堀江 久永

INTRODUCTION: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity. RESEARCH DESIGN AND METHODS: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2). RESULTS: Acetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue. CONCLUSIONS: The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.

BACKGROUND: Goblet cell carcinoid (GCC) is a neuroendocrine tumor usually found in the appendix. GCCs exhibit characteristic findings with mixed endocrine-exocrine features such as staining positive for neuroendocrine markers and producing mucin. The primary GCC of the rectum is exceedingly rare. CASE PRESENTATION: A 77-year-old Japanese male presented with hematochezia. Anal tenderness and a hard mass in the anal canal were found on the digital rectal examination, and colonoscopy was performed. Colonoscopy showed an irregularly shaped mass in the anal canal. Biopsy showed mixed features including adenocarcinoma in situ, well-differentiated adenocarcinoma, and mucinous carcinoma with invasive proliferation. No metastatic lesions were found on the computed tomography scan. Pelvic magnetic resonance imaging scan showed extramural growth of a tumor on the ventral side of the rectum without invasion to the prostate. Laparoscopic abdominoperineal resection was performed. The final diagnosis was well-differentiated adenocarcinoma in the mucosa and goblet cell carcinoid from the submucosa to the adventitia of the rectum. The patient was discharged from the hospital on postoperative day 16. Six months after resection, a computed tomography scan revealed multiple metastatic lesions in the liver. Several chemotherapy regimens were given, and the patient has stable disease 27 months after surgery. CONCLUSION: We present a patient with rectal GCC with metachronous liver metastases. Since GCC grows intramurally and is biologically aggressive compared to typical carcinoid lesions, the disease is usually diagnosed at an advanced stage. The development of optimal adjuvant chemotherapy is needed for those patients.

BACKGROUND: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. METHOD: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. RESULTS: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in Balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg × 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. CONCLUSION: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

INTRODUCTION: Metastases to the thyroid gland in patients with colorectal cancer are uncommon. We report a patient with rectal cancer who developed a metastasis to the thyroid gland. PRESENTATION OF CASE: The patient was a 45-year-old female five years status post rectal cancer resection. A thyroid lesion was detected on PET-CT scan with synchronous lung metastases. After pulmonary resection, a partial thyroidectomy was performed and pathological examination with immunohistochemical staining confirmed that the lesion was a metastasis from previous rectal cancer. She is free from recurrence two years after thyroid surgery. DISCUSSION: Colorectal metastases to the thyroid gland are usually seen with widespread disease, often with lung and liver metastases. The overall outcomes of previously reported patients with thyroid metastases were extremely poor, with most patients dying within months of diagnosis. Careful attention should be given to other sites of metastatic disease including the thyroid gland during postoperative follow-up. PET scan may be helpful to establish the diagnosis. CONCLUSION: Treatment decisions must be individualized, and depend on the presence of systemic disease. Selected patients may benefit from resection of metastases, and PET scan may be useful to identify patients who will benefit from resection.

INTRODUCTION: Internal hernias are rare after laparoscopic colorectal resections. We report a patient with an internal hernia through a defect in the transverse mesocolon following laparoscopic resection. PRESENTATION OF CASE: A 52-year-old male underwent laparoscopic colectomy for transverse colon cancer and had an unremarkable postoperative course. Thirty days postoperatively, he presented to the emergency room with sudden onset abdominal pain and vomiting. Enhanced abdominal computed tomography scan showed strangulated small intestine in the left upper abdomen. An internal hernia through the mesenteric defect created during the recent colon resection was suspected, and emergency laparotomy was performed. One hundred thirty cm of small intestine was found herniated through a mesenteric defect. After repositioning the ischemic-appearing intestine, a 5 cm defect in the transverse mesocolon was found which had not been closed during the previous laparoscopic operation. No intestinal resection was needed, and the mesenteric defect closed with non-absorbable sutures. The post-operative course was unremarkable except for paralytic ileus, which resolved without further intervention. DISCUSSION: The incidence of internal hernia through a mesenteric defect after laparoscopic colorectal resection is quite low. Therefore, routine closure of the mesenteric defect after laparoscopic colorectal resection is not required. However, a left sided defect in the transverse mesocolon might be at higher risk of causing an internal hernia on anatomic grounds. CONCLUSION: We believe that mesenteric defects should be closed after laparoscopic resection of the left side of transverse colon, regardless of their size.

Aim: Peritoneal metastases (PM) frequently occur in patients with gastric cancer and result in a poor prognosis. Exosomes play pivotal roles in tumor metastasis through the transfer of microRNAs (miRNAs). We examined the exosomal miRNA profile in peritoneal fluids to identify novel biomarkers to reflect tumor burden in the peritoneum. Methods: Exosomes were isolated from peritoneal fluids of patients of gastric cancer with macroscopic (P1) or microscopic (P0CY1) peritoneal metastasis (PM) and comprehensive miRNA expression analysis was carried out. Expressions of candidate miRNAs were then validated in all 58 samples using TaqMan Advanced miRNA Assays. Results: In initial screening, we carried out comprehensive analysis of exosomal miRNA using peritoneal fluids from 11 and 14 patients with or without PM, respectively, and identified 11 dysregulated miRNAs in PM (+) samples. Validation analysis showed that four miRNAs (miR-21-5p, miR-92a-3p, miR-223-3p, and miR-342-3p) were significantly upregulated in 12 PM (+) samples, and their expression levels showed positive correlation with peritoneal cancer index. In contrast, miR-29 family were all downregulated in patients with PM (+) samples. Moreover, in 24 patients with pT4 tumor, miR-29 at gastrectomy tended to be lower in six patients with peritoneal recurrence with significant differences in miR-29b-3p (P = .012). Conclusion: Expression pattern of miRNAs in peritoneal exosomes well reflects the tumor burden in the peritoneal cavity and could be a useful biomarker in the treatment of PM.