iTriangular Stapling Technique: A Novel Reconstruction Method and Clinical Outcomes of Cervical Esophagogastric Anastomosis after Esophagectomy.

BACKGROUND: We herein report the feasibility and safety of cervical end-to-end anastomosis by the iTriangular stapling technique (iTST), which was developed as an extension of the triangular stapling technique (TST) after minimally invasive esophagectomy (MIE). METHODS: A total of 45 patients with thoracic esophageal cancer who underwent reconstruction with cervical esophagogastric anastomosis by iTST using a linear stapler after MIE between January 2016 and January 2019 were retrospectively reviewed. We modified and improved upon the TST by adding a 1- to 2-cm vertical incision on the anterior wall of the remnant esophageal stump to enlarge the anastomotic lumen and thereby reduce the risk of anastomotic stenosis. The short-term patient outcomes were determined to assess the safety and feasibility of our procedures. RESULTS: The median operating time was 686 (range, 319-1110) minutes, and the median blood loss was 170 (range, 5-1180) ml. There were no cases of anastomotic stenosis in this study, although 2 patients (4.4%) developed minor anastomotic leakage. A case (2.2%) of tracheal fistula due to the apex of the triangular anastomosis was resolved simply by delaying the patient's oral intake. The mean length of the hospitalization was 21 days. CONCLUSIONS: The iTST provides a larger lumen unlimited by the size of the esophagus in cervical esophagogastric anastomosis. This technique is feasible, and sufficient short-term results have been achieved. Further studies with the accumulation of more cases will be required to prove the benefits of iTST for reconstruction after MIE.

Metastatic Invasive Lobular Carcinoma of the Breast Presenting Peritoneal Metastasis with Bilateral Ureteral Obstruction.

The most common sites for recurrence of breast cancer are the lungs, liver, and bones. The frequency of peritoneal, gastrointestinal metastasis is significantly lower than those, and bilateral ureteral obstruction caused by peritoneal metastasis is relatively rare. A 66-year-old woman was referred to our hospital because of appetite loss and frequent urination. She was on adjuvant hormonal therapy for local recurrence of right breast cancer. She was diagnosed with bilateral ureteral obstruction due to extramural compression. Exploratory laparoscopy revealed omental cake and peritoneal nodules of which pathological examination showed peritoneal metastasis of invasive lobular carcinoma. Peritoneal metastases from breast cancer are unusual and consequently difficult to identify without non-invasive tools. Exploratory laparoscopy revealed that the cause of hydronephrosis in this case was peritoneal metastasis of invasive lobular carcinoma. Clinical history and histological study play a pivotal role in determining the correct diagnosis.

[A Case of Carcinoma Showing Thymus-Like Differentiation (CASTLE) of the Thyroid].

The case presented herein was a 70-year-old woman who had no compliant, but had a mass in the lower part of the right lobe of the thyroid detected by ultrasound (US). The US image of the tumor, measuring 13 mm in diameter, showed a low and heterogeneous internal echo level with calcification and an irregular margin. The tumor appeared to extend to the adjacent sternothyroid muscle, and cervical lymph node swelling was detected in a computer tomography (CT) image, but no metastatic lesion was found by positron emission tomography (PET)-CT. In a fine needle aspiration cytology of the tumor, papillary thyroid carcinoma was suggested because of the atypical epithelial cells having some changes other than intranuclear inclusion bodies. A subtotal thyroidectomy and central neck lymph node dissection were performed. The excised tumor was histologically composed of irregular nests or sheets of atypical squamoid epithelial cells with some ductal structures that leached to the sternothyroid muscle and involved the right lower parathyroid gland. Carcinoma showing thymus-like differentiation (CASTLE) was diagnosed histopathologically and immunohistochemically with the following immunohistochemical results: Cluster of differentiation 5 (CD5) (+), tumor protein p63 (p63) (+), KIT proto-oncogene receptor tyrosine kinase (c-KIT(CD117)) (+), thyroglobulin (-), and thyroid transcription factor-1 (TTF-1) (-). CASTLE is a rare carcinoma of the thyroid that architecturally resembles thymic epithelial tumors. Many CASTLE patients have been misdiagnosed as other carcinomas, such as anaplastic carcinoma, poorly differentiated carcinoma or squamous cell carcinoma of the thyroid. Immunohistochemical examination, including CD5 played an important role in the final diagnosis of CASTLE, although the distinction from diagnosis as squamous cell carcinoma or mucoepidermoid carcinoma in Hematoxylin-Eosin staining was challenging in our case. Nodal metastasis and perithyroidal tumor extension of CASTLE can predict its worse prognosis. Thus, at least careful follow-up studies are mandatory in cases of CASTLE.

