Hiroki Fukunaga

Comparative Detection of Lymph Node Micrometastases of Stage II Colorectal Cancer by Reverse Transcriptase Polymerase Chain Reaction and Immunohistochemistry

PURPOSE Inconsistent conclusions have been drawn about the clinical significance of micrometastases in lymph nodes (LNs) of node-negative colorectal cancer (CRC) patients. We performed a comparative study of detection of micrometastases using immunohistochemistry (IHC) by anti-cytokeratin antibody and carcinoembryonic antigen (CEA)-specific reverse-transcriptase polymerase chain reaction (RT-PCR) in the same patients, in an attempt to move closer to their clinical application. PATIENTS AND METHODS Sixty-four CRC patients, with RNA of good quality available from paraffin-embedded LN specimens, were selected from 84 stage II patients who underwent curative surgery between 1988 and 1996. We investigated associations between the presence of micrometastases by each method and prognosis. RESULTS Micrometastases were detected in 19 (29.6%) of 64 patients by RT-PCR and in 35 (54.7%) of 64 patients by IHC. By RT-PCR analysis, patients exhibiting a positive band for CEA mRNA had a significantly worse prognosis than those who were RT-PCR-negative, with respect to both disease-free and overall survival (P =.027 and.015, respectively). By IHC analysis, the presence of micrometastasis did not predict patient outcome in terms of either disease-free or overall survival. Infiltrating pattern of tumor growth characteristic was significantly associated with shorter disease-free survival among various clinical or pathologic factors. By multivariate Cox regression analysis, micrometastasis detected by RT-PCR and the Crohns-like lymphoid reaction were both independent prognostic factors. CONCLUSION Micrometastases detected by RT-PCR, but not IHC, may be of clinical value in identifying patients who may be at high risk for recurrence of CRC and who are therefore likely to benefit from systemic adjuvant therapy.

Correlation of GLUT-1 Overexpression, Tumor Size, and Depth of Invasion with 18F-2-fluoro-2-deoxy-d-glucose Uptake by Positron Emission Tomography in Colorectal Cancer

We investigated the wide variability of 18F-2-fluoro-2-deoxy-d-glucose (FDG) uptake, semiquantified as standardized uptake value (SUV), in positron emission tomography (PET) scanning, in 20 patients with colorectal cancer (CRC), including 1 with synchronous hepatic metastasis. The sensitivity of PET in CRC diagnosis was 100%, with a mean SUV of 8.0 (3.1–11.9). Tumor size and depth of invasion were associated with higher SUVs (P=.0004, .042, respectively). Strong glucose transporter-1 (GLUT-1) expression had significantly positive correlation with the SUV (r=.619, P=.003). GLUT-1 expression revealed positive staining in 17 (85%) of the 20 primary lesions. The central part of the tumor, thought to be relatively hypoxic, had stronger GLUT-1 expression and a higher SUV than the periphery, in both the primary tumor and hepatic metastatic foci. Our data suggest that the SUVs of FDG uptake in PET may be a noninvasive biomarker for advanced CRC, indicative of a large hypoxic tumor with deep invasion.

Antisense to Cyclin D1 Inhibits Vascular Endothelial Growth Factor–Stimulated Growth of Vascular Endothelial Cells: Implication of Tumor Vascularization

Purpose: Our aim was to determine the effects of cyclin D1 inhibition on tumor-associated neovascularization and endothelial cell growth. Experimental Design: We have generated adenovirus system for antisense to cyclin D1 (AS CyD1) and evaluated in vitro and in vivo effects. Small interfering RNA against cyclin D1 was also used to analyze cyclin D1 inhibition-associated vascular endothelial growth factor (VEGF) regulation. Results: The xenografts treated with adenoviral AS CyD1 showed less vessel density and displayed smaller tumor size in colon cancer cell lines HCT116 and DLD1. In vitro studies indicated that AS CyD1 decreased VEGF protein expression in DLD1 but not in HCT116. Cyclin D1 small interfering RNA caused a decrease in VEGF expression at protein and RNA levels in DLD1. A modest decrease was noted in the VEGF promoter activity, with inactivation of the STAT3 transcription factor through dephosphorylation. On the hand, the cyclin D1 inhibition plus STAT3 inhibitor markedly decreased VEGF expression in HCT116, although VEGF did not change by the STAT3 inhibitor alone. In cultures of human umbilical vein endothelial cells (HUVEC), VEGF augmented cyclin D1 expression and cell growth. AS CyD1 significantly inhibited HUVEC growth even in the presence of VEGF. AS CyD1 also significantly suppressed in vitro tube formation in VEGF-treated HUVEC and in vivo macroaneurysm formation in VEGF-treated Matrigel plug. Conclusions: Our results suggest that cyclin D1 may play a role in the maintenance of VEGF expression and that AS CyD1 could be potentially useful for targeting both cancer cells and their microenvironment of tumor vessels.

