Junya Kizaki

Characteristics and prognosis of gastric cancer in young patients

The clinicopathological features of gastric cancer (GC) differ between younger and older patients, and it is thought that younger patients have a worse prognosis than older patients due to delayed diagnosis and more aggressive tumor behavior. These characteristics, however, remain controversial. A total of 3,818 patients with pathologically confirmed primary gastric adenocarcinoma were treated at our institution. We analyzed the difference in demographic and clinicopathological characteristics between 169 young [≤40 years of age, younger group (YG)] and 3,649 older [>40 years of age, older group (OG)] GC patients. There was a significantly higher proportion of females in the YG compared with the OG (53.3 and 31.0%, respectively; P<0.0001). The 5-year overall survival of the YG was significantly lower compared to that of the OG (59.7 and 65.9%, respectively; P=0.049). However, YG patients with curative resection had a similar 5-year survival rate to OG patients with curative resection (88.0 and 85.8%, respectively; P=0.547). Female patients in the YG showed a significantly lower survival rate than males in the YG (44.3 and 73.1%, respectively; P=0.0002). Multivariate analyses revealed that macroscopic type, depth of invasion, peritoneal metastasis, distant metastasis and curative resection were independent prognostic factors for the YG with GC. Young GC patients who undergo curative resection do not have a worse prognosis than older patients. Early diagnosis is important in successfully carrying out a curative resection and offering a better prognosis, particularly in females.

Prognosis of metastatic splenic hilum lymph node in patients with gastric cancer after total gastrectomy and splenectomy.

AIM To clarify the significance of combined resection of the spleen to dissect the No. 10 lymph node (LN). METHODS We studied 191 patients who had undergone total gastrectomy with splenectomy, excluding non-curative cases, resection of multiple gastric cancer, and those with remnant stomach cancer. Various clinicopathological factors were evaluated for any independent contributions to No. 10 LN metastasis, using χ(2) test. Significant factors were extracted for further analysis, carried out using a logistic regression method. Furthermore, lymph node metastasis was evaluated for any independent contribution to No. 10 LN metastasis, using the same methods. The cumulative survival rate was calculated using the Kaplan-Meier method. The significance of any difference between the survival curves was determined using the Cox-Mantel test, and any difference was considered significant at the 5% level. RESULTS From the variables considered to be potentially associated with No. 10 LN metastasis, age, depth, invasion of lymph vessel, N factor, the number of lymph node metastasis, Stage, the number of sites, and location were found to differ significantly between those with metastasis (the Positive Group) and those without (the Negative Group). A logistic regression analysis showed that the localization and Stage were significant parameters for No. 10 LN metastasis. There was no case located on the lesser curvature in the Positive Group. The numbers of No. 2, No. 3, No. 4sa, No. 4sb, No. 4d, No. 7, and No. 11 LN metastasis were each found to differ significantly between the Positive Group and the Negative Group. A logistic regression analysis showed that No. 4sa, No. 4sb, and No. 11 LN metastasis were each a significant parameter for No. 10 LN metastasis. There was no significant difference in survival curves between the Positive Group and the Negative Group. CONCLUSION Splenectomy should be performed to dissect No. 10 LN for cases which have No. 4sa, No. 4sb or No. 11 LN metastasis. However, in cases where the tumor is located on the lesser curvature, splenectomy can be omitted.

Molecular targeting to treat gastric cancer

Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.

Molecular targeting therapy using bevacizumab for peritoneal metastasis from gastric cancer

AIM To clarify the significance of vascular endothelial growth factor (VEGF) in peritoneal metastasis from gastric cancer, using the gastric cancer cell line MKN-45 compared with the high potential peritoneal dissemination gastric cancer cell line MKN-45P. METHODS The supernatant of culture medium of MKN-45 cells or MKN-45P cells was collected and the concentrations were measured of various cytokines, matrix metalloproteinases, growth factor and angiogenic factors, including VEGF. We performed an initial pilot study to explore whether bevacizumab, a humanized monoclonal antibody against VEGF, had any suppressive effect on the peritoneal dissemination from gastric cancer in an experimental nude mouse model of peritoneal metastasis. RESULTS The concentrations of interleukin-6 (IL-6), IL-8, VEGF and matrix metalloproteinase-2 protein in the culture supernatant were each significantly higher than each of those for MKN-45. In the in vivo study, the volume of ascites and the mitotic index were significantly lower in the therapy group than in the non-therapy group. The survival curve of the therapy group was significantly higher than that of the non-therapy group. These results suggested that VEGF was correlated with peritoneal metastasis from gastric cancer. CONCLUSION Findings suggested that bevacizumab for inhibiting VEGF could suppress peritoneal dissemination from gastric cancer.

