野田 弘志

Although epithelial-mesenchymal transition (EMT) has been implicated as the pivotal event in metastasis, there is insufficient evidence related to EMT in clinical settings. Intratumor heterogeneity may lead to underestimation of gene expression representing EMT. In the present study, we investigated the expression of EMT-associated genes and microRNAs in primary colorectal cancer while considering intratumor heterogeneity. One-hundred and thirty-three multiple spatially separated samples were obtained from 8 patients with metastatic colorectal cancers and 8 with non-metastatic colorectal cancers, from the tumor center (TC), invasive front (IF) and metastasis. Differences in gene and microRNA expression were investigated by microarray and quantitative reverse-transcription PCR. Gene expression microarray analysis detected 7920 sites showing differing levels of gene expression among the TC, IF and metastasis. Expression of the EMT-associated gene zinc-finger E-box-binding homeobox 1 (ZEB1) significantly increased in the IF (P<0.01). To exclude individual differences, the expression ratio between TC and IF in each tumor was applied to analysis. This approach enabled recognition of the activation of the VEGF and Wnt signaling pathways, which were involved in metastasis via promotion of EMT. While no activation of these pathways was seen at the TC, regardless of whether tumors were metastatic or non-metastatic, they were preferentially activated at the IF in metastatic tumors, where high ZEB1 expression was seen in connection with decreased miR-200c expression. Multiple sampling in a tumor revealed that heterogeneous ZEB1 expression induced by EMT-associated signaling pathways played a pivotal role in metastasis via regulation of miR-200c.

Mesenteric leiomyosarcoma is a rare disease with poor prognosis. Previously, mesenteric leiomyosarcoma was not differentiated from gastrointestinal stromal tumor (GIST), which is the most common mesenchymal tumor of the gastrointestinal tract, and several cases of GIST may have been misclassified as mesenteric leiomyosarcoma. Thus, the actual clinicopathological characteristics of mesenteric leiomyosarcomas remain unclear. We herein describe a case of leiomyosarcoma arising in the descending mesocolon in a patient who developed metachronous liver metastasis. A 76-year-old woman reported a mass in her left upper abdomen. Computed tomography imaging revealed a low-density tumor adjacent to the descending colon. The patient underwent surgery and the tumor was resected along with part of the descending colon. Immunohistochemical differential diagnosis revealed that the tumor was positive for smooth muscle actin and desmin, and negative for CD117 (c-KIT) and S-100, which are characteristic of gastrointestinal leiomyosarcoma. A single liver metastasis developed 24 months after the operation. The patient underwent curative resection of the metastatic lesion. Sixteen months following surgery for the liver metastasis and 40 months after the initial removal of the primary lesion, the patient remains disease-free. The prognosis of leiomyosarcoma remains poor and standardized chemotherapy for this rare disease has not yet been established. Early diagnosis and surgical removal of the tumor is the only potentially curative option for liver metastasis of mesenteric leiomyosarcoma.

Intraductal papillary mucinous neoplasm (IPMN) has been associated with a high incidence of extrapancreatic malignancies (EPMs). However, it is controversial whether IPMN is prognostic for EPM. We aimed to help clarify the issue studying this association in patients with histologically proven IPMN. We reviewed 51 surgically resected IPMNs in Saitama Medical Center, Jichi Medical University between January 1991 and June 2012. Mean follow-up was 63.7 +/- 47.8 months. The observed EPM incidence was compared with the expected incidence of cancer in Japan. Of the 51 IPMNs, 14 were malignant and the rest benign. Seventeen EPMs developed in 15 patients (29.4%), nine of which occurred prior to IPMN diagnosis. For all IPMNs, the standardized incidence ratio (SIR) was significantly increased for the six types of reported EPMs (SIR=2.18, CI=1.31-3.42, P=0.004). Benign IPMNs showed no association with EPMs (SIR=0.92, CI=0.43-1,76, P=0.87). In contrast, malignant IPMNs showed a higher association (SIR=3.83, CI=1.87-7.03, P=0.0009). However, the association was mostly due to the prior EPMs, as removal of metachronous EPMs had no significant effect (SIR=3.63, CI=1.59-7.17, P=0.005). Thus, only malignant IPMNs drive the significant association with prior EPMs, showing a near 4-fold increased incidence compared to the general Japanese population. Histological characterization of IPMNs may offer clinical value for EPM patient management. We hypothesize that these observations may be explained if some patients with EPMs present a higher risk to develop IPMNs (and vice versa), possibly resulting from an uncharacterized multiple cancer predisposition condition.