Fusion Image of Positron Emission Tomography and Computed Tomography for the Diagnosis of Local Recurrence of Rectal Cancer

BackgroundThe aim of this study was to evaluate the clinical and therapeutic value of digital fusion image (FI) of positron emission tomography (PET) using 18F-fluorodeoxy glucose and computed tomography (CT) in patients who were suspected of having a local recurrence of rectal cancer.MethodsForty-two patients (32 men and 10 women; mean age, 61.4 years, range, 40–79 years) with a suspicion of local recurrence after curative resection of rectal cancer were prospectively recruited and underwent 18F-fluorodeoxy glucose-PET and CT. The FI was reconstructed with a commercially available digital software program, T-B Fusion. Wilcoxon signed rank test was used to compare FI with CT alone or PET alone.ResultsFI yielded a correct diagnosis in 39 (93%) of 42 patients, whereas CT alone and PET alone did so in 33 (79%) and 37 (88%) patients, respectively. FI had better diagnostic accuracy than CT alone (P = .0138) and PET alone (P = .0156). Overall, FI altered patient management in 11 (26.2%) patients on the basis of additional information, including differentiation of the tumor from the postoperative scar in 6 patients, exact anatomical location in 3 patients, and both in 2 patients.ConclusionsFI has a potential clinical value in the treatment of suspected local recurrence of rectal cancer.

Adenocarcinoma Arising Below an Ileoanal Anastomosis After Restorative Proctocolectomy for Ulcerative Colitis: Report of a Case

We report a case of adenocarcinoma developing in remnant rectal mucosa below a hand-sewn ileal pouch–anal anastomosis (IPAA) after restorative proctocolectomy for ulcerative colitis (UC). To our knowledge, this is the first such case to be reported from Japan. A 60-year-old man with a 13-year history of UC underwent proctocolectomy with a hand-sewn IPAA and mucosectomy for anal stenosis and serious tenesmic symptoms. About 7 years later, a follow-up endoscopy showed a flat elevated malignant lesion, 2 cm in diameter, below the ileoanal anastomosis. He was treated by abdominoperineal resection of the pouch and anus with total mesorectal excision. Histopathological examination of the resected specimen confirmed the presence of a well-differentiated adenocarcinoma but there were no metastatic lymph nodes. He recovered uneventfully and remains well without evidence of recurrent disease 2 years and 3 months after his last operation.

Complete Response of Highly Advanced Colon Cancer with Multiple Lymph Node Metastases to Irinotecan Combined with UFT: Report of a Case

Massive lymph node metastasis of the para-aortic region and supraclavicular lymph nodes, Virchows lymph node metastasis due to colon cancer, is extremely rare. We herein report a case of such systemic lymph node metastasis that was successfully treated with a combination of irinotecan (CPT-11) and UFT, a combination drug of tegafur and uracil. The patient was a 57-year-old woman who had a tumor in the ascending colon, and massively swollen para-aortic and supraclavicular lymph node metastasis. She was treated with combination chemotherapy of CPT-11 and UFT. The main tumor was detected as a decompressed scar, and the supraclavicular and para-aortic lymph nodes had completely disappeared after the second cycle of treatment. A histopathological examination and immunohistochemistry with cytokeratin showed complete remission of adenocarcinoma in the tumor and para-aortic lymph nodes. She remains alive without recurrence 52 months after chemotherapy. Combination chemotherapy of CPT-11 and UFT may be of potential value in the treatment of advanced colorectal carcinoma, and both histopathological and immunohistochemical confirmation of a complete remission may indicate prolonged disease-free survival.

