Masaichi Ogawa

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells.

Human metastatic colorectal carcinomas (CRCAs) express carcinoembryonic antigen (CEA) and/or MUC1 tumor‐associated antigens as potential targets for the induction of active specific immunity. In the present study, freshly isolated metastatic CRCA cells were successfully fused with immature autologous human monocyte‐derived dendritic cells (DCs). The created heterokaryons (DC/CRCA) coexpress the CRCA‐derived CEA and MUC1 antigens and DC‐derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, both CD4+ and CD8+ T cells were activated by fusion cells, as demonstrated by the production of high levels of IFN‐γ. More importantly, coculture of fusion cells with patient‐derived peripheral blood mononuclear cells (PBMCs) resulted in the induction of antigen‐specific cytotoxic T lymphocytes (CTLs). CTLs were effective at lysis of not only autologous CRCA cells but also the CEA and/or MUC1‐positive and HLA partially matched target cells. Antigen‐specific CTL responses were confirmed by tetrameric analysis. Coculture of PBMCs with fusion cells resulted in increased frequency of CEA‐ and MUC1‐specific CTLs simultaneously. Taken together, these results indicate that freshly isolated human metastatic CRCA cells expressing the CEA and/or MUC1 may represent a potential partner for the creation of DC/tumor fusion cells targeting induction of antigen‐specific CTL responses. Our report demonstrates the simultaneous induction of CRCA‐specific CTL responses restricted by HLA‐A2 and ‐A24.

Perioperative change in peripheral blood monocyte count may predict prognosis in patients with colorectal liver metastasis after hepatic resection

Prognostic value of perioperative change in peripheral blood leukocyte subset count of cancer patients have not been fully investigated. Therefore, we retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease‐free as well as overall survival after hepatic resection for colorectal liver metastasis (CRLM).

Thymidine phosphorylase mRNA expression may be a predictor of response to post‑operative adjuvant chemotherapy with S‑1 in patients with stage III colorectal cancer

The aim of the present study was to investigate markers in surgically resected specimens of colorectal cancer that can be used to predict the response to chemotherapy. The mRNA expression levels of enzymes involved in 5-fluorouracil (5-FU) metabolism and folate metabolism were measured in formalin-fixed, paraffin-embedded tumor sections obtained from the primary tumors of 54 patients with resected stage II or III colorectal cancer who received S-1 for one year. The 5-FU metabolizing enzymes studied were thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase (TP). The folate metabolizing enzymes studied were folypolyglutamate synthetase, γ-glutamyl hydrolase and dihydrofolate reductase. The associations between the mRNA expression levels of these enzymes and clinical variables were investigated. Tumors were classified as exhibiting high or low expression as compared with the median mRNA expression level of each metabolizing enzyme defined as the cutoff value. The associations between the high and low expression levels of each enzyme and disease-free survival (DFS) were analyzed with the use of Kaplan-Meier curves and the log-rank test. DFS was not significantly associated with the relative mRNA expression level of any metabolizing enzyme in the study group as a whole, but there was a trend toward longer DFS in patients with high TP expression (P=0.066). In patients with stage III colorectal cancer, high TP expression was associated with significantly improved outcomes compared with low TP expression (P=0.039). These results indicate that the mRNA expression of TP, a metabolizing enzyme of 5-FU, is a significant predictor of response to post-operative chemotherapy with S-1 in patients with stage III colorectal cancer.