We herein describe the case of an adult with a complicated huge lymphangioma of the small bowel mesentery. Computed tomography (CT) confirmed a 45X30X14 cm multiple and separate, mixed and solid cystic tumor without enhancement by contrast medium in the abdominal cavity. Mesenteric CT angiography with three-dimensional (3D) reconstruction showed that the tumor did not involve the first jejunal artery, although the tumor did involve the subsequent jejunal and ileal arteries and the corresponding segment of the small bowel. Under anatomic guidance based on mesenteric CT angiography with 3D reconstruction, we were able to successfully excise the tumor. Mesenteric lymphangioma should be excised even when the tumor is asymptomatic. Mesenteric CT angiography with 3D reconstruction is useful for the surgical treatment of huge mesenteric tumors.

Background: Improvement in the prognosis of colorectal cancer (CRC) patients has led to increasing occurrences of multiple primary malignancies (MPMs) alongside CRC but little is known about their characteristics. This study was undertaken to clarify the clinical and pathological features of MPMs, especially those at extra colonic sites, in patients with CRC. Methods: We reviewed 1,111 patients who underwent operations for primary sporadic CRC in Saitama Medical Center, Jichi Medical University between April 2007 and March 2012. Two patients with familial adenomatous polyposis, one with hereditary non-polyposis colorectal cancer, two with colitic cancer, and any patients with metastasis from CRC were excluded. We compared the clinicopathological features of CRC patients with and without MPMs. As a control, we used a database compiled of patients with gastric cancer (GC) detected by mass screening performed in the Saitama Prefecture in Japan 2010 and compared these with CRC patients with synchronous GC. Results: Multiple primary malignancies at extracolonic sites were identified in 117 of 1,111 CRC patients (10.5%). The median age was 68 (range, 29 to 96) versus 71 (50 to 92) (P < 0.001). The incidence of GC (44.4% (52 of 117)) was the highest of all MPMs. All CRC patients with GC were older than 57 years. Synchronous GC was detected in 26 patients. By contrast, out of 200,007 screened people, 225 people were diagnosed as having GC in the Saitama Prefecture. The age-standardized incidence of synchronous GC in CRC patients was significantly higher (0.53%) than in the control group (0.03%) (odds ratio, 18.8; 95% confidence interval, 18.6 to 19.0; P < 0.001). Conclusion: Patients with CRC who were older than 50 years preferentially developed GC synchronously and metachronously. Thus, this patient group should undergo careful perioperative screening for GC.

Although the first-line treatment for liver metastases arising from colorectal cancer is surgery, it is unknown whether this treatment is equally effective for liver metastases with peritoneal dissemination. We report a case of long-term survival after oxaliplatin-based chemotherapy and surgery for metachronous liver metastases with peritoneal dissemination from triple colon cancer. A 76-year-old man with a history of stage III descending colon cancer developed recurrent localized peritoneal dissemination and multiple liver metastases 30 months after surgery. He underwent partial liver resection, partial peritoneal resection, and 8 courses of capecitabine plus oxalitlatin (XELOX). There has been no disease recurrence 75 months after the initial surgery. While though there is no consensus for treatment of liver metastasis with peritoneal dissemination, surgery combined with systemic chemotherapy may be beneficial.