Standardized uptake value on FDG-PET as a marker for disease activity in patients with non-Hodgkin’s lymphoma: comparison with serum soluble interleukin-2 receptor values

BackgroundWe compared standardized uptake values (SUVs) on positron emission tomography with a glucose analog, 2-[F-18] fluoro-2-deoxy-D-glucose (FDG-PET) and serum soluble interleukin-2 receptor (sIL-2R) values in patients with non-Hodgkin’s lymphoma (NHL) in the pre-, mid- (after three or four cycles), and post-treatment periods of chemotherapy (pre, mid, and post, respectively), and we examined whether the SUV was a useful tumor marker for NHL.MethodsThe SUVs on PET and sIL-2R values were retrospectively evaluated based on all the clinical information available in 40 patients (31 in pre, 24 in mid, and 24 in the post periods). Patients in complete remission status were classified as group A and those with active residual disease in the mid and post periods were classified as group B.ResultsIn pre, the SUV and sIL-2R values exhibited sensitivity of 100% and 84%, respectively. In mid, the SUV was lower in group A than in group B, while sIL-2R was not different. The SUV yielded better specificity than sIL-2R (88 % vs 25 %, respectively), though the difference was not significant. In mid, the SUV in patients later assigned to group A in post was lower than than the SUV in group B, whereas sIL-2R was not different. In post, the specificity and accuracy of SUV were better than those of sIL-2R (95 vs 47 %, and 96 vs 58 %, respectively). Both the SUV and sIL-2R were lower in group A than in group B.ConclusionThe SUV on PET was better than the serum sIL-2R as a marker to evaluate the disease status of NHL, and was considered to be a useful tumor marker for NHL.

Antiemetic efficacy of selective serotonin receptor (5HT3) antagonist, granisetron, on delayed chemotherapy-induced nausea and vomiting (CINV) in CPT-11 and 5-FU based chemotherapy (CT)

8187 Background: Though significant advances have been made in cancer treatment, CINV still remains significant patients (pts) concerns. Antiemetic guidelines based on emesis rate category have been proposed for the prevention of CINV (Support Care Cancer 2002; 10: 519-22). Dexamethasone (Dex) and 5HT3 antagonist are recommended for the prevention of acute and delayed CINV of CT using high emesis category drugs. However, there is no standard recommendation for delayed CINV of moderate emesis category drugs, such as CPT-11. The efficacy of granisetron, 5HT3 antagonist, on delayed CINV after CPT-11 and 5-FU based CT was investigated. METHODS Pts who had a delayed CINV were eligible for the study. Treatment regimen was consisted of a 90-min infusion of CPT-11 150mg/m2 on day 1 and 15, and UFT 375mg/m2/day on days 3-7, 10-14, 17-21 and 24-28, q5w. All pts received intravenous betamethasone and granisetron for prophylaxis against acute emesis on the day of CPT-11 administration. When pts had delayed CINV, 2 mg of granisetron was orally administered on days 2-6, and 16-20 of next treatment cycle. The severity of their gastrointestinal symptoms (anorexia, nausea, vomiting) on days 2-7, and 16-21 was recorded every day according to NCI-CTC, and pts preference of this treatment was recorded using questionnaire on days 8 and 22. The efficacy of the treatment was assessed in each patient by the comparison of severity of CINV with or without oral granisetron. RESULTS 16 pts (53.3%) of 30 pts who had received the CT had delayed CINV. The incidence of grade 2 or more vomiting was significantly greater in female than in male pts (54.6% vs 32.1%, p=0.002). Although granisetron did not improve the overall incidence of anorexia, nausea, and vomiting, the incidence of grade 2 or more vomiting in female pts was significantly reduced by granisetron (54.6% vs 32.4%, p=0.001). The questionnaire on pts preference revealed 76% of pts had preference for the treatment. CONCLUSIONS Oral administration of granisetron for prevention against delayed CINV might be effective in female pts. No significant financial relationships to disclose.