Intracranial hemorrhage in patients treated with bevacizumab: report of two cases.

Treatment with bevacizumab, an antiangiogenic agent, in patients with metastatic or unresectable colorectal cancer was approved less than 4 years ago in Japan. Bevacizumab improves the survival of patients with metastatic colorectal cancer; however, it may lead to complications such as bleeding, which are sometimes fatal. Bevacizumab should be administered only after careful consideration because the potential risks of therapy outweigh its benefits. Therefore, pharmaceutical companies do not recommend bevacizumab therapy for patients with brain metastases. While some reports support the cautious use of bevacizumab, others report that it is not always necessary to prohibit its use in patients with metastases to the central nervous system (CNS), including the brain. Thus, bevacizumab therapy in colorectal cancer patients with brain metastases is controversial, and it is unclear whether brain metastases are a risk factor for intracranial hemorrhage during anti-vascular endothelial growth factor (VEGF) therapy. We report a 64-year-old man and a 65-year-old man with recurrent colorectal cancer without brain metastases; these patients developed multifocal and solitary intracranial hemorrhage, respectively, after the administration of bevacizumab. Our findings suggest that intracranial hemorrhage can occur even if the patient does not have brain metastases prior to bevacizumab treatment and also suggest that brain metastases are not a risk factor for intracranial hemorrhage with bevacizumab treatment. These findings also question the necessity of excluding patients with brain metastases from clinical trials on anti-VEGF therapy.

Medium- and long-term results of jejunal pouch reconstruction after a total and proximal gastrectomy.

PURPOSE: We developed several kinds of jejunal (J)-pouch reconstruction after a gastrectomy for gastric cancer. The aim of this study was to investigate the advantages of these methods. METHODS: As for the treatment of malignant gastric diseases at stage II or earlier, we employed the J-pouch reconstruction (Roux-en-Y method: JPRY, or J-pouch interposing: JPI) following a total gastrectomy. We also used JPI after a proximal gastrectomy for early gastric cancer located in the upper third of the stomach. RESULTS: Out of a total of 80 patients, JPRY was performed in 40 patients and JPI in 40. No anastomotic leaks were associated with the use of an automatic stapler. The stapler (Endo GIA; U.S. Surgical, Norwalk, CT, USA) with a 60-mm-long white cartridge minimized bleeding from the anastomotic site and reduced the operative time. While two patients died of recurrence, all other patients are alive and well for a maximum of 15 years after surgery. The motility of the J pouch was satisfactory after both surgical procedures, as measured by the bile regurgitation test or the transit test employing radiopaque markers. The mean percentage of the radiopaque markers eliminated from the J pouch 1 h after breakfast was 7.5% in the JPRY group and 0%-33% in the JPI group. After another hour, the corresponding percentage was 19.5% in the JPRY group and 14%-60% in the JPI group. CONCLUSION: Our procedures for J-pouch reconstruction are considered to result in a favorable postoperative quality of life and prognosis. J-pouch reconstruction is therefore advantageous in terms of operative morbidity, postoperative clinical signs, symptoms, and dietary status.

Microbiological evaluation after gastrectomy and reconstruction for gastric cancer.

The purpose of this study was to evaluate microbial flora in the mucosa of reconstructed organs after gastrectomy for gastric cancer and improve postoperative quality of life by treating the flora. The number of aerobes was significantly higher in the gastric remnant in the proximal gastrectomy-jejunal pouch interposition group (n=8) than the distal gastrectomy-Billroth II reconstruction (G-BII) group (n=2) or the pylorus-preserving gastrectomy (PPG) group (n=8). The mean number and positive rate of anaerobes tended to be higher in jejunal pouch reconstruction groups. No Helicobacter pylori were detected in any specimens after the G-BII and jejunal pouch reconstruction. However, the gastric remnant and duodenum in the distal gastrectomy-Billroth I reconstruction group (n=5; positive rate of 80% and 20%, respectively) and the PPG group (positive rate of 63% and 25%, respectively) showed H. pylori. We concluded that more anaerobes tended to grow in the mucosa of reconstructed organs after jejunal pouch reconstruction than other procedures. Some patients after jejunal pouch reconstruction worried about their halitosis. Therefore, elimination of anaerobes may relieve it and improve postoperative quality of life.

Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients.

Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including in the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important in affecting gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. The CDX2 homeobox transcription factor plays a key role in intestinal development, but CDX2 is also expressed in most of the intestinal metaplasia and part of the carcinomas of the stomach. We analyzed the methylation status of the CDX2 5' CpG island in gastric cancer cell lines by methylation-specific PCR (MSP), and then CDX2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. We further examined the methylation status of CDX2 in primary gastric carcinomas by MSP and compared it with the past lifestyle of the patients, including dietary habits. Methylation of CDX2 was found in 20 (34.5%) of the 58 male patients and one (6.7%) of the 15 female patients. Since the methylation frequency was low in the female patients, the analysis was performed only on the male cases. CDX2 methylation was correlated with the decreased intake of green tea and cruciferous vegetables, and also with full or overeating habits. These findings are consistent with epidemiological observations on gastric cancer. We also analyzed the methylation status of p16/INK4a and hMLH1, but their frequencies were not associated with dietary factors or other lifestyle factors. Thus, diet could be an important factor determining the methylation status of genes such as CDX2 and the resultant aberrant expression of genes involved in carcinogenesis.

Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma.

SOX2, a SRY-related HMG box protein, is thought to be an important transcription factor during organogenesis, including the stomach although the expression and function are unclear. We investigated SOX2 protein expression to clarify its roles in differentiation and carcinogenesis of the stomach. Using polyclonal SOX2 antibodies, expression of SOX2 in gastric normal mucosae, intestinal metaplasia and carcinomas from 68 gastric carcinoma patients was studied by immuohistochemistry. SOX2 was strongly and moderately expressed in the nuclei of the foveolar epithelium and intestinal metaplasia, respectively, the expression being much higher than that in carcinomas (p<0.0001). Using antibodies to MUC5AC, MUC2 and CD10, the 68 gastric carcinomas were classified into gastric type, intestinal type, mixed gastric and intestinal type, and null type. A significant difference in SOX2 expression was observed between the gastric and intestinal types (p<0.05), with a higher expression in the former than in the latter. Moreover, over-expression of SOX2 induced the mRNA expression of endogenous MUC5AC, a specific mucin marker for the gastric type, in COS-7 cells. Our findings indicate that SOX2 may play a role in differentiation of the human gastric epithelium, and that SOX2 may be involved in gastric carcinogenesis, particularly in the gastric type.