Background/Aims: Intra-abdominal infection (IAI) after pancreaticoduodenectomy (PD) is a common cause of prolongation of postoperative hospital stay and readmission to the hospital following discharge. Methodology: Two hundred and six patients undergoing PD were reviewed to investigate the risk factors for IAI after PD. Patients were separated into two groups: those who developed IAI after PD (Group A; n=44), and those who had not developed IAI after PD (Group B; n=162), the two groups were then compared to identify the risk factors for IAI after PD. A hundred and six patients (51.5%) underwent preoperative biliary drainage (PBD). Results: Multivariate analysis revealed that pancreatic fistula (PF) was an independent risk factor for IAI after PD (p<0.001; odds ratio=9.58; 95% confidence interval=4.37-21.0), but PBD was not a significant risk factor. Conclusions: We demonstrated that the adequate PBD might not affect IAI after PD. On the other hand, PF was an independent risk factor for IAI after PD. A large randomized controlled trial, which would prove the effect of early removal of a prophylactic placed drain to prevent IAI, should be planned.

A 73-year-old female was referred to our hospital with a diagnosis of advanced transverse colon cancer with severe anemia and body weight loss. Preoperative evaluations, including colonoscopy, gastroduodenoscopy, and computed tomography, revealed not only a transverse colon cancer massively invading the duodenum, but also a non-functioning endocrine tumor in the pancreatic tail. We performed middle-preserving pancreatectomy (MPP) with right hemicolectomy for these tumors with a curative intent. After the resection, about 6 cm of the body of the pancreas was preserved, and signs of diabetes mellitus have not appeared. The postoperative course was complicated by a grade B pancreatic fistula, but this was successfully treated with conservative management. After a 33-day hospital stay, the patient returned to daily life without signs of pancreatic exocrine insufficiency. Although the long-term follow-up of the patient is indispensable, in this case, MPP might be able to lead to the curative resection of transverse colon cancer massively invading the duodenum and non-functioning endocrine tumor in the pancreatic tail with preservation of pancreatic function. © 2010 Springer.

A 58-year-old female was referred to our hospital with a diagnosis of bowel obstruction due to advanced transverse colon cancer invading the duodenum. Two months after the emergency bypass operation for the bowel obstruction, we performed an en bloc right hemicolectomy with pancreaticoduodenectomy (RHCPD) with a curative intent. During the operation, we could not dissect the tumor from the superior mesenteric vein, so we performed a segmental cylindrical resection of the superior mesenteric vein and its reconstruction. The post-operative course was uneventful, and after a 34-day hospital stay the patient returned to daily life. A histologic examination also revealed a well-differentiated tubular adenocarcinoma invading the duodenum. All the surgical margins were negative and lymph node metastasis was not found. There were no signs of recurrence for 8 months after the operation. Complete resection clearly influences survival time of patients, and surgeons should not hesitate to perform RHCPD. © 2010 Springer.

症例は78歳，男性．68歳時から多発肝嚢胞と腎嚢胞を指摘されていた．2007年12月，経過観察のCTで多発肝嚢胞と一部嚢胞内に充実性腫瘤を認めたため精査加療目的に2008年3月当科紹介受診．腹部超音波で肝両葉に多発嚢胞を認め，左葉S3の嚢胞内と右葉S7の嚢胞内に乳頭状隆起性腫瘤があった．腹部CTでもS3とS7の嚢胞内に淡く造影効果を伴う軟部組織濃度の腫瘤を認めた．FDG-PETでは肝内に異常集積像を認めなかった．ERCP，MRCPではS3とS7の嚢胞と胆管との交通は確認できなかった．嚢胞性腫瘍を強く疑い，肝部分切除術を施行した．病理学的所見としてはいずれも多房性嚢腫であった．一部に認められた，壁の充実性部分は肥厚した嚢胞壁を形成する血管結合組織で，画像上で嚢胞内隆起性病変と考えた部分は嚢胞内出血による凝血塊と，その部分的な器質化であった．腺腫や癌を疑う所見はなかった．同時多発性で増大傾向のある肝嚢胞内出血の症例は極めて稀であり，若干の文献的考察を加えて報告する．<br>

