Jun Isogaki

Downregulation of EphA7 by hypermethylation in colorectal cancer

A significant reduction of EphA7 expression in human colorectal cancers was shown using semiquantitative reverse transcription–polymerase chain reaction analysis in 59 colorectal cancer tissues, compared to corresponding normal mucosas (P=0.008), and five colon cancer cell lines. To investigate the mechanism of EphA7 downregulation in colorectal cancer, we examined the methylation status of the 5′CpG island around the translation start site in five colon cancer cell lines using restriction enzymes, methylation-specific PCR, and bisulfite sequencing and found evidence of aberrant methylation. The expression of EphA7 in colon cancer cell lines was restored after treatment with 5-aza-2′-deoxycytidine. Analysis of methylation status in totally 75 tumors compared to clinicopathological parameters revealed that hypermethylation of colorectal cancers was more frequent in male than in female (P=0.0078), and in moderately differentiated than in well-differentiated adenocarcinomas (P=0.0361). There was a tendency that hypermethylation in rectal cancers was more frequent than in colon cancers (P=0.0816). Hypermethylation was also observed in colorectal adenomas. This is the first report describing the downregulation of an Eph family gene in a solid tumor via aberrant 5′CpG island methylation. It provides the evidence that EphA7 gene is involved in human colorectal carcinogenesis.

Clinical Outcome and Clinicopathological Characteristics of Recurrence after Laparoscopic Gastrectomy for Advanced Gastric Cancer

Background: Although laparoscopic gastrectomy has been recognized as a treatment of early gastric cancer, the indication for laparoscopic gastrectomy with D2 lymph node dissection has remained controversial. D2 lymph node dissection is considered to be feasible for advanced gastric cancer in some high-volume institutions specifically trained for the laparoscopic procedure. This study was undertaken to determine the clinical outcome and clinicopathological characteristics of patients who showed recurrence following laparoscopic gastrectomy for advanced gastric cancer. Methods: From August 1999 through February 2009, among 805 patients who underwent laparoscopic gastrectomy associated with regional lymph node dissection, a total of 209 patients undergoing gastrectomy associated with lymph node dissection who consequently obtained complete resection for advanced gastric cancer were subjected to the retrospective analysis to evaluate clinical outcome. Results: The mean period of postoperative observation was 1,068 days. The final stages of the 209 cases were as follows: 83 in IB, 56 in II, 46 in IIIA, and 24 in IIIB. The 5-year survival rate was 89.1% in stage IB, 93.1% in stage II, 52.5% in stage IIIA, and 46.5% in stage IIIB, respectively. A total of 27 patients (12.9%) had recurrence. Postoperative recurrence of gastric carcinoma occurred in peritoneal dissemination in 13 patients, liver in 7, distant lymph nodes in 6, ovary in 3, lung in 2, skin in 1, and meninges in 1 patient. There were neither port-site metastases nor locoregional recurrence. Conclusion: The characteristics and the rate of postoperative recurrence after laparoscopic gastrectomy for advanced gastric cancer were not greatly different from those of the open conventional procedure. Although further observation is required to finally conclude long-term survival, laparoscopic radical gastrectomy may possibly be indicated for patients with advanced gastric cancer.

Robot-assisted surgery for gastric cancer: experience at our institute.

Objective: The robot-assisted surgical system was developed for minimally invasive surgery and is thought to have the potential to overcome the shortcomings of laparoscopic surgery. We introduced this system for the treatment of gastric cancer in 2008. Here we report our initial experiences of robot-assisted surgery using the da Vinci system. Methods: A retrospective review of robot-assisted gastrectomy for gastric cancer patients was performed in our institute. The clinicopathological features and surgical outcomes were analyzed. Whereas the procedures of the gastrectomy were similar to those of the usual laparoscopic surgery, several aspects such as the port placement and the role of the assistant were modified from those for conventional laparoscopic surgery. Results: From January 2008 to December 2010, 61 patients with gastric cancer underwent robot-assisted surgery. Gastrectomy was distal in 46 patients, total in 14, proximal in 1 and no operation was converted to the open procedure. D2 lymph node dissection was performed on 28 patients in the distal gastrectomy group and on 11 in the total gastrectomy group. Complications occurred in 2 cases (4%): these consisted of ruptured sutures and hemorrhage from the anastomotic site. Conclusions: This study demonstrated that robot-assisted gastrectomy using the da Vinci system can be applied safely and effectively for patients with gastric cancer.

