH1 was also performed, and KIFC1-positive ESCC cases were significantly frequently found in ALDH1-positive ESCC cases compared with ALDH1-negative ESCC cases. Spheroid colony formation is an effective method to characterize CSCs, thus we analyzed sphere number and size at 15days in ESCC cells downregulated for KIFC1 by siRNA transfection. Both the number and size of sphere from TE-1 cells were significantly reduced in KIFC1 siRNA-transfected TE-1 cells than in negative control siRNA-transfected cells. These results suggest that KIFC1 plays an important role in ESCC pathogenesis., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Purpose: The aim of this study was to evaluate the safety and feasibility of gastrectomy in elderly patients aged over 80 years., Patients and Methods: A total of 393 patients who underwent gastrectomy for gastric cancer were assigned to 2 groups: those aged over 80 years(n=48; elderly group)and those less than 80 years(n=345).Clinicopathological features, operative factors, post-operative complications(Clavien-Dindo Grade II or higher), and mortality were retrospectively analyzed., Results: Rates of distal gastrectomy(73% vs 59%, p=0.043)and D1 or D1+dissection(73% vs 58%, p=0.046)were significantly higher in the elderly group.There were no significant differences in post-operative complication rates(23% vs 20.3%, p=0.255)or mortality rates(2.1% vs 0.6%)., Conclusion: Our results indicate that gastrectomy in elderly patients aged over 80 years may be safe and feasible.

Introduction: When esophagojejunostomy is performed using a circular stapler after laparoscopic total gastrectomy, fixing the anvil to the end of the esophagus is challenging. We describe an easy method for fixation of the anvil using a one-handed sliding-knot technique after the anvil has been inserted into the esophagus., Materials and Surgical Technique: After removing the stomach, the main operator makes a whip stitch at the end of the esophagus using a long piece of monofilament string. Both ends of the string are pulled out from the port. A knot is then made and brought close the esophagus twice (sliding granny knots). After inserting the anvil into the esophagus, the main operator pulls the main standing string with one hand, applying vibration only. This causes the knots to tighten the anvil. Then, one or two knots are added to make sure that the anvil is firmly fixed in place. In addition, we routinely add one more ligation with a ready-made ligating loop., Discussion: This method is easy and reliable, and does not require special devices or skills when performing reconstruction after laparoscopic total gastrectomy. Because of these factors, it has the potential to be widely used to perform esophagojejunostomy., (© 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.)

An 82-year-old man underwent total gastrectomy(D2 lymph node dissection)in August 2006. The pathological findings indicated T4a, N3, M0, Stage IIIC gastric cancer, but adjuvant chemotherapy was not initiated. In October 2009, he presented to the hospital with dyschezia. During colonoscopy, the scope could not pass through the colon, thus indicating rectal stenosis. The biopsy findings indicated the presence of signet ring cell carcinoma, which was determined to be due to the peritoneal dissemination from the gastric cancer. To avoid the need for creating a stoma, radiation therapy(2 Gy×20; total dose, 40 Gy)and chemotherapy(weekly paclitaxel and S-1)were initiated. Rectal stenosis was improved and complete remission was maintained until May 2013.

A 45-year-old man was transferred to our hospital because of advanced gastric cancer and peritoneal dissemination. After he received an S-1 plus cisplatin( CDDP) regimen for 6 courses, the primary lesion and ascites had disappeared. However, the primary lesion recurred, and he underwent treatment with 16 courses of an S-1 plus docetaxel regimen. He subsequently developed peripheral neuropathy, and was switched to the irinotecan (CPT-11) regimen. As he experienced appetite loss, it was impossible to continue the chemotherapy. Therefore, he underwent a salvage surgery and an R0 resection was performed. However, 9 months after the surgery, he experienced paraaortic lymph node recurrence and peritoneal dissemination. The patient died 13 months after the surgery.