Evaluation of the R2* value in invasive ductal carcinoma with respect to hypoxic-related prognostic factors using iterative decomposition of water and fat with echo asymmetry and least-squares emission (IDEAL).

OBJECTIVE: To correlate the R2* value obtained by iterative decomposition of water and fat with echo asymmetry and least-squares emission (IDEAL) with fibrotic focus (FF), microvessel density and hypoxic biomarker (HIF-1α) in breast carcinoma. METHODS: Forty-two patients who were diagnosed with invasive ductal carcinoma (IDC) of the breast underwent breast MRI including IDEAL before surgery. The entire region of interest (ROI) was delineated on the R2* map, and average tumour R2* value was calculated for each ROI. Histological specimens were evaluated for the presence of FF, the microvessel density (the average microvessel density and the ratio of peripheral to central microvessel density), and the grading of HIF-1α. RESULTS: FF was identified in 47.6% (20/42) of IDCs. Average R2* value for IDC with FF (42.4±13.2 Hz) was significantly higher than that without FF (28.5±13.9 Hz) (P = 0.01). Spearman rank correlation suggested that the average R2* value correlated with the grade of HIF-1α and the ratio of peripheral to central microvessel density for IDCs (P < 0.001). CONCLUSION: Quantification of tumour R2* using IDEAL is associated with the presence of FF and the overexpression of HIF-1α, and may therefore be useful in predicting hypoxia of breast carcinoma. KEY POINTS: • R2* value obtained by IDEAL correlates with the overexpression of HIF-1α. • R2* value obtained by IDEAL is associated with fibrotic focus. • R2* quantification may be useful in predicting hypoxia of breast carcinoma.

A Case of Matrix-Producing Carcinoma of the Breast.

A 61-year-old woman was referred to our hospital because of a right breast mass. A 19 mm hard mass was palpable in the A area of the right breast. A contrast-enhanced MRI showed rim enhancement at the peripheral region of the tumor, which was thought to represent the carcinoma component mainly at the periphery and the matrix component inside the tumor. A low density mass with rim enhancement at the peripheral region was observed in a contrast-enhanced CT, the same as in the MRI. Neither axillary lymph node metastasis nor distant metastasis was observed. A core needle biopsy of the tumor lead to a diagnosis of matrix-producing carcinoma (MPC). A breast-conserving mastectomy with sentinel lymph nodes biopsy was performed on the right breast MPC (T1c, N0, M0 Stage I). Histopathologically, the tumor demonstrated overt carcinoma with direct transition to a cartilaginous or osseous matrix and lacked an intervening spindle cell component. Immunohistochemistry showed estrogen receptor (ER) (-), progesterone receptor (PgR) (-), human epidermal growth factor receptor 2 (HER2) (-), and Ki67 index of 50%, so-called triple negative breast cancer. The tumor was also positive for SRY-related HMG box-9 (SOX9), which is a useful marker of chondroid differentiation in normal and neoplastic tissues. The patient lived free from recurrence for 5 years, even though her adjuvant therapy was only radiation therapy without adjuvant chemotherapy. MPC is an uncommon and relatively rare variant of metaplastic carcinoma, and the prognosis for patients with MPC is poorer than that for patients with ordinary breast cancer. Here we report a case of MPC of the breast with characteristic rim enhancement in contrast-enhanced MRI and CT. The intrinsic subtype and prognosis of MPC is controversial, and then we may need more experience with MPC cases.

Laparoscopic approach for port site mass diagnosed as a Schloffer tumor following surgery of ascending colon cancer.

