Eiki Ojima

C-Reactive Protein as a Prognostic Variable That Reflects Uncontrolled Up-Regulation of the IL-1-IL-6 Network System in Colorectal Carcinoma

Up-regulation of the IL-1-IL-6 network stimulates systemic expression of C-reactive protein (CRP).This cytokine network system plays a pivotal role in inducing angiogenic growth factors in in-testinalmucosa. Serum CRP level and tissue concentrations of cytokines in colorectal cancerpatients were determined and an in vitro model was employed to determine the time course ofinduction of IL-6 in Caco-2 cells. Increased serum CRP was associated with recurrent diseaseand shorter survival time. Intense surgical stress and the presence of an acute phase reactantwere independently associated with overexpression of IL-6 in the tumor. Enhanced IL-6 pro-teinexpression in Caco-2 cells induced by the initial treatment with IL-1β or lipopolysaccha-ridecould be abrogated by additional presupplementation of IL-1ra. The presence of an acutephase reactant reflects uncontrolled up-regulation of the local IL-1-IL-6 network system in thetumor, which may enhance the survival and proliferation of remnant cancer cells after tumorresection.

Effectiveness of gene expression profiling for response prediction of rectal cancer to preoperative radiotherapy

BackgroundOur aim was to determine whether the expression levels of specific genes could predict clinical radiosensitivity in human colorectal cancer.MethodsRadioresistant colorectal cancer cell lines were established by repeated X-ray exposure (total, 100 Gy), and the gene expressions of the parent and radioresistant cell lines were compared in a microarray analysis. To verify the microarray data, we carried out a reverse transcriptase-polymerase chain reaction analysis of identified genes in clinical samples from 30 irradiated rectal cancer patients.ResultsA comparison of the intensity data for the parent and three radioresistant cell lines revealed 17 upregulated and 142 downregulated genes in all radioresistant cell lines. Next, we focused on two upregulated genes, PTMA (prothymosin α) and EIF5a2 (eukaryotic translation initiation factor 5A), in the radioresistant cell lines. In clinical samples, the expression of PTMA was significantly higher in the minor effect group than in the major effect group (P = 0.004), but there were no significant differences in EIF5a2 expression between the two groups.ConclusionsWe identified radiation-related genes in colorectal cancer and demonstrated that PTMA may play an important role in radiosensitivity. Our findings suggest that PTMA may be a novel marker for predicting the effectiveness of radiotherapy in clinical cases.

Deficiency in systemic interleukin-1 receptor antagonist production as an operative risk factor in malnourished elderly patients with colorectal carcinoma.

Objective:Aging and tumor-related malnutrition are associated with increased inflammatory cytokine levels. However, it is unclear whether this influences the outcomes of surgery. We explored the relationships between cytokines and surgical complications among patients undergoing surgery for colorectal cancer. Design:Laboratory experiment. Setting:Surgery department of school of medicine. Patients:One hundred patients with colorectal cancer. Interventions:The perioperative circulating levels of interleukin (IL)-1&bgr;, IL-6, and IL-1 receptor antagonist (Ra) were determined, and the numbers of circulating lymphocytes and neutrophils were counted. Measurements and Main Results:Trends toward increasing postoperative infection were observed among patients who were older and had lower body mass index. Preoperative IL-1Ra and intraoperative blood loss, however, remained the only two independent predictors of postoperative infection. Clinically, patients with low preoperative IL-1Ra most frequently were the elderly with low body mass index. Postoperatively, elderly patients with low body mass index showed an exaggerated IL-6 response, followed by an exaggerated postoperative inflammatory response and increased postoperative loss of body weight. In contrast, normal immunoreactivity was preserved in well-nourished elderly patients. Conclusions:In colorectal cancer patients undergoing surgery, low preoperative IL-1Ra is associated with postoperative infection. In our patient population, lower IL-1Ra level is commonly observed in the elderly with low body mass index. These findings suggest that postoperative infection, frequently seen in the nutritionally deficient elderly, may be the result of defective immunoinflammatory adaptation system.

Pelvic insufficiency fractures after preoperative radiotherapy for rectal carcinoma

Insufficiency fractures of the pelvic bones are rare complications of radiotherapy, but they can cause significant morbidity. We report a patient who developed pelvic insufficiency fractures because of preoperative hypofractionated radiotherapy with chemotherapy for rectal carcinoma. She was treated with a four-field box technique, receiving 20 Gy in four fractions, and she underwent concurrent pharmacokinetic modulating chemotherapy (PMC; intravenous infusion of 5-fluorouracil [FU], 750 mg/body per 24 h and oral administration of uracil and futrafur [UFT] 400 mg/day) over a 1-week period. She developed severe buttock and femoral pain 10 months after this preoperative therapy. Physical examination at this time was unremarkable, with an absence of neurological signs, and radiographic examination was also normal, resulting in the patient initially being undiagnosed. However, 2 months after the onset of her initial pain, she was diagnosed as having pelvic insufficiency fractures on conventional radiographs. Although preoperative chemoradiotherapy has been widely accepted for improving local control and survival in patients with primary rectal carcinoma, surgeons need to be aware of this rare complication that can arise even 10 months after preoperative chemoradiotherapy.

Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in a colon cancer cell line

BackgroundOur aim was to clarify the significance of widely accepted irinotecan (CPT-11)/5-fluorouracil (5-FU) combinations in colon cancer by investigating their sequential effect.MethodsThe sequential effect of CPT-11/5-FU in two colon cancer cell lines, LoVo and SW480, was evaluated by WST-8 colorimetric assay. The cell cycle distributions of each drug were analyzed by flow cytometry, and then the chemoresistant mechanisms and expression of a drug transporter (MDR1), the bcl-2 apoptotic pathway, metabolizing enzymes [carboxylesterase (CE), dihydropyrimidine dehydrogenase], and target enzymes (topoisomerase I, thymidine synthase) associated with sequence-dependent cytotoxicity were examined.ResultsThe cytotoxicity of 5-FU (10, 100, 1000 µM) followed by CPT-11 (1 µM) was significantly greater than that of CPT-11 (1 µM) followed by 5-FU (10, 100, 1000 µM) (P < 0.05). Reverse transcription-polymerase chain reaction analysis revealed that exposure to 5-FU downregulated both MDR1 and bcl-2 mRNA and simultaneously upregulated CE2 mRNA expression, suggesting enhancement of subsequent CPT-11 cytotoxicity.ConclusionsThe cytotoxic effects of the CPT-11/5-FU combinations were shown to be schedule-dependent in human colon cancer cells. The findings suggest that 5-FU followed by CPT-11 administration might be the optimal sequence for CPT-11/5-FU treatment of advanced colon cancer.

Combined Measurement of Hepatocyte Growth Factor and Carcinoembryonic Antigen as a Prognostic Marker for Patients with Dukes A and B Colorectal Cancer: Results of a Five-Year Study

PurposeThere is no marker capable of differentiating patients with Dukes A and B colorectal cancer with aggressive diseases from those with indolent diseases. We evaluated the results of five years of actuarial survival data to determine whether serial monitoring of serum hepatocyte growth factor could provide prognostic information on these patients.MethodsBlood samples of 147 colorectal cancer patients were obtained and the serum concentration of hepatocyte growth factor was measured.ResultsElevated serum hepatocyte growth factor levels were associated with stage progression. Although the overall positive rate of hepatocyte growth factor in the patients was the same as that of the carcinoembryonic antigen, the positive rate of hepatocyte growth factor in the Dukes A patients was two times higher than that of the carcinoembryonic antigen, and nearly 40 percent of the carcinoembryonic antigen-negative patients had a positive serum hepatocyte growth factor in the Dukes A and B classification. In this subgroup, patients with positive serum hepatocyte growth factor or carcinoembryonic antigen levels had a poorer prognosis, whereas positive serum hepatocyte growth factor level after surgery could predict disease recurrence.ConclusionsA combination of serum hepatocyte growth factor and carcinoembryonic antigen tests might be useful for selecting patients with aggressive diseases in Dukes A and B classification.

Laparoscopic sigmoidectomy using a hemi-double-stapling technique.

Background: The double-stapling technique (DST) is frequently used in laparoscopic sigmoidectomy. Unfortunately, anastomotic leakage after laparoscopic intracorporeal colorectal anastomosis with DST is seen with some frequency. Methods: We performed DST on 40 patients (June 2007 to August 2008) and hemi-DST on 50 patients (September 2008 to December 2011) undergoing laparoscopic sigmoidectomy. Results: There were no occurrences of anastomotic leakage in the hemi-DST group, and 2 instances of anastomotic leakage in the DST group were observed. In these patients, the leakage appeared at the lateral intersecting anastomotic margins. Conclusions: Using the hemi-DST for laparoscopic intracorporeal colorectal anastomosis will make laparoscopic sigmoidectomy a safer procedure.

Serum immunosuppressive acidic protein reflects systemic deterioration of colorectal cancer patient condition

Immunosuppressive acidic protein (IAP) is a potent biological marker for immunological surveillance in patients with malignant tumors. This study aimed to investigate the significance of serum IAP as an index of disease status, clinicopathological findings and prognosis in colorectal cancer.