Background: The aim of this prospective study was to evaluate the feasibility and safety of laparoscopy-assisted distal gastrectomy (LADG) initiated by surgeons with much experience of open gastrectomy and laparoscopic surgery., Methods: Three surgeons who each had experience with more than 300 cases of open gastrectomy, more than 100 cases of laparoscopic cholecystectomy, more than 5 cases of laparoscopic colectomy, and more than 5 cases of laparoscopic partial gastrectomy were nominated as LADG operators. All three operators received training for LADG with study materials including videotapes, a box simulator, and an animal laboratory, with lectures and assistance from LADG instructors who each had experience of more than 50 LADG operations. Then the nominated LADG operators performed LADG with the instructors, in which their skills were evaluated and certified. Thereafter, they performed LADG without assistance from the instructors. The target of this study was clinical stage I gastric cancer that was resectable by distal gastrectomy. D1 + alpha, D1 + beta, or D2 dissection was performed laparoscopically. Basically reconstruction was done extracorporeally with a Billroth-I gastroduodenostomy. An extramural review board checked the surgical quality of the operations performed by the three surgeons. The primary endpoint was morbidity and mortality., Results: A total of 193 patients were enrolled in this study between August 2004 and July 2009. The median blood loss was 35 ml and the median operation time was 250 min. Conversion to open surgery was seen in 6 patients; 4 due to bleeding and 2 due to advanced disease. Overall morbidity was 1.6 %, including grade 2 anastomotic leakage in 0.5 % and grade 2 pancreatic fistula in 0.5 %. No mortality was observed. The number of cases required until the LADG operators acted as LADG surgeons without an instructor was 3 for each of the three surgeons. When comparing the data between that in the training period (n = 9) and the operators' data (n = 174), the median operation time was significantly longer in the training period (355 min) than in the latter period (247.5 min) (p = 0.015). Median blood loss was also greater in the training period (150 ml) than the latter period (32.5 ml), but the difference did not reach statistical significance (p = 0.084). During the training period, no patient developed any complications of ≥ grade 2., Conclusion: These results suggested that LADG could be initiated and performed feasibly and safely if surgeons with much experience of open gastrectomy and laparoscopic surgery received adequate training for LADG.

This randomized Phase II trial is being conducted to evaluate the impact of omentectomy for advanced gastric cancer on patient survival. The primary endpoint is the 3-year relapse-free survival rate and the secondary endpoints are 5-year overall survival, intraoperative blood loss, length of the operation and postoperative morbidity (especially postoperative ileus). The planned sample size is 250 patients (125 for complete removal of the omentum and 125 for preservation of the omentum) to determine whether omentum-preserving gastrectomy may be a candidate procedure for a Phase III trial in a randomized Phase II setting.

We report a case of patient who is alive 10 years after total gastrectomy and partial liver resection for gastric cancer and liver metastasis, respectively. The patient is 69-year-old man who was examined in another hospital for nausea, tarry stool, and weight loss. Diagnosis by stomach fluoroscopy revealed gastric cancer and he was admitted to our hospital in September 2002. Computed tomography (CT) scan and ultrasonography (US) revealed liver metastasis in S7. Distant metastases were not detected. The patient underwent distal gastrectomy, transverse colon partial resection, and a hepatic partial resection in October 2002. Pathological findings showed SI, N1, and M1. Though adjuvant chemotherapy was given, a local recurrence was detected in the liver in February 2003. Hepatic arterial infusion (HAI) was started in April 2003. After 8 courses, HAI was discontinued because of hepatic artery obstruction. No additional distant metastases were found. Therefore, transdiaphragmatic radiofrequency ablation (RFA) was performed by thoracotomy. Currently, the patient is treatment free and remains alive after 10 years with no recurrence.