Schloffer tumor is a foreign body granuloma that develops in the subcutaneous layer of the abdomen over several months to several years after surgery due to sutures. Here, we performed a laparoscopic resection for a benign Schloffer tumor that showed positive F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) at the port site of a laparoscopic right hemicolectomy for advanced colon cancer. We report a case in which systemic chemotherapy was avoided as a result of the histological examination following the laparoscopic approach. A 66-year-old female, who underwent laparoscopic right hemi colectomy for stage IIIA ascending colon cancer, was revealed an enhanced mass at the right side of the abdominal subcutaneous layer. PET examination showed a high accumulation of FDG. Laparoscopic tumor resection was performed. Pathological findings reported the formation identical to the Schloffer tumor. Schloffer tumor, which is rare, should be considered as one of the differential diagnoses for tumor with FDG-PET positivity at the port site during the postoperative surveillance period of colorectal cancer.

Peritumoral Fat Content Identified Using Iterative Decomposition of Water and Fat with Echo Asymmetry and Least-squares Estimation (IDEAL) Correlates with Breast Cancer Prognosis.

PURPOSE: Adipocytes around aggressive breast cancer (BC) are less lipid different from naive adipocytes (cancer-associated adipocytes, CAAs), and peritumoral edema caused by the release of cytokines from CAAs can conduce to decrease the peritumoral fat proportion. The purpose of this study was to correlate peritumoral fat content identified by using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with lymph node metastasis (LNM) and recurrence-free survival (RFS) in BC patients and to compare with T2-weighted (T2WI) and diffusion-weighted images (DWI) analyses. METHODS: This retrospective study consisted of 85 patients who were diagnosed with invasive carcinoma of breast and underwent breast MRI, including IDEAL before surgery. The scan time of fat fraction (FF) map imaging using IDEAL was 33s. Four regions of interest (ROIs), which are 5 mm from the tumor edge, and one ROI in the mammary fat of the healthy side were set on the FF map. Then average peritumoral FF values (TFF), average FF values on the healthy side (HFF), and peritumoral fat ratio (PTFR, which is defined as TFF/HFF) were calculated. Tumor apparent diffusion coefficient (ADC) values were measured on ADC map obtained by DWI. Peritumoral edema was classified into three grades based on the degree of signal intensity around the tumor on T2WI (T2 edema). RESULTS: The results of stepwise logistic regression analysis for four variables (TFF, PTFR, T2 edema, and ADC value) indicated that TFF and T2 edema were significant factors of LNM (p < 0.01). RFS was significantly associated with TFF (p = 0.016), and 47 of 49 (95.9%) patients with TFF more than 85.5% were alive without recurrence. CONCLUSION: Peritumoral fat content identified by using IDEAL is associated with LNM and RFS and may therefore be a useful prognostic biomarker for BC.

Peritumoral Fat Content Correlates with Histological Prognostic Factors in Breast Carcinoma: A Study Using Iterative Decomposition of Water and Fat with Echo Asymmetry and Least-Squares Estimation (IDEAL).

PURPOSE: To correlate peritumoral fat content using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with histologic prognostic factors in breast carcinoma. MATERIALS AND METHODS: This study consisted of 100 patients who were diagnosed with invasive carcinoma of breast and underwent breast MRI including IDEAL before surgery. The scan time of IDEAL fat fraction (FF) map imaging was 33 s. Four regions of interests (ROIs), which are a distance of 5 mm from the tumor edge, and one ROI in the mammary fat of the healthy side were set on the FF map. Then average peritumoral FF values (FFt), average FF values in the healthy side (FFh), and peritumoral fat ratio (pTFR: defined as FFt/FFh) were calculated. Histologically, the presence of lymph node metastasis and the MIB-1 index were evaluated. RESULTS: FFt and pTFR for breast carcinoma with lymph node metastasis (79.27 ± 10.36 and 0.897 ± 0.078) were significantly lower than those without (86.23 ± 4.53 and 0.945 ± 0.032) (P < 0.001 and P = 0.005). Spearman rank correlation suggested that the FFt correlated with the MIB-1 index (r = -340, P = 0.001). CONCLUSION: Quantification of peritumoral fat using IDEAL-iron quantification is associated with the histologic prognostic factors, and may be a practical tool for therapeutic strategy of breast carcinoma.

[A case of small cell lung cancer (extensive disease) with liver metastasis acquiring stable disease by hepatic arterial infusion chemotherapy].

