Haruo Shimizu

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens. Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114–23. ©2010 AACR.

Increased cyclooxygenase-2 expression in large flat colorectal tumors (laterally spreading tumors)

Background: Little is known about the molecular biological features of large flat tumors or laterally spreading tumors (LSTs) of the colon and rectum. Methods: The cyclooxygenase (COX)–2 protein expression level of LSTs was assessed immunohistochemically and compared with that of exophytic colorectal tumors. COX-2 expression in the dysplastic epithelial cells and the interstitial cells was evaluated independently. Results: Sixty-five LSTs and 65 exophytic tumors were randomly selected from the archives, and 61 and 59, respectively, were successfully analyzed. LSTs showed significantly more intense COX-2 protein expression in the dysplastic epithelial cells than the exophytic tumors (P > 0.0001). COX-2-positive interstitial cells were also observed more frequently in LSTs than in the exophytic tumors (P = 0.015). Conclusions: Overexpression of COX-2 protein may play a crucial role in the tumorigenesis of colorectal LSTs. Chemoprevention, using nonsteroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors may be effective for treating this unique neoplasm, which sometimes defies endoscopic treatment.

De novo CD5-Positive Diffuse Large B Cell Lymphoma Solely Presenting as Multiple Subcutaneous Nodules

Lymphomas may involve the subcutaneous tissue as a manifestation of generalized disease. However, they rarely present with multiple involvement of the subcutaneous fat tissue without other sites of the disease. We describe a patient with CD5+ diffuse large B cell lymphoma (DLBL) that was confined to the subcutaneous tissue. A 74-year-old woman with rheumatoid arthritis was admitted because of multiple subcutaneous nodules. The patient had not been treated with cytotoxic drugs or methotrexate. The biopsied specimen disclosed diffuse infiltration of large cells with a starry sky-like appearance. The cells were positive for CD5, CD19, CD20, CD25, IgM, λ-chain, and negative for CD10, CD23 or cyclin D1. Thus a diagnosis of CD5+ DLBL was made. The patient was treated with a modified CHOP protocol and complete remission was achieved.

Pharyngeal cancer surveillance using narrow band imaging during conventional upper gastrointestinal endoscopy.

Background: Recent studies have suggested that narrow band imaging (NBI) is useful for detecting superficial pharyngeal cancer. Nevertheless, pharyngeal observation is not a routine practice during upper gastrointestinal (GI) endoscopy. Two aims of this study were to evaluate the feasibility of pharyngeal observation during upper GI endoscopy and to determine the prevalence of pharyngeal cancer in asymptomatic high-risk patients. Methods: Fifty-year-old or older asymptomatic males with smoking and drinking habits were prospectively recruited as a pharyngeal cancer high-risk group. A total of 224 high-risk patients underwent pharyngeal observation using NBI before conventional upper GI endoscopy. The feasibility of pharyngeal examination without sedation was assessed by a questionnaire for the first 60 participants. Results: The median time for pharyngeal observation was 1.7 min. The questionnaire demonstrated 88% of participants thought the pharyngeal examination acceptable. The NBI examination identified 5 superficial pharyngeal cancers (2 Tis and 3 T1) in 224 high-risk patients; the prevalence of pharyngeal cancer in this group was 2.2%. Three of the 5 patients had a concurrent or past history of esophageal squamous cell carcinoma (ESCC). Conclusions: Pharyngeal observation using NBI during upper GI endoscopy is well tolerated and recommended for all high-risk patients, particularly those with a history of ESCC.

Clinical outcomes of sigmoid colon volvulus: identification of the factors associated with successful endoscopic detorsion

Background/Aims Although multiple treatment options exist for the management of sigmoid colon volvulus, no study has examined the factors associated with successful endoscopic detorsion. This study aimed to examine the clinical course of patients with sigmoid colon volvulus and to identify factors related to successful endoscopic detorsion. Methods This study included 30 cases (21 patients) of sigmoid volvulus from among 545 cases of intestinal obstruction at a single center. We retrospectively examined the clinical course and the factors associated with the possibility of endoscopic detorsion of sigmoid colon volvulus. Results The rate of laxative use among the study participants was 76.2%; the rate of comorbid neuropsychiatric disorders was 61.9%; and 57.1% of patients had a history of open abdominal surgery. All patients were initially treated with endoscopic detorsion, and this procedure had a 61.9% success rate. The recurrence rate after detorsion was as high as 46.2%, but detorsion during revision endoscopy was possible in all cases. Statistical analysis revealed that the absence of abdominal tenderness (P=0.027), the use of laxatives (P=0.027), and a history of open abdominal surgery (P=0.032) were factors predictive of successful endoscopic detorsion. Conclusions The results of our study are consistent with previous reports with respect to the success rate of endoscopic detorsion, the subsequent recurrence rate, and the proportion of patients requiring surgical treatment. In addition, we identified the absence of abdominal tenderness, the use of laxatives, and history of open abdominal surgery as factors predicting successful endoscopic detorsion of sigmoid colon volvulus.