Cronkhite-Canada syndrome complicated with multiple gastric cancers and multiple colon adenomas

Background: We experienced a case in which Cronkhite-Canada Syndrome presented with complications of multiple gastric cancers and multiple colon adenomas. Case Report: Our case is a 64-year-old male who visited a nearby hospital with diarrhea and weight loss. The patient was anemic and hypoproteinemic, with multiple polyps in the stomach, duodenum, and large intestine. He also presented with alopecia, onychatrophia, cutaneous pigmentation, and dysgeusia, and was diagnosed with Cronkhite-Canada Syndrome. Follow-up examinations found multiple gastric cancers and colon adenomas. We performed a total gastrectomy and a polypectomy of the large intestine lesions, revealing 4 well-differentiated adenocarcinomas in the resected stomach, and tubular adenomas in the large intestine lesions. Intraoperative findings included scattered melanoid pigmentation on the mesentery and the small intestinal wall. Tumor cells were positive for p53 and Ki67 and partially positive for MUC5AC and MUC2. Cronkhite-Canada Syndrome polyps are generally classified as juvenile type polyps, and these polyps rarely become cancerous. However, of the 383 cases of Cronkhite-Canada Syndrome reported in Japan, complications of gastric cancer were found in 39 cases (10.2%), and only 8 cases with multiple gastric cancer were reported in Japan. including the cases we have personally experienced. There were only two English literatures on Cronkhite-Canada Syndrome complicated with gastric cancer. So it is necessary to notify this information of Cronkhite-Canada Syndrome to the world. Conclusions: Close gastrointestinal examination and strict follow-up are believed to be essential for Cronkhite-Canada Syndrome patients.

Characteristics and prognosis of synchronous multiple early gastric cancer

AIM To assess the clinicopathologic characteristics, risk factors, and prognosis for synchronous multiple early gastric cancer (SMGC). METHODS A total of 146 patients with SMGC and 1194 patients with single gastric cancer who had undergone gastrectomy between 1989 and 2008 were retrospectively analyzed to determine their clinicopathologic characteristics and postoperative survival. Tumors were classified into groups on the basis of location and histology. Smoking habits were evaluated using the Brinkman index. Clinical and pathological factors were compared using either Fishers exact test or Pearsons χ(2) test. Logistic regression analysis was performed to identify independent risk factors. Survival rate was calculated using the Kaplan-Meier method. RESULTS SMGCs accounted for 10.9% of gastric cancer cases and occurred predominantly in elderly male patients with a family history of gastric cancer who were both smokers and drinkers. These tumors were typically macroscopically elevated and histologically differentiated. There were no significant differences between SMGC and single gastric cancer patients with respect to tumor location, tumor size, lymph node metastasis, the number of metastatic lymph nodes, venous invasion, or tumor stage (P = 0.052, P = 0.347, P = 0.595, P = 0.805, P = 0.559, and P = 0.408, respectively). Further, there was no significant difference in postoperative survival between the patient groups (P = 0.200). Of the 146 SMGC patients, a single patient had remnant cancer. CONCLUSION A careful preoperative endoscopy is necessary for patients who are at high risk of SMGC, and minimally invasive treatment may be indicated in some cases.