The patient was a 58-year-old male with small cell lung cancer [T2N1M1 (HEP) ED case] who was treated systemic chemotherapy with 2 courses of CDDP+CPT-11 and 3 courses of CBDCA+PTX. After 5 courses of chemotherapy, the total response was stable disease (SD). Because the primary lesion had achieved a minor response, however, liver metastasis evidenced no change. Because of his good performance status, he was immediately treated by hepatic arterial infusion chemotherapy ( HAI) using CPT-11 to control the liver metastasis. After the HAI of weekly CPT-11 during eleven months until progression of primary lung lesion, no change in size of the liver metastasis was recognized with decreasing ProGRP (18,400 -->5,800). HAI is considered very useful for disease control without progression and for good quality of life.

Chemopreventive effect of 4-[3,5-Bis(trimethylsilyl) benzamido] benzoic acid (TAC-101) on MNU-induced colon carcinogenesis in a rat model.

PURPOSE: 4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative. The chemopreventive effect and the mechanism of action of TAC-101 were investigated using a rat chemical colon carcinogenesis model. MATERIALS AND METHODS: Colon tumors were induced using intra-rectal instillation of N-methyl-N-nitrosourea (MNU) in F344 rats. These rats were divided into five groups, control, high dose (TAC-101 8 mg/kg)-long period (four weeks), high dose-short period (one week), low dose (TAC-101 0.8 mg/kg)-long period and low dose-short period. After the large bowels were resected at 20 weeks, the number of aberrant crypt foci (ACF) and tumors in the colon were counted. Proliferating cell nuclear antigen (PCNA) positive index, apoptotic index (AI) and Fas expression were also evaluated using immunohistochemistry. RESULTS: The tumor incidence and the tumor number in the high dose-long period group were decreased in comparison to those in the other groups, but not significantly. However, the number of ACF or PCNA positive indices in the high dose-long period group was significantly decreased in comparison to that in the other groups. On the other hand, the AI and the Fas expression pattern in the tumor and the normal appearing mucosa were not changed in any of the groups. CONCLUSION: TAC-101 might inhibit MNU induced colon carcinogenesis via a decrease of ACF. The mechanism of this chemoprevention may be related to a reduction in cell proliferation, but is not directly associated with apoptosis.

The prognostic significance of the expression of monocarboxylate transporter 4 in patients with right- or left-sided colorectal cancer.

AIM: Monocarboxylate transporter 4 (MCT4) is a proton pump that exchanges lactate through the plasma membrane. The present study investigated the clinical significance of the expression of MCT4 in patients with right- or left-sided colorectal cancer (CRC). METHODS: Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-MCT4 antibodies. The relationships among the MCT4 expression, the clinicopathological factors, and the prognosis were evaluated. RESULTS: Thirty-six (62.1%) of 58 patients with right-sided CRC and 95 (53.1%) of 179 patients with left-sided CRC showed the high expression of MCT4. The MCT4 expression was significantly correlated with gender and lymph node metastasis in patients with right-sided CRC, and size, depth of invasion, distant metastasis, and tumor-node-metastasis stage in patients with left-sided CRC. A univariate analysis demonstrated that the expression of MCT4 was a significant prognostic factor in both right- and left-sided CRC patients. A multivariate analysis demonstrated the expression of MCT4 was a significantly independent prognostic factor in patients with left-sided CRC, but not in those with right-sided CRC. CONCLUSIONS: Our results suggest that the high expression of MCT4 is a useful marker for tumor progression and a poor prognosis in CRC patients, especially those with left-sided CRC.

Prognostic significance of the local expression of interleukin-12 in patients with advanced gastric cancer.

BACKGROUND: Interleukin (IL)-12 is a heterodimeric cytokine that exhibits potent antitumor and antimetastatic activities. Very few studies have so far investigated the local expression of L-12 in tumor specimens of gastric cancer. The purpose of this study was to investigate the immunohistochemical expression of IL-12 in patients with gastric cancer. PATIENTS AND METHODS: IL-12 was immunohistochemically stained using monoclonal antihuman IL-12 antibody (1-1A4) in surgical specimens of 117 gastric cancer patients. The IL-12-positive cell density was calculated. The relationships among the IL-12-positive cell density, clinicopathological factors and 5-year survival rate were evaluated. RESULTS: Among the patients (n=117), the 5-year survival rate after surgery was not statistically different between the patients with high and low IL-12 positive cell-density. However, in the patients with advanced gastric cancer (n=85), those with a high IL-12-positive cell density showed a significantly better prognosis in comparison with those with a low IL-12-positive cell density (p=0.0104). A multivariate analysis indicated that the IL-12-positive cell density and TNM stage are significant prognostic factors. CONCLUSION: IL-12-positive cell density may be a significant independent prognostic factor in surgical specimens of advanced gastric cancer.