Impact of anastomotic complications on outcome after laparoscopic gastrectomy for early gastric cancer

The effects of anastomotic complications after laparoscopically assisted gastrectomy (LAG) have not been studied widely. The aims of this observational study were to identify potential factors that predict anastomotic complications and investigate the impact of anastomotic complications in patients undergoing gastrectomy for early gastric cancer.

Totally laparoscopic pancreaticoduodenectomy for locally advanced gastric cancer.

BackgroundIn patients having locally advanced cancer of the stomach with suspected tumor infiltration to the pancreatic head or the duodenum, a concurrent pancreaticoduodenectomy with gastrectomy is occasionally prerequisite to achieve a microscopically tumor-free surgical margin.Materials and methodsWe present the first series of successful totally laparoscopic pancreaticoduodenectomy (TLPD) for advanced gastric cancer with suspected infiltration to the pancreatic head.ResultsTLPD was successfully performed without adverse events during surgery and resulted in favorable short-term outcomes of three patients with locally advanced gastric cancer with suspected invasion to the pancreas.ConclusionsAlthough TLPD for locally advanced gastric cancer is a technically difficult challenging operation that requires careful dissection along the major vessels, intracorporeal tie sutures, and the placement of an external drainage tube into a narrow pancreatic duct, this procedure is technically feasible and safe in the hands of experienced surgeons. Long-term follow-up is mandatory to validate oncological outcome.

Mutational analyses of multiple target genes in histologically heterogeneous gastric cancer with microsatellite instability.

It has been recognized that gastric cancer often shows histological heterogeneity in a single tumor. Although microsatellite instability (MSI) has been reported in gastric cancer, the significance of genomic instability in gastric cancers with histological heterogeneity within a single tumor has never been addressed. We investigated MSI at 8 microsatellite loci in 40 normal/tumor DNA pairs from 20 gastric cancers with histological heterogeneity. Six of 20 patients (10 DNAs of 40 tumor DNAs) had severe MSI in more than 3 loci. Four of the MSI‐positive cases had frameshift mutations in the poly(A)10 tract of the TGFβRII gene. This mutation was found only in the MSI‐positive component in the 2 cases (cases 4 and 5) in which only 1 component exhibited MSI. The other 4 cases demonstrated homozygous or heteroclonal mutations (1 and 2 base deletions) in the poly(A)8 tract of the hMSH3 gene; no mutation was detected in the poly(C)8 tract of the hMSH6 gene in any of the MSI‐positive cases. The profile of alterations in multiple targets was different between the 2 components in most of the cases (5/6). These findings suggest that mismatch repair deficiency in MSI‐positive tumors causes multiple gene inactivations through frameshift mutations in short repetitive sequences in a heterogeneous way within a histologically heterogeneous tumor.

Delayed vascular injury and severe respiratory distress as a rare complication of a central venous catheter and total parenteral nutrition

Complications related to central venous catheters (CVCs) in the postoperative period can be fatal. We recently had a case of bilateral pleural effusion and respiratory distress caused by delayed vascular injury. A 79-y-old Japanese woman was admitted to our hospital because of advanced gastric carcinoma. A multiple-lumen CVC was placed through the left subclavian vein 1 d before surgery for postoperative nutritional management. The patient suddenly complained of dyspnea, and the chest X-ray film revealed right massive pleural effusion. Although the patients symptoms soon disappeared after the thoracentesis, she again developed severe respiratory distress, and an endotracheal intubation was performed and her respiration was managed by mechanical ventilation. Computed tomographic scan of the chest revealed a displacement of the tip of the CVC out of the wall of the superior vena cava, mediastinitis, and leakage of intravenous fluid, which may have been caused by delayed vascular injury due to the CVC. The CVC was removed immediately after the diagnosis of delayed vascular injury at 10 d after surgery. The patient soon recovered with conservative treatment and was discharged from the hospital 43 d after surgery. This case highlights an extremely rare presenting complication of CVC placement and total parenteral nutrition.

Laparoscopic excision of the cystic lymphangioma occurred in the lesser omentum: report of a case and review of literature.