Expression of CXCR‑4 and IDO in human colorectal cancer: An immunohistochemical approach

C-X-C chemokine receptor type 4 (CXCR4), the receptor for the chemokine stromal cell-derived factor (SDF)-1 [also known as C-X-C motif chemokine 12 (CXCL12)], is involved in lymphocyte trafficking. Recent studies have demonstrated that, during pregnancy, a placental enzyme called indoleamine 2, 3-dioxygenase (IDO) exerts a key role in suppressing the maternal T-cell response against the fetus. In the present study, the significance of CXCR4 and IDO expression in human colorectal cancer (CRC) has been investigated by immunohistochemical assay, and their association with survival was analyzed. Tumor specimens (n=60) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC (I or IV) were assessed. In the stage IV group, 23 of 30 cases (77%) stained positive for CXCR4, and 9 of 30 (30%) were positive for IDO. By contrast, in the stage I group, 7 of 30 cases (23%) stained positive for CXCR4, and 15 of 30 cases (50%) were positive for IDO. The 5-year survival rate of those with high CXCR4 expression in tumor specimens (n=30) was significantly worse compared with those with negative CXCR4 expression (16.3 vs. 60.7%, P=0.02). By contrast, the 5-year survival rate of those with high IDO expression in tumor specimens (n=24) was not significantly different compared with those with negative IDO expression (36.4 vs. 56.8%). In the stage I group, 4 patients in the high IDO expression group (n=15) had distant metastases (2 in the liver 1 in the brain, and 1 in the lung). Taken together, CXCR4 appears to be a novel predictive indicator of survival, and IDO expression in the early stage may be a predictor of distant metastasis.

Chronic abdominal pain, appendiceal mucinous neoplasm, and concurrent intestinal endometriosis: a case report

IntroductionAlthough both appendiceal tumor and intestinal endometriosis have been reported as rare causes of abdominal pain, the coexistence of appendiceal mucinous neoplasm and ileal endometriosis has not previously been reported.Case presentationA 41-year-old Japanese woman presented with a positive fecal occult blood test and a 3-year history of menstruation-related lower abdominal pain. A colonoscopy demonstrated extrinsic compression of the cecum, suggesting a mass arising from the appendix or adjacent structures. Abdominal imaging showed a 6-cm cystic mass with intraluminal thick fluids originating from the appendix. At ileocecal resection for an appendiceal tumor, a 2-cm mass in the terminal ileum was incidentally found, which was included in the surgical specimen. Microscopic examination confirmed a diagnosis of a mucinous neoplasm of the appendix with endometriosis of the terminal ileum.ConclusionsTo avoid urgent surgery for subsequent serious events associated with disease progression, appendiceal tumor and intestinal endometriosis should be ruled out in patients with chronic abdominal pain.

Preoperative peripheral blood neutrophil count predicts long-term outcomes following hepatic resection for colorectal liver metastases

Preoperative systemic inflammatory response is associated with a poor long-term prognosis following resection surgery for malignant tumors. Several markers of systemic inflammation have been reported to be associated with the outcome; however, they have not currently been fully investigated. Therefore, the association between preoperative peripheral blood neutrophil count and oncological outcome following hepatic resection for colorectal liver metastasis (CRLM) was retrospectively investigated. The present study comprised 89 patients who had undergone hepatic resection for CRLM between January 2000 and March 2010. The association between preoperative peripheral blood neutrophil count and disease-free survival, in addition to overall survival, was investigated. In multivariate analysis, the presence of neoadjuvant chemotherapy (P=0.015), bilobar distribution (P=0.015) and neutrophil count ≥3,500/µl (P=0.025) were independent and significant predictors of poor disease-free survival, while significant predictors of poor overall survival consisted of >4 lymph node metastases (P=0.001), neo-adjuvant chemotherapy (P=0.003), bilobar distribution (P=0.039) and neutrophil count ≥3,500/µl (P=0.040). Additionally, tumor diameter (P=0.021) and monocyte count (P<0.0001) were observed to be significantly greater in the elevated neutrophil count group. In conclusion, preoperative peripheral blood neutrophil count may be an independent and significant indicator of poor long-term outcomes in patients with CRLM following hepatic resection.