[A case of low grade ductal carcinoma in situ of the breast with difficulties in making the preoperative diagnosis after detection by FDG-PET].

A 56-year-old woman underwent FDG-PET screening, which demonstrated delayed-phase uptake in the lower part of the left breast. The findings of mammography, ultrasonography, MRI and cytological examination were compatible with ductal carcinoma in situ (DCIS), but core needle biopsy showed no evidence of malignancy. Therefore, partial resection of the left breast with sentinel lymph node biopsy was performed to make a definite diagnosis. Histological examination showed that this tumor was low grade DCIS. FDG-PET is a very useful examination to detect malignant diseases, but it is quite difficult to distinguish them from benign ones. It is suggested that delayed-phase uptake of FDG-PET is useful for diagnosis of DCIS.

Clinical performance metrics of 3D stereoscopic digital mammography compared with 2D digital mammography: observer study.

OBJECTIVE: To assess the clinical performance of three-dimensional stereoscopic digital mammography (3DsDM) compared with two-dimensional digital mammography (2DDM) for breast lesion diagnosis with jackknife free-response receiver operating characteristics (JAFROC) observer study. METHODS: 40 pairs of standard-dose 2DDM and their 3DsDM images were used for an observer performance study. A total of 18 lesions were identified as the reference standard of actionable breast lesions (Breast Imaging Reporting and Data System Category 3 or more) by two breast radiologists. Ratings and locations of "lesions" determined by observers were utilized for assessing the statistical significance of differences between eight radiologists' performances with the 2DDM images and with the 3DsDM images in jackknife free-response receiver operating characteristic analysis. RESULTS: The average figure-of-merit values for all radiologists increased to a statistically significant degree, from 0.859 with the 2DDM images to 0.936 with the 3DsDM images (p < 0.001). The average sensitivity for detecting actionable lesions was improved from 74.3 to 92.4% at a false-positive rate of 0.2 per case by use of the 3DsDM images. The mean reading time per case with 2DDM images was not significantly different from that with 3DsDM images. CONCLUSION: The use of 3DsDM would improve the observer performance for breast lesion without considerably extending the reading time. Advances in knowledge: Use of 3DsDM improves radiologists' performance for breast lesion detection.

Significance of lymphangiogenesis as assessed by immunohistochemistry for podoplanin in patients with esophageal carcinoma.

BACKGROUND: Although lymph node involvement is an important prognostic factor for survival in patients with esophageal carcinoma, little is known about lymphangiogenesis in esophageal carcinoma. Podoplanin, a mutin-type transmembrane glycoprotein, specifically recognizes the lymphatic endothelium and is used as a lymphatic-specific marker. Anti-human podoplanin antibody was therefore used to quantify and evaluate the lymphangiogenesis in esophageal carcinoma. PATIENTS AND METHODS: Lymphatic endothelial cells were detected by immunohistochemistry using mouse monoclonal anti-human podoplanin antibody. The relationship between lymphatic microvessel density (LMVD) and lymphatic vessel invasion (LVI), clinicopathological factors and the prognosis in 29 patients with esophageal carcinoma was investigated. RESULTS: LMVD was significantly higher in esophageal carcinoma patients who had any of the following characteristics: T3-T4 (p=0.0370), tumors more advanced than stage III (TNM staging) (p=0.0351), lymphatic invasion (p=0.0095) and LVI (+) (p=0.0016). LVI significantly correlated with lymph node metastasis (p=0.0003), TNM staging (p=0.0182) and LMVD (p=0.0388). The survival rate of patients with a low LMVD tended to be higher than that of patients with a high LMVD (5-year survival rate, 62.5% vs. 29.4%, p=0.0832). CONCLUSION: The evaluation of lymphangiogenesis using podoplanin immunohistochemistry may be useful in predicting lymph node metastasis and the prognosis in patients with esophageal carcinoma.

4- [3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) induced fas expression and activated caspase-3 and -8 in a DLD-1 colon cancer cell line.