Background and Aim: We have studied and reported the usefulness of tumor local chemohyperthermia at a low-grade temperature below 43°C with docetaxel-embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor., Methods: Human MKN45 gastric cancer cells were implanted in the hind limbs of Balb-c/nu/nu mice. DML, magnetite-loaded liposome, and docetaxel were injected into the tumors with or without being exposed to an alternating current magnetic field. Docetaxel and tumor necrosis factor-α concentrations, the cell cycle, and cell death rates in the tumor were examined., Results: Docetaxel concentrations were significantly higher in the DML-injected group than in the docetaxel-injected group 3 days after injection. A G2/M peak was observed 1 day after treatment in the DML-injected and exposed group and the docetaxel-injected group, while it was observed 3 days after treatment in the DML-injected without heating group and the magnetite-loaded liposome group. The tumor cell death rate gradually increased in the DML-injected group, with or without being exposed, while it gradually decreased after its peak in other groups. The tumor necrosis factor-α concentration in the tumor treated with DML with heating remained at a high level on the 7th day after treatment, while it decreased after its peak in other groups., Conclusion: The antitumor effect of this treatment derives from a combination of hyperthermia and chemotherapy locally in the tumor., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

We assessed the effects of direct injection of docetaxel-loaded immuno-(trastuzumab)-liposomes (IDL) on a xenograft mouse tumor model to determine potential clinical applications of intratumoral tailored chemotherapy against Her2/neu-overexpressing gastric cancer. The NCI-N87 Her2/neu overexpressing gastric cancer cell line xenograft mouse model was treated with IDL or docetaxel-loaded liposomes (DL). The ratio of the tumor volume of the treatment:control was determined. In addition, docetaxel pharmacokinetics in tumors were measured using high-performance liquid chromatography, and the cell viability and cell cycle distribution of Her2/neu positive cells were determined by flow cytometric analysis. The IDL group showed a significantly higher distribution of docetaxel in the N87 xenograft tumor tissues and superior antitumor efficacy compared to crude administration of docetaxel and/or trastuzumab and DL. The number of viable Her2/neu positive cells decreased following treatment with either free trastuzumab or IDL. On day 7 after treatment, a decrease in the G0/G1 phase of the cell cycle was observed in the DL and IDL groups compared to the control group. No local adverse effects were observed. These results suggest that intratumoral administration of IDL maintains a high concentration of docetaxel within the tumor leading to a safe and effective regional cancer therapeutic strategy. In addition to the inherent cytotoxic effect of trastuzumab, conjugation of trastuzumab to a liposome further enhanced the retention of docetaxel within the tumors. These data suggest that immuno-liposome mediated delivery of drugs is a promising new therapeutic option for patients with advanced gastric cancer that overexpress Her2/neu.

Background: We retrospectively assessed the survival benefit of novel anticancer agents (NACA) after volume-reduction surgery for far-advanced gastric cancer (FAGC)., Methods: From 1995 to 2005, 41 patients with FAGC underwent chemotherapy after volume-reduction surgery. Those treated since 2000 who received NACA were referred to as group A, and those treated before 2000, who received anticancer agents other than NACA, were referred to as group B. In addition, 21 patients with unresectable gastric cancer treated since 2000 who received NACA were referred to as group C. We investigated the significance of volume-reduction surgery during treatment with NACA., Results: The median survival time (MST) was significantly prolonged in group A (626 days) compared to group B (364 days; P = 0.0156). Multivariate analysis showed that having one noncurative factor (NCF), and the use of NACA, were factors that contributed to survival time. Comparison between the subgroup of group A that had one NCF and the subgroup that had two or more NCFs revealed MSTs of 700 days and 180 days, respectively, with a significantly longer MST among the patients with one NCF (P = 0.0021). In addition, no difference from the MST of 333 days in group C was seen among the group A patients with two or more NCFs., Conclusion: The postoperative survival time of patients with one NCF was prolonged by the advent of NACA, but no significant prolongation was observed in the patients with two or more NCFs.