Laparoscopic surgical challenge for T4a colon cancer

For patients with T4a colon cancer, the risk of peritoneal dissemination after surgery remains unclear. Seven hundred and eleven patients with T3 or T4a colon cancer, 80 years of age or younger, underwent curative resection (open surgery in 512 and laparoscopic surgery in 199) at the four Jikei University hospitals between 2006 and 2012. Their risk factors for peritoneal dissemination after surgery were evaluated retrospectively. Number of lymph node metastases, postoperative liver metastases and postoperative peritoneal dissemination events in the T4a group were significantly greater than the number in the T3 group. Peritoneal dissemination after surgery developed in four patients (0.7%) in the T3 group and in six patients (5%) in the T4a group. Risk factors for peritoneal dissemination consisted of macroscopic type (P = 0.016), serosal invasion (P = 0.017) and number of lymph node metastases (P = 0.009) according to the Cox proportional hazards regression model. However, tumor diameter and surgical approach (laparoscopic vs open) were not significant factors for peritoneal dissemination. There were no significant differences between the postoperative relapse‐free survival rates for each surgical approach within the T3 or T4a group. Because of comparable postoperative peritoneal dissemination in T3 and T4a colon cancer by the surgical approach (laparoscopic or open), laparoscopic surgery for patients with T4a colon cancer seems justified.

A White Tone Sessile Type Polyp; Submucosal Invasion Sigmoid Colon Cancer - 6 mm in a Diameter

A 53-year-old woman received a total colonoscopy for a FOBT (Faecal Occult Blood Test) positive and detected a sessile type poly in the sigmoid colon. Colonoscopy exhibited a “somewhat of a white tone” and measured 6 mm sessile type poly, with no irregular pit pattern, and suspected an adenoma. Also, endoscopic mucosal resection was done. The pathological diagnosis was a well differentiated adenocarcinoma and the depth of invasion was 1,200 micron. Submucosal invasive adenocarcinoma with 6 mm, non-depressive sessile type case is very rare. Therefore, one should recommended an endoscopic mucosal resection, not observation, when the endoscopic findings was recognized a “white tone” sessile type polyp.

Arterial Infusion Chemotherapy in Patient with Repeated Recurrent Tumor of Cecal Cancer: Report of a Case

Purpose: We report a patient with a repeated recurrent tumor after Right-hemicolectomy for advanced cecal cancer who was treated by intra-arterial infusions of 5-fluorouracil (5-FU). Methods: A computed tomography scan revealed a pelvic mass involving the psoas major muscle and quadratos lumborum muscle, in contact with the widely projecting toward L2-S2. The fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed an accumulation spot in the same place. This case was deemed in operable, and one-shot bolus of 5-FU was administered through the tumor feeding arteries: the left 3rd, 4th lumbar, and ilio - lumbar arteries at a dosage of 250 mg/body from each artery. Results: A partial regression of the tumor was observed by computed tomography. The serum level of carbohydrate antigen 19–9 returned normal in 8 months. During chemotherapy, the side effect and complications were tolerable, and she experienced only grade-1 nausea caused by 5-fluorouracil. Conclusion: A long–time, intra-arterial 5-fluorouracil infusion could control effectively and safely.

A Case of Mucin-producing Cholangiocarcinoma with Dilatation of the Common Bile Duct.

初回手術で発見できなかった粘液産生性肝内胆管癌を経験したので報告する.症例は56歳の女性で, 黄疸・発熱を主訴に来院した.腹部超音波検査および内視鏡的逆行性胆道造影では総胆管, 左肝内胆管の拡張と総胆管内の陰影欠損を認めた.以上より, 総胆管結石症と診断し手術を施行した.術中, 総胆管を切開すると大量のゼリー様物質の排出を認めたが, 胆道鏡では肝内外胆管内に, それ以外の異常を発見できなかった.手術後T-tubeから胆汁とともにゼリー様物質の流出が続いたが, 胆汁の細胞診では悪性細胞は認められなかった.T-tubeを介して胆道鏡を施行したところ左肝管内に乳頭状の腫瘤性病変を認め, 生検で乳頭状腺癌の診断を得た.改めて肝左葉, 左尾状葉, 肝外胆管切除術を施行した.病理診断は, 粘液産生性肝内胆管癌であった.本疾患は比較的まれな疾患であり, 本邦での報告例は40例に満たないので文献的考察を加え報告する.