BACKGROUND: 4-[3,5-Bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative which has a specific binding affinity to the retinoic acid receptors (RAR)alpha and RARbeta. Using time-dependent FACScan analysis, it was observed that TAC-101 induced apoptosis in a DLD-1 human colon cancer cell line. In this study, the induction of apoptosis-related proteins and the activities of caspases in a DLD-1 cell line under medication with TAC-101 were investigated. MATERIALS AND METHODS: DLD-1 cells were cultured with different concentrations of TAC-101 for 12, 24 and 48 h. The expressions of Fas, TNF-R1, DR3, bcl-2, Bax and Bid were measured using a Western blot analysis. The activities of caspase-3, -8 and -9 were measured using a colorimetric protease assay kit. RESULTS: The Western blot analysis showed that TAC-IO1 had almost no effect on the level of Bcl-2, Bax or Bid protein. Although TAC-101 did not change the expression of TNF-R1 and DR3, TAC-101 increased the expression of Fas in both a time- and a dose-dependent manner. A 3-fold increase in caspase-3 activity and a 1.5-fold increase in caspase-8 activity were observed in cells treated with TAC-101 in comparison to the control cells (p<0.01). CONCLUSION: Our data indicate that the death receptor root of the apoptotic signal transduction in DLD-1 cells mainly participates in the apoptotic induction of TAC-101. Because the compounds inducing apoptotic activity are frequent targets of cancer therapy, TAC-101 may be a good candidate for use in the treatment of colon cancer.

Correlation between the urinary dihydrouracil-uracil ratio and the 5-FU plasma concentration in patients treated with oral 5-FU analogs.

BACKGROUND: The determination of dihydropyrimidine dehydrogenase (DPD) deficiency is important in avoiding severe 5-fluorouracil (FU) toxicity. The dihydrouracil (UH2)-uracil (Ura) ratio (UH2/Ura) in plasma might be an important indicator of the risk of 5-FU catabolic deficiency. In order to clarify this possibility, the pyrimidine metabolites and the UH2/Ura were measured in urine and the plasma level of 5-FU was evaluated in patients with gastric and colorectal cancer. PATIENTS AND METHODS: Patients with primary gastric (n=14) and colorectal (n=8) cancer who had undergone surgery were recruited in this study. These patients were divided into the S-1 treatment group, which drug is a novel oral formulation of tegafur, oxonic acid and 5-chloro-2, 4-dihydroxypyridine (CDHP) (n=14) and a group receiving other drugs which include UFT (Uracil/Tegafur) or oral doxifluridine (n=8). The urinary levels of UH2 and Ura were measured by high-performance liquid chromatography (HPLC) using column swiching. The plasma level of 5-FU was assessed by gas chromatography-mass spectrometry (GC-MS). RESULTS: The UH2/Ura or UH2/Ura (treated/no treated) in the S-1 group significantly decreased in comparison to that in the other-drug group and the plasma 5-FU concentration in the S-1 group significantly increased compared to that in the group treated with other drugs. The plasma 5-FU concentration levels significantly indicated a positive correlation with urinary Ura. Moreover, UH2/Ura treated with 5-FU analogs or UH2/Ura (treated/no treated) significantly showed a negative correlation with the plasma 5-FU concentration levels. CONCLUSION: Our findings indicate that either urinary Ura, the UH2/Ura or UH2/Ura (treated/no treated) can predict the plasma 5-FU concentration levels or DPD deficiencies.

Expression levels of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in patients with gastrointestinal cancer.