Background/aims: The present study was conducted to investigate the relationship between bone metabolic disorder after gastrectomy for gastric cancer and vitamin D metabolites or the hormones involved in calcium metabolism., Methodology: Twenty-one patients who had undergone gastrectomy for gastric cancer and had been followed for less than 10 years were assessed for bone disorder by microdensitometry. The levels of 1,25-dihydroxy vitamin D (1,25(OH)2VD), 25-hydroxy vitamin D (25(OH)VD), 24,25-dihydroxy vitamin D (24,25(OH)2VD), N-PTH, calcitonin, estradiol, osteocalcin, and ALP were measured and assessed for correlations with clinicopathological factors, including the operative procedure and the number of years since surgery., Results: Bone disorder was found in 9 out of 21 patients (42.9%). The prevalence was significantly higher in patients who had undergone surgery more than 2 years before assessment, so there was a relationship between the period after surgery and bone disorder. Among the vitamin D metabolites, the level of 1,25(OH)2VD was normal in all patients, whereas 25(OH)VD was reduced in 6 out of 21 patients (28.6%) and 24,25(OH)2VD was reduced in 17 patients (81.0%). The 1,25(OH)2VD was significantly higher in the patients with Grade I to III bone disorder compared to the patients with normal bones or early bone disease. The 1,25(OH)2VD/25(OH)VD ratio was significantly higher in the patients without passage of food through the duodenum due to the reconstructive method, while the 25(OH)VD/24,25(OH)2VD ratio was significantly higher in the patients with remaining of duodenal food passage. PTH was decreased in about 50% of the patients, while calcitonin was normal in all patients. Estradiol was decreased in one female patient, while it was elevated in 10 of the 17 men (58.8%). The osteocalcin level was high in all patients irrespective of the period after surgery., Conclusions: After gastrectomy, the incidence of bone metabolic disorder increases with time. Changes of vitamin D metabolites, particularly 25(OH)VD and 24,25(OH)2VD, seem to be closely associated with post-gastrectomy bone disease.

Background/aims: In this study, we examined the expression of MMP-2, MMP-7, and MT1-MMP in peritoneal dissemination of gastric cancer, so as to clarify a possible role of these MMPs in developing peritoneal dissemination, using culture cells and an animal model with peritoneal dissemination., Methodology: Total RNA was extracted from tumor tissues of disseminated foci from 7 patients with gastric cancer and human gastric cancer cell lines of STSA, STKM-1, MKN-28, MKN-45, and KATOIII. Expressions of mRNA for MMP-2, MMP-7, and MT1-MMP were analyzed by reverse transcriptase-polymerase chain reaction. To examine relationships between the expression of these mRNAs and the ability to establish peritoneal dissemination, nude mice were injected into the intraperitoneal cavity with 106 cultured cells of those 5 gastric cancer cell lines., Results: MMP-7 was expressed in 6 of 7 tissues (85.7%) and MT1-MMP in 2 of 7 tissues (28.6%), while MMP-2 was not detected in any of 7 tumor tissues. All 7 tumors had either MMP-7 or MT1-MMP. MMP-7 was recognized in 4 of 5 cells (80%) and MT1-MMP in 2 of 5 cells (40%), while MMP-2 was not found at all. All 5 cancer cells expressed at least one MMP mRNA. In the animal experiments, nude mice inoculated with STKM-1 or MKN-45 cells developed peritoneal dissemination, while those with other cell lines did not. MMP-7 was found both in STSA and MKN-28 (dissemination negative), and in STKM-1 and MKN-45 (dissemination positive). MT1-MMP mRNA was detected in one of two dissemination positive cell lines and in one of three dissemination negative ones., Conclusions: Our results suggested the importance of MMP-7 and MT1-MMP in the peritoneal metastases of gastric cancer, however, it has to be further dissected what role these MMPs might play in detaching of cancer cells from the gastric wall and establishing peritoneal disseminating foci.

A resected case of gastric cancer is described. The patient was a 60-year-old woman who presented a type 3 gastric tumor complicated by invasion of the head of the pancreas and liver. Radical resection was not indicated, and we administered the following combination chemotherapy with TS-1 and CDDP. 120 mg/day of TS-1 was orally administered for 3 weeks followed by 2 drug-free weeks as 1 course and 9 5 mg (60 mg/m(2)) of CDDP was administered intravenously on day 8. After two courses, total gastrectomy and D2 lymph node dissection were performed. Radical surgery for cure was conducted. Microscopically, the histological effect was judged to be grade 1a. One year after the operation, the patient is still alive without recurrence and metastasis. TS-1/CDDP therapy is useful for advanced gastric cancer.