Intraperitoneal cyst occurring in the lesser omentum is extremely rare entity. Because of the absence of abdominal symptoms, omental cyst is occasionally found accidentally in imaging examination performed during health screening. We experienced a case of cystic lymphangioma that occurred in the lesser omentum, which was successfully resected under complete laparoscopic procedure. A 50-year-old Japanese woman was admitted to our hospital because a cystic mass was found in the abdomen. Abdominal computed tomography scan was performed because she had a traffic accident, despite complaining no abdominal symptoms. The abdominal computed tomography scan and magnetic resonance imaging revealed a large cystic mass in the lesser omentum adjacent to the lesser curvature of the stomach, which was resected with a complete laparoscopic procedure. As the cystic wall was closely attached to the lesser curvature of the gastric wall, an ultrasonic coagulating shear was quite helpful to entirely mobilize the cyst from the surrounding structure such as lesser curvature of the stomach. After placing clips to the feeding vessels to the cyst branched from the accessory hepatic vessels, the entire cyst was mobilized without leakage of cystic content. The postoperative course was uneventful with slight delayed gastric emptying due to partial denervation of the lesser curvature of the stomach. The patient was discharged on eighth day after surgery without any postoperative complications. This is the first case of cyst of lesser omentum resected under complete laparoscopic procedure and certainly highlights advantage and feasibility of laparoscopic approach for cases with abdominal cystic lesions. Laparoscopic excision of cystic lymphangioma in the lesser omentum provides all the advantage of minimally invasive procedure.

Simultaneous imaging of membrane antigen and the corresponding chromosomal locus in pathology archives

A new procedure for the simultaneous staining of membranous antigens, such as tyrosine kinase‐type cell surface receptor HER2 (c‐erbB2), and the corresponding chromosome (chromosome 17 for c‐erbB2) in the same cell for use in examining pathology archives is presented. A multistep procedure involving microwave‐assisted fluorescence in situ hybridization and immunofluorescence yielded cell images having c‐erbB2 on the membrane and genomic signals from the chromosome 17 centromere and the c‐erbB2 locus. Furthermore, a combination of microwave‐assisted chromogenic in situ hybridization and immunohistochemistry found colorized signals from both chromosome 17 centromere in the nuclei and c‐erbB2 on the membranes of individual cells. Quantitative image analysis further confirmed the presence of a significantly stronger c‐erbB2 immunoreactivity on cells containing three or more signals from chromosome 17 than from those with less than three signals. It was possible to extend the constellation of cell surface markers and corresponding chromosomes or locus‐specific makers to several other genes including CDH1. In this case, the disappearances of CDH1 expression, a CDH1 locus signal, and a centromere enumeration probe (CEP) 16 signal were simultaneously demonstrated in the less‐adhesive tumor cells. Thus, it is believed that this procedure might pave the way for exploiting pathology archives for the genotype–phenotype analysis of individual cells.

Lymph node dissection with cervical approach as a salvage surgery for locoregional failure after definitive chemoradiotherapy in a patient with recurrent esophageal carcinoma: report of a case

Salvage surgery is one important therapeutic option after locoregional failure of definitive chemoradiotherapy (dCRT) in patients with advanced or recurrent esophageal carcinoma. We have performed cervical lymph node dissection as a salvage surgery after chemoradiotherapy in a patient with recurrent esophageal carcinoma. A 54-year-old Japanese man was admitted to our hospital because of multiple lymph node metastases after endoscopic submucosal dissection (ESD) for early-stage esophageal carcinoma. The patient underwent a circumferential ESD of early-stage esophageal carcinoma in another hospital. The esophageal carcinoma, measuring 75 × 60 mm in size, was a superficial spreading type located in the middle portion of the thoracic esophagus. Histology of the resected specimen revealed a moderately to poorly differentiated squamous cell carcinoma, and the depth of invasion was limited within the mucosal layer associated with a small area being attached to the muscularis mucosae. Five months after ESD, lymph node metastases in the regions of right recurrent nerve and the left tracheobronchus were found, for which dCRT was performed. These metastatic lymph nodes disappeared in the chest CT scan images. Lymph node metastasis in the region of the right recurrent nerve then reappeared 8 months after the completion of CRT. Considering the solitary lymph node metastasis and surgical invasiveness, lymph node dissection using a cervical approach was selected as a salvage surgery. Cervical approach for the lymph node dissection in the region of right recurrent nerve may be one feasible option as a minimally invasive salvage surgery for patients with recurrent esophageal carcinoma after dCRT.