BACKGROUND: Thymidine phosphorylase (TP) is a key enzyme involved in pyrimidine nucleoside metabolism. Dihydropyrimidine dehydrogenase (DPD) is the major catabolic enzyme of 5-fluorouracil (5-FU). These are important enzymes in the pyrimidine salvage pathway and are considered to be key enzymes for determining the prognosis of patients with gastrointestinal cancer. In the present study, TP and DPD were quantified and evaluated in gastric and colorectal cancer. PATIENTS AND METHODS: In 111 cases of malignancy, including 30 gastric cancers and 81 colorectal cancers, the expression levels of both TP and DPD in fresh-frozen samples from either tumor or adjacent normal tissue were quantified using enzyme-linked immunosorbent assay (ELISA). The relationships between TP or DPD expression levels in tumor tissues or adjacent normal tissues and clinicopathological factors were evaluated. RESULTS: The TP expression levels in gastric or colorectal tumor tissues were found to be significantly higher than those in the adjacent normal tissue. Although the DPD expression levels in gastric tumor tissue were significantly higher than those in adjacent normal tissue, the DPD expression levels in colorectal tumor tissue were nearly identical to those in the adjacent normal tissue. The DPD expression levels in gastric tumor tissues were significantly higher than those in colorectal tumor tissues. The TP expression levels correlated significantly with the DPD expression levels in tumor or adjacent normal tissues. The DPD expression levels in tumor tissues significantly correlated with those in adjacent normal tissue. CONCLUSION: The difference in DPD expressions between gastric and colorectal cancer tissues may reflect the organ specificity of the carcinomas and a difference in chemotherapeutic sensitivity to 5-FU or its analogs. The correlation between TP and DPD expression levels suggests the existence of a common regulatory pathway.

Relationship between interleukin-12-expressing cells and antigen-presenting cells in patients with colorectal cancer.

BACKGROUND: Interleukin-12 (IL-12) is a powerful cytokine that plays an important role in cell-mediated immunity. Although IL-12 is produced by antigen-presenting cells (APCs), the relationship between IL-12 expression and APCs in colorectal cancer tissue remains unknown. PATIENTS AND METHODS: Immunohistochemical detection of APCs and IL-12 was performed in 22 colorectal cancer specimens. CD83 and CD68 were used for the markers of mature dendritic cells (DCs) and macrophages, respectively. Double staining with CD83 or CD68 and IL-12 was also performed to detect IL-12-secreting cells. CD83-, CD68- and IL-12-positive-cell densities, clinicopathological factors and survival were analyzed. RESULTS: CD83-, CD68- or IL-12-positive-cells were stained in the tumor stroma. Double-stained CD83/IL-12- or CD68/IL-12-positive-cells were also detected in the same area. The CD83-positive-cell density was significantly higher in patients with a high IL-12-positive-cell density than those with a low IL-12-positive-cell density. The CD83-positive-cell density was significantly lower in patients with T3-T4 depth of invasion, lymph node metastasis or tumors more advanced than stage II. The IL-12-positive-cell density tended to be lower in patients with T3-T4 depth of invasion or venous invasion. Patients with high CD83- or IL-12-positive-cell density in their cancer specimens showed significantly better prognosis. CONCLUSION: This study provides new information on the significance of mature DCs, macrophages and IL-12-secreting cells in the local environment of colorectal cancer. Survival in patients with colorectal cancer was reflected by mature DCs and/or IL-12-positive-cell density.

4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) induces apoptosis in colon cancer partially through the induction of Fas expression.

BACKGROUND: 4-[3,5-Bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative, which has a specific binding affinity to the retinoic acid receptors (RAR)-alpha and -beta. Apoptotic induction by TAC-101 was investigated using a rat hepatic metastatic model of rat RCN-9 colon cancer cells in vivo and FACScan analysis with the DLD-1 human colon cancer cell line in vitro. MATERIALS AND METHODS: Hepatic metastatic tumors were induced using intra-portal injection of RCN-9 cells into F344 rats in vivo. TAC-101 (8 mg/kg) was orally administered for 5 consecutive days a week for 4 weeks. Subsequently, hepatic tumors were counted after laparotomy. Apoptotic index (A.I.) in the hepatic tumors was evaluated using immunohistochemistry for single-stranded DNA. The proliferative index (P.I.), Fas and Fas ligand were also immunohistochemically evaluated. Moreover, evaluation of apoptosis by TAC-101 in vitro using FACScan analysis was performed in the DLD-1 human colon cancer cell line. RESULTS: Oral administration of TAC-101 resulted in a significant inhibition of hepatic metastasis without weight loss of the rats. TAC-101 significantly decreased P. I. but increased A. I. in the hepatic metastatic tumors. TAC-101 did not affect the expression of Fas ligand, but obviously increased the expression of Fas in the metastatic tumors. Moreover, TAC-101 induced early apoptosis in DLD-1 cells in a time-dependent manner in vitro. CONCLUSION: These findings suggest that TAC-101 inhibits hepatic metastasis of colon cancer and induces apoptosis partially through enhanced Fas expression.