A patient was a 66-year-old male who had advanced gastric cancer with left gastric artery lymph node metastasis and invasion of pancreas and spleen. We thought a complete resection was difficult, so he was given neo-adjuvant chemotherapy by combined of TS-1 100 mg/day (2 weeks administration and 1 week rest) and Paclitaxel (PTX) 75 mg/body (day 1, 8). After 2 courses of this neo-adjuvant chemotherapy, tumor and lymph node swelling had decreased in size, and the tumor markers were reduced remarkably (CEA 9 2.5 --> 12.2 ng/ml, CA 19-9 2, 739 --> 19 3 U/ml). He underwent total gastrectomy and Roux-en Y reconstruction. No.4 d and No.7 lymph nodes were swollen and hard, but white with a neurotic-like appearance. On pathological study, no malignancy was seen in the lymph nodes, and a good partial response was achieved. In this chemotherapy, no side effects were seen, and he maintained good quality of life. TS-1/PTX therapy was thought to be an effective neoadjuvant chemotherapy for advanced gastric cancer.

We reported 2 cases with advanced gastric cancer, successfully treated with TS-1 and CDDP. Case 1 had Type 3 gastric cancer with left supra-clavicular (Virchow) and para-aortic lymph node metastases. Those distant node metastases completely disappeared after two courses of neoadjuvant chemotherapy (NAC) consisting of TS-1/ CDDP, and radical surgery for cure was conducted. The second case had Type 3 carcinoma with peritoneal dissemination. The primary lesion significantly decreased after four courses of the combination chemotherapy. The patient has been alive for 1 year and a half after 14 courses of TS-1/CDDP with stable disease. Significance of TS-1/CDDP in far advanced gastric cancer was discussed.

Background/aims: To confirm the impact of bursectomy on survival, we reviewed the clinical records of patients who underwent radical total gastrectomy with bursectomy for gastric cancer invading the serosa, with special reference to the location of tumor invasion., Methodology: From the records, patients were selected for this retrospective cohort study according to the following criteria: (a) Invasion beyond the serosal surface, (b) No metastases to liver, peritoneum, or distant organs, (c) Negative for peritoneal lavage cytology, and (d) Patients underwent curative D2 total gastrectomy with complete omental bursectomy. A total of 134 patients were eligible. These patients were divided into a group I which included patients with tumors that invaded only the posterior wall and a group II which included those with others. Survival was examined by uni- and multivariate analyses., Results: Survival rates at 3 and 5 years were 67.3% and 53.0% for group I and 68.8% and 53.8% for group II. There was no significant difference in the survival between the two groups (p=0.969), even if survival was stratified by various clinicopathological factors. Multivariate analyses demonstrated that the significant independent factors for the survival were macroscopic type and lymph node metastasis. Location of the invasion was not a significant factor., Conclusions: These results suggested that bursectomy did not inhibit the spreading of tumor cells into the retro-stomach space. There might be no survival benefit of bursectomy in patients with gastric cancer.

Background/aims: We investigated the effects of TS-1 on the survival of nude mice developing peritoneal dissemination of gastric cancer., Methodology: MKN-45 cells were injected into the peritoneal cavity of nude mice and a model of peritoneal dissemination was developed. TS-1 was administered orally every day from day 1 to day 10 or day 10 to day 19., Results: Survival time of these treatment groups was significantly longer than untreated controls. In a pharmacokinetic study, TS-1 was administered on day 10 and the 5-fluorouracil levels were retained and maintained for a longer time, in the ascites and tumor than in plasma. The area under the concentration curve for 5-FU in the tumor was higher, than in plasma or ascites., Conclusions: TS-1 could be effective in treating peritoneal dissemination of gastric cancer, due to the supply of 5-fluorouracil in the tumor by systemic and intraperitoneal circulation.