【症例1】71歳,男性。平成19年に糖尿病と診断、腹部超音波検査(US)で膵腫瘍認め紹介受診。CTで膵頭体部に嚢胞性病変あり,主膵管の拡張および内部に壁在結節を認めた。病変は主膵管と交通があり,IPMCと診断。膵全摘術施行。術後腹水の貯留認めたが改善し,軽快退院となる。病理では慢性膵炎像を混じた急性出血性変化による嚢胞腔形成と診断された。 【症例2】59歳,男性。平成19年にアルコール性膵炎で他院に入院。CTとMRCPで膵頭部に多房性嚢胞性病変認め,紹介受診。USとEUS上病変は主膵管と交通があり,内部に壁在結節認め、分枝型IPMNと診断。膵頭十二指腸切除術施行。病理診断は慢性膵炎であった。術後問題なく,軽快退院となる。 【考察】膵嚢胞性病変の鑑別診断にはIPMN,MCT,SCT,仮性嚢胞,SPTなどがある。慢性膵炎後の仮性嚢胞はIPMNとの鑑別が困難なことがあり,注意が必要である

Mucin-producing carcinoma of the gallbladder is very rare. We report here a case of mucin-producing carcinoma of the gallbladder associated with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). A 74-year-old female had been treated with salazosulfapyridine and ursodesoxycholic acid becase of UC and PSC. After 7 years of treatment, laboratory data showed that the liver function took a turn for the worse, and the patient was admitted to our hospital for further examination. Enhanced computed tomography and ultrasonography showed an enlarged gallbladder associated with wall thickening and diffuse papillary protrusion. Endoscopic retrograde cholangiography showed stenosis and dilatation of the bile duct, which were compatible with PSC. Under the diagnosis of an early carcinoma of the gallbladder, we performed simple cholecystectomy. The tumor showed a papillary growth pattern located diffusely in the gallbladder with a massive amount of mucin filling the gallbladder. Histologically, it was diagnosed as a papillary adenocarcinoma localized in the mucosal layer. To the best of our knowledge, this is the first case of mucin-producing carcinoma of the gallbladder associated with PSC and UC. PSC and UC patients should be regarded as a high-risk group not only for cholangiocarcinoma but also carcinoma of the gallbladder.

Sporadic colorectal cancer (SCRC) occurring in young patients represent a subset with a higher proportion of advanced tumors and a poor prognosis, however, the genetic basis of SCRCs has not yet been sufficiently studied. We assigned 16 SCRC patients aged 40 years or less to group 1, and 30 SCRCs patients aged 65 years or more to group 2. The methylation status in the promoter of 7 tumor suppressor genes regarding these two groups was then examined. The average number of hypermethylated tumor-related genes per sample in group 1 was 1.50 +/- 0.07, which was significantly lower than that in group 2 of 2.73 +/- 1.24 (p=0.0040). The frequencies of the promoter hypermethylation of hMLH1, p15INK4b, p16INK4a, and RASSF1A in group 1 were 12.5%, 12.5%, 12.5%, 6.3%, and 0.0%, which were substantially less frequent than those same rates observed in group 2. In contrast, the frequencies of the promoter hypermethylation of APC, MGMT, p14ARF, in group 1 were 43.8%, 37.5%, and 31.3%, which were as frequent as those seen in group 2. The promoter hypermethylation of APC, MGMT, and p14ARF is therefore considered to be closely related to the development of SCRCs in young patients, regardless of aging.

We herein report a rare case of a strangulated obstruction of the small intestine caused by a transomental hernia. A 66-year-old male was brought from another hospital by ambulance due to strangulated small bowel obstruction. He had no history of surgery. He had an acute onset of abdominal pain with nausea, vomiting and abdominal distension. Other symptoms were tachycardia, low blood pressure, abdominal tenderness in physical examinations, inflammatory changes, and metabolic acidosis in the blood analysis. Abdominal computed tomography showed a marked dilatation of the small intestine, which was poorly enhanced with massive ascites. In addition, no mesenteric vascular occlusion but the radial distribution of the mesentery anterior to the transverse colon was observed. A diagnosis of strangulated obstruction was made, and emergency surgery was performed. Intraoperatively, massive bloody ascites were observed and the small intestine was incarcerated through a hiatus of the greater omentum with necrosis. We performed an open incision of the hiatus to release the incarceration and then resected the necrotic portion. The postoperative course was favorable and the patient was discharged on hospital day 10. This case emphasizes the importance of internal hernias, including considering a transomental hernia as a potential cause of an interstinal obstruction in patients without a history of surgery.