mFOLFOX6 chemotherapy enabling curative resection in a patient with locally advanced duodenal adenocarcinoma and lymph node metastases

A 65-year-old man was referred to our hospital with a primary complaint of unintentional weight loss. Upper gastrointestinal endoscopy showed a large duodenal tumor, and computed tomography (CT) showed tumor invasion of the pancreatic head, associated with lymph node swelling around the tumor and abdominal aorta. After 4 courses of chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6), follow-up upper gastrointestinal endoscopy and biopsy showed no evidence of a duodenal tumor. However, follow-up CT showed persistent lymph node swelling near the superior mesenteric artery. The patient therefore underwent pancreaticoduodenectomy with curative intent. At 18 months after the surgery, there were no findings suggestive of tumor recurrence.

A case of adenosquamous carcinoma of the lower bile duct diagnosed preoperatively via transpapillary biopsy.

A 78-year-old man presented to our hospital with fever and brownish urine. Upon thorough examination, a diagnosis of obstructive jaundice and acute cholangitis associated with a lower bile duct tumor was made. Endoscopic retrograde cholangiopancreatography revealed entire circumferential stenosis of the lower bile duct. Examination of a transpapillary biopsy specimen of the lesion suggested adenosquamous carcinoma. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed adenocarcinoma of the lower bile duct and squamous cell carcinoma components;a case of adenosquamous carcinoma was accordingly diagnosed. The lower bile duct tumor directly extended into the pancreatic parenchyma for approximately 1mm. We performed radical surgery and administered adjuvant chemotherapy with gemcitabine because of advanced neural invasion after consulting with the patient. There was no sign of recurrence 46 months after surgery. As adenosquamous carcinoma of the extrahepatic bile duct is rare, it is difficult to preoperatively diagnose the condition. Only a few cases have been reported till date.

Autoimmune Hemolytic Anemia Triggered by Infection with Human Parvovirus B19 after Total Abdominal Colectomy for Ulcerative Colitis

A 50-year-old man was admitted to our hospital for an adhesive ileus 14 years after total abdominal colectomy for ulcerative colitis (UC). The ileus decreased with conservative treatment, however, autoimmune hemolytic anemia (AIHA) was diagnosed due to worsening anemia, a positive direct Coombs test, low haptoglobin, high lactase dehydrogenase, reticulocytosis, and an increase in the erythroblastic series in a bone-marrow examination. Human parvovirus B19 (PV-B19) IgM and PV-B19 DNA were present, indicating the development of AIHA triggered by an infection with PV-B19. The patient is currently being monitored after spontaneous remission. This is the first report of UC after total abdominal colectomy complicated by AIHA triggered by PV-B19 infection.

Rapidly growing early gastric cancer with microsatellite instability

A 77-year-old man underwent gastrointestinal endoscopy that revealed a small flat elevated lesion in the gastric antrum. Endoscopically, we assessed the tumor as intramucosal cancer or adenoma, and biopsy specimens were diagnosed as showing borderline malignancy. At the second examination, performed 6 months later, the elevated lesion had grown, showing remarkable changes in its appearance, and a diagnosis of adenocarcinoma was confirmed pathologically. The patient underwent distal gastrectomy about 8 months after the first examination, and the tumor in the resected specimens showed a moderately differentiated adenocarcinoma invading through the entire submucosal layer, with metastasis to a regional lymph node. Microsatellite analysis of this early gastric cancer disclosed mutations in all six markers examined, indicating high-level microsatellite instability (MSI-H). The tumor also showed frameshift mutations of TGFβRII and BAX genes, as well as hypermethylation of the hMLH1 promoter. These results suggest that a deficiency of the mismatch repair system played a critical role in the progression of this cancer.