Background: The objective of this study was to evaluate the accuracy of the intraoperative assessment of early gastric cancer (EGC) and lymph node status., Methods: A total of 280 patients underwent gastrectomy for primary gastric cancer at the Department of Surgery, Yokohama City Kowan Hospital, from 1994 to 2002. Of these 280 patients, 140 were diagnosed as having EGC during surgery (sT1), while the rest were diagnosed with advanced disease (sT2-T4). Of the former 140 patients, 136 patients, who underwent curative resection with D1 or D2 lymphadenectomy, were further investigated for the assessment of lymph node status., Results: The sensitivity, specificity, and accuracy of the surgical diagnosis of EGC were 96.4% (135 of 140), 90.0% (126 of 140), and 93.2% (261 of 280), respectively, while these values for the assessment of lymph node metastases were 55.6% (5 of 9), 94.5% (120 of 127), and 91.9% (125 of 136), respectively. In a further analysis in which patients with tumors of macroscopically depressed type and undifferentiated histology were excluded, all patients staged as sT1sN0 had no lymph node metastases pathologically., Conclusion: Although the depth of tumor invasion can be correctly assessed intraoperatively, it is difficult to be precise regarding the presence of nodal metastases. One practical solution to this problem might be to employ limited surgery for those patients with macroscopically elevated and histologically differentiated tumors.

We report a case of small cell carcinoma of the stomach in a 60-year-old man. The patient was found to have a gastric tumor by routine upper gastrointestinal endoscopy for chronic gastrititis, and was admitted to the hospital. The patient underwent a curative distal gastrectomy with D2 lymph node dissection following a diagnosis of early gastric cancer at the posterior wall of the antrum, in June 2001. Surgical findings were T1, N1, P0, H0, M0, stage I b. The final pathological diagnosis was small cell carcinoma of the stomach with severe lymphatic and vascular invasion (INF alpha, sm, ly3 v2, n1 (+)). In a review of 47 cases seen in the Japanese literature, only 5 patients had early gastric cancer. Lymph node metastasis was observed in 95.0% of all cases, and liver metastasis in 41.0%. Four of the 5 patients with early gastric cancer (80.0%) had lymph node metastases. The prognosis was reported to be extremely poor because small cell carcinoma frequently metastasizes to lymph nodes and/or the liver even in an early stage. The chemotherapy selected by many hospitals is mainly CDDP, but the use of chemotherapeutic drugs varied from hospital to hospital and no effective chemotherapy for the disease has been established as yet.

Background/aims: This study was conducted to clarify the impact of pancreaticosplenectomy on the prognosis of patients with gastric carcinoma., Methodology: Two hundred and seventy-two patients who underwent total gastrectomy with distal pancreatectomy and splenectomy were retrospectively reviewed., Results: Lymph node metastases at the splenic hilum (#10) and along the splenic artery (#11) occurred in 12.4% and 19.2% of cases, respectively. The 5-year survival rate of those without metastasis at #10 was 62.8%. Once nodal metastasis occurred, the prognosis became very poor; only 18.2% in those with a single positive node and 15.4% of those with two or more positive nodes at this location survived 5 years. Similar trends in survival were observed with respect to nodes at #11. When stratified by nodal status as currently determined by microscopic examination, pancreaticosplenectomy saved 4.5% of patients with positive nodes, but was insufficient in 17.3% of cases and was not necessary in the 78.2% of cases who were node negative at these locations., Conclusions: The data indicate that pancreaticosplenectomy can save some patients with positive nodes in these regions; however, the small survival benefit does not provide a basis for the general application of this highly morbid procedure. To further evaluate these results in a randomized study, selection of a subset of patients who are likely to have metastasis is the key.

Current trends in the treatment of gastric cancer indicate the emergence of a more sophisticated approach, with tailored therapy applied to individual cases. Treatment includes a broader spectrum of therapeutic options (Fig. 3), including EMR, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and typical radical surgery with lymph node dissections. Precise characterization of the lesions, especially the depth of invasion in the gastric wall, its size, histology and whether there is ulceration, is the key to successful treatment of N0 mucosal cancer. Micrometastasis and metastasis at the molecular level are issues that require further investigation. Laparoscopic surgery may be more widely accepted. The limitations of nodal dissection based on the concept of a sentinel node should be carefully evaluated in future studies. [figure: see text] Many treatment options, ranging from minimally invasive surgery to D2 node dissection, are available to the surgical oncologist who is treating EGC. As more information is gathered, surgeons will be better able to select patients who are good candidates for minimal surgical procedures.