Recent studies have suggested that epigenetic inactivation of tumour-related genes by promoter methylation participates in the development of gastric cancer. We newly identified the frequently aberrant promoter methylation of alpha-1B-adrenergic receptor (ADRA1B) in colorectal cancer by methylation-sensitive representational difference analysis (MS-RDA) and examined the methylation status of the ADRA1B promoter in 34 paired samples of colorectal cancer and surrounding epithelial tissue, and 34 paired samples of gastric cancer and surrounding epithelial tissue. In colorectal cancers, only four of 34 (11.8%) tumours showed ADRA1B promoter methylation. In contrast, ADRA1B promoter methylation was detected in 24 of 34 (70.6%) gastric cancers and in 14 of 34 (41.2%) surrounding epithelial tissues. The frequency of ADRA1B promoter methylation was higher in gastric epithelial tissues with intestinal metaplasia (41.6%) than in those without intestinal metaplasia (25.0%). Reverse transcription-PCR detected reduced ADRA1B expression in 12 of 18 (66.7%) gastric cancers, and its promoter methylation was detected in 11 of these 12 (91.7%) gastric cancers with reduced ADRA1B expression. Thus, ADRA1B promoter is frequently methylated in gastric cancer. Our results suggest that the ADRA1B gene is an important tumour-related gene frequently involved in the development and progression of gastric cancer.

The development of colorectal neoplasms proceeds mainly via the adenoma-carcinoma sequence. BRAF and RASSF1A are members of Ras-signaling pathways, but the roles of their aberrations in colorectal carcinogenesis remain unclear. The authors studied mutations of the BRAF and K-ras genes, RASSF1A promoter methylation, and p53 overexpression in 43 polypoid-type and 30 flat-type early-stage colorectal cancers. No tumor simultaneously showed any combination of K-ras mutations, BRAF mutations, and RASSF1A promoter methylation. Three of the 73 tumors (4.1%) had BRAF mutations. All BRAF mutation-positive tumors were flat-type cancers, not associated with coexisting adenoma or p53 overexpression. RASSF1A promoter methylation was detected in 12 out of 73 tumors (16.4%), and the proportion of positive cases was similar in polypoid-type and flat-type cancers. BRAF mutations, K-ras mutations, and RASSF1A promoter methylation independently participate in early-stage colorectal carcinogenesis. BRAF mutations are involved only in flat-type cancers, whereas RASSF1A promoter methylation is involved in both polypoid-type and flat-type cancers. Thus, BRAF mutations most likely participate in de novo colorectal carcinogenesis, K-ras mutations in the adenoma-carcinoma sequence of colorectal carcinogenesis, and RASSF1A promoter methylation in both cascades.

重複胆嚢との鑑別を要した孤立性嚢胞状肝内胆管拡張症の1例を報告する.症例は63歳,男性.腹部検診目的で行った超音波検査で胆嚢頸部に接する嚢胞状腫瘤性病変を指摘された.腹部CTでは肝S5に18mm大の低吸収域と内部石灰化陰影を認め, ERCPでB5分枝の嚢胞状拡張と内部結節影を認めた.他の肝内・肝外胆管や胆嚢に異常なく,合流異常も認めなかった.嚢胞内細胞診で悪性所見はなく,結石を伴う重複胆嚢 (Gross分類のCtype) または孤立性肝内胆管拡張症の術前診断で手術を行った.胆嚢摘出後,肝S5の表面に半球状の病変を確認し,嚢胞に沿って肝実質を剥離, B5合流部まで追及後摘出した.内部に黒色石が多数存在したが,腫瘤像は認めなかった.病理検査では腫瘍性変化はなく,嚢胞壁に筋層構造は認めず,胆管系の腺管構造を伴うことから最終的には良性肝内胆管拡張症と診断した.