A Study of Gastric Cancer Cases with Liver Metastasis

The prognosis of gastric cancer patients with liver metastasis is very poor because many cases of gastric cancer with liver metastasis have multiple metastatic nodules in the liver and other non-curative factors, such as severe lymph node metastasis and/or peritoneal metastasis. The prognosis for gastric cancer patients with synchronous liver metastasis and the significance of hepatectomy including metachronous liver metastasis from gastric cancer in Kurume University Hospital are reported. Methods: A total of 77 gastric cancer patients with synchronous liver metastasis were admitted between 1995 and 2010 to Kurume University Hospital. There were 17 hepatectomy cases (synchronous metastasis 12 cases, metachronous metastasis 5 cases) from 1984 to 2010. Results: With respect to prognostic factors for gastric cancer cases with liver metastasis, significant differences were observed for peritoneal metastasis, histology, lymph node metastasis, gastrectomy, systemic chemotherapy, the number of stage IV factors, the number of metastatic nodules (within 3), and intra-hepatic arterial infusion (HAI). Multivariate analysis showed that histology, chemotherapy, and HAI were independent prognostic factors. The number of metastatic nodules in all 17 hepatectomy cases was within 3. Three of five cases with hepatectomy for metachronous metastasis were alive more than 5 years after hepatectomy. On the prognosis of hepatectomy cases, there were significant differences for synchronous or metachronous metastasis, lymph node metastasis, the number of stage IV factors, and the stromal volume of the primary site. Conclusions: Multimodal treatment including HAI is considered effective for gastric cancer cases with liver metastasis. If patients have no stage IV factors except for H factor, and the number of metastatic nodules is within 3, hepatectomy is recommended, especially for patients with metachronous liver metastasis, medullary stromal volume type, and low-grade lymph node metastasis.

A Patient with Advanced Gastric Cancer and Situs Inversus Totalis: Report of a Case

Situs inversus totalis (SIT) is a rare congenital anomaly in which the positions of the abdominal and thoracic cavity structures are reversed. The reported incidence of SIT is one in 10,000 to 50,000 live births. There are few reports of gastric cancer in individuals with SIT or of the potential complications of surgical intervention in such cases. We report the case of a 79-year-old woman with SIT who underwent surgical treatment for advanced gastric cancer at our hospital and review the pertinent literature. Prior to surgery, abdominal computed topography angiography with 3-dimensional reconstruction was performed to uncover any variations and to verify the exact structures and locations of vessels. Total gastrectomy with D2 lymphadenectomy and cholecystectomy were performed safely and with careful consideration of the mirror-image anatomy.

Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer

The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole‐exome and whole‐genome sequencing have elucidated genomic alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer‐relevant genes in Type IV, we performed whole‐exome sequencing and genome‐wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein‐coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog (MRAS), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin‐like growth factor 1 receptor (IGF1R) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.

A Case of Gastric Cancer with Neuroendocrine Carcinoma, Signet Ring Cell Carcinoma Components, and Intramural Metastases

Patient: Male, 67 Final Diagnosis: Gastric cancer with neuroendocrine carcinoma Symptoms: — Medication: — Clinical Procedure: Total gastrectomy • splenectomy with D2 lymph node dissection Specialty: Surgery Objective: Rare co-existance of disease or pathology Background: Many neuroendocrine carcinomas exhibit medullary infiltration and expanded proliferation. Differentiated tubular adenocarcinoma is frequently seen in the superficial region in many neuroendocrine carcinoma cases. However, the present case showed non-medullary infiltration and signet ring cell carcinoma in the superficial region, with intramural metastases distributed throughout the whole of the stomach. Case Report: A 67-year-old man was referred to our institution for treatment of gastric cancer. Type IIc-like advanced gastric cancer was detected in the greater curvature of the middle body of the stomach. The patient underwent total gastrectomy, splenectomy with D2 lymph node dissection, and Roux-en-Y reconstruction with curative resection. The tumor was diagnosed as a large-cell endocrine carcinoma of the stomach. A solid growth of signet ring cells was seen in the mucosa and submucosa. Intramural metastases were observed in many other depressed lesions. Large-cell carcinoma invaded the submucosa, mainly in the intramural metastatic site. Metastasis to one lesser curvature lymph node was also seen on histological examination. The final diagnosis was a gastric cancer of type 0–IIc (T4a) [M] (with intramural metastases) at T4aN1H0P0M0 Stage IIIA. This patient has remained alive without recurrence for 72 months after surgery. Conclusions: We recommend close preoperative examination of neuroendocrine carcinoma, taking intramural metastases into consideration.