術前診断に苦慮したforegut cystの1例を経験したので文献的考察を加えて報告する。症例は30歳の女性,主訴は左側腹部鈍痛であった。腹部超音波,CT検査,超音波内視鏡では膵尾部と連続する辺縁明瞭な腫瘤が存在し,内部はcystic partとsolid partの混在が認められた。また,血液検査ではCA19-9の上昇がみられた。ERCPでは膵管に拡張はなく嚢胞との交通も認めなかった。以上より膵臓原発のsolid and pseudopapillary tumorを第一に考え,開腹手術を行った。術中所見で腫瘍は膵尾部とは連続性がなく腹腔内腫瘍として腫瘍摘出術を行った。術後の病理組織診断はforegut cystであった。また,病理組織ではCA19-9染色で重層扁平上皮,気管支上皮,嚢胞内容物に陽性所見が認められた。腹腔内にみられるforegut cystは極めて稀であるが,鑑別診断として挙げる必要があると考えられる。

Islet cell tumors of the pancreas are uncommon. Approximately 15% of islet cell tumors are nonfunctioning and have a higher malignancy rate than their functioning counterparts. Though, because of the rarity of malignant nonfunctioning islet cell tumors, the natural history of a patient with this tumor has not been clearly defined. We describe a young patient with unresectable malignant nonfunctioning islet cell tumor associated with multiple liver metastases. He was treated with palliative therapies to improve his quality of life, but did not undergo surgical removal of tumors or systemic chemotherapy. He survived for 46 months since laparotomy for histological diagnosis. Our findings may represent the natural history of patients with unresectable malignant nonfunctioning islet cell tumor, and suggest that palliative therapy may contribute not only to the improvement of a patients' quality of life but also the prolongation of survival.

We report a case of a 65-year-old male with stage IV gastric cancer accompanied by liver metastases, which showed a significant response after administration of TS-1. One hundred and twenty mg/body/day of TS-1 was orally administered without hospitalization. After 3 months, upper GI endoscopy showed improvement of primary gastric lesion, and cancer cells could not be detected under biopsy. After 2 months, computed tomography (CT) showed a reduction in the multiple liver metastases. Moreover, after 15 months, CT showed a complete regression of the multiple liver metastases, for a complete response (CR). The serum level of carcinoembryonic antigen (CEA) was reduced from 115 to within normal range. Noticeable critical adverse effects did not appear. Treatment on an outpatient basis, therefore, greatly contributed to his quality of life. We judged that TS-1 might be a candidate anti-cancer drug for first-line chemotherapy for advanced gastric cancer.

BACKGROUND. The growth pattern of early gastric carcinoma, as based on a volumetric analysis, reflects the biologic characteristics of a tumor. The penetrating growth (Pen) type tumor has an unfavorable prognosis, compared with the case of a superficially spreading (Super) type. The wild-type of the p53 protein plays an important role in cell growth regulation and apoptosis. The p21 protein, which is encoded by the WAF1/CIP1 gene, is a downstream target effector of wild-type p53 protein, and these proteins act as tumor suppressors in a negative cell-cycle regulation. METHODS. In 133 Japanese patients with early gastric carcinoma with submucosal invasion, expressions of p53 and p21 proteins were studied immunohistochemically, and the relation between growth pattern and expressions was analyzed. RESULTS. Early gastric carcinomas were grouped into the superficially spreading (Super) type 40 (30.1%) cases, expansively penetrating growth (Pen-A) type 28 (21.1%), infiltratively penetrating growth (Pen-B) type 20 (15.0%), small mucosal type 35 (26.3%), and mixed type 10 (7.5%). The Pen-A type tumors were characterized by the highest incidence of p53 expression and loss of p21 expression, and the rate of p53-positive and/or p21-negative cases was 71.4%. There were significant differences in the incidence of the p53 expression (50.0% vs. 25.0%), the loss of p21 expression (53.6% vs. 27.5%), and the 5-year survival rate (83.2% vs. 97.2%) between the Pen-A type and the Super type. CONCLUSIONS. Thus, deregulation of the cell cycle by p53 and p21 in this study was shown to play an important role in progression of Pen-A type early gastric carcinoma. (C) 2001 American Cancer Society.