Malignant Melanoma of the Nipple: A Case Report.

Malignant melanoma rarely originates from the female nipple. Tumors that develop on the skin of the breast are often subject to a delayed diagnosis. Cytologic examination provides excellent diagnostic capabilities and is a safe procedure with a lower risk of local implantation, compared to needle or incisional biopsy. We herein report a patient who underwent surgical resection of a primary malignant melanoma of the nipple. An elastic soft nodule was observed on the left nipple, and no abnormal lesions were identified in the breast. Eventually, a malignant melanoma was diagnosed from the clinical and cytological evaluation findings. This bulky tumor was classified as a stage IIIC nodular melanoma, with a thickness of 12 mm. The patient received adjuvant chemotherapy and exhibits no evidence of recurrence 7 years after surgery.

[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.

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.

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.

Lymphatic microvessel density is an independent prognostic factor in colorectal cancer.

PURPOSE: Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. METHODS: We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. RESULTS: A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). CONCLUSIONS: Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal 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.

[Two cases of nonrecurrent inferior laryngeal nerve--different branching levels from vagus nerve].

We observed two cases of nonrecurrent inferior laryngeal nerve (NRILN). Case 1, a 71 year old man was diagnosed as having papillary carcinoma. NRILN was found during his operation. It directly branched from the right cervical trunk of the vagus nerve at the level of the cricoid cartilage and then entered the larynx after running behind the thyroid gland. Case 2, a 64 year old woman was diagnosed as having primary hyperparathyroidism. In this patient, the NRILN branched at the level of the inferior pole of the thyroid gland, rose up beside the tracheal wall and entered the larynx. In both patients, preoperative CT scan and postoperative MR angiography revealed the aberrant right subclavian artery. A postoperative barium swallow test showed the compression of the esophagus by this anomalous artery in case 1. Although it is possible to predict the presence of NRILN by preoperative imaging tests, the branching level from the vagus nerve is unpredictable. Surgery must be performed with this point in mind, if the presence of NRILN is suspected.

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.

4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.

4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.

A rare case of primary hyperparathyroidism with clear cell adenoma.

We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 x 2.8 x 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.

[A case of advanced gastric cancer effectively treated by combined chemotherapy of paclitaxel (TXL) and CDDP].

The patient was a 73-year-old man with unresectable advanced gastric cancer and celiac and supraclavicular lymph node metastases. Neoadjuvant chemotherapy consisting of paclitaxel (TXL) and CDDP was administered. TXL (80 mg/m2) and CDDP (25 mg/m2) was administered weekly on day 1, 8 and 15 as 1 cycle. After 4 cycles of TXL/CDDP administration, the lymph node metastases and gastric tumor had decreased almost completely in size and distal partial gastrectomy was performed. After surgery, the patient was treated with 4 courses of TXL/CDDP and has survived without recurrence to the present. TXL/CDDP is associated with few adverse events in hospital visits, and is thought to be an effective chemotherapy against advanced gastric cancer.

Detection of a smaller, 32-kDa 8-oxoguanine DNA glycosylase 1 in 3'-methyl-4-dimethylamino-azobenzene-treated mouse liver.

We previously reported that 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) increased the 8-hydroxyguanine (8-OH-Gua) content in nuclear DNA and the base excision repair activity in mouse liver. However, to understand the mechanism of 3'-MeDAB carcinogenesis, a further investigation of the 8-OH-Gua repair systems was necessary. In this report, we examined the expression of the repair enzyme, 8-oxoguanine DNA glycosylase 1 (OGG1), in 3'-MeDAB-treated mouse liver. We prepared four kinds of anti-peptide polyclonal antibodies raised against mouse OGG1 (mOGG1). The sequences used as epitopes were designed from positions located close to the N-terminus, the nuclear localization signal (NLS), and the regions containing Lys(249) and Asp(267), which are involved in the catalytic mechanisms of mOGG1 (glycosylase and lyase, respectively). Immunoblotting, using all four antibodies, revealed a 32-kDa protein (mOGG1-32) in addition to the 38-kDa mOGG1 in the 3'-MeDAB-treated mouse liver. Moreover, immunostaining with mOGG1 antibody yielded strong, positive signals in the 3'-MeDAB-treated mouse liver nuclei. However, we could not detect any difference in the Ogg1 mRNA expression pattern. Although the function of mOGG1-32 remains unclear, these findings suggest that 3'-MeDAB may alter the function of the DNA repair protein, and this action may be related to 3'-MeDAB carcinogenesis.

Relationships between S-100 protein-positive cells and clinicopathological factors in patients with colorectal cancer.

BACKGROUND: An increased number of dendritic cells (DCs), as indicated by positive S-100 protein staining, has been shown to correlate with good prognosis in several malignancies. The clinicopathological significance of S-100 protein-positive cells in human colorectal cancer is unclear and was thus examined. PATIENTS AND METHODS: We investigated the relationships between the density of S-100 protein-positive cells at the peripheral area of the tumor, prognosis and clinicopathological factors in 30 patients with colorectal cancer. S-100 protein-positive cells were detected by immunohistochemistry using a mouse monoclonal antibody against S-100 protein. RESULTS: The number of S-100 protein-positive cells was significantly higher in patients with a good prognosis or those without recurrence or worsening of their condition, but was significantly lower in patients with lymph node metastasis, T3-T4, hepatic metastasis or tumors more advanced than stage III (TNM). CONCLUSION: S-100 protein-positive cells may act as one line of defense against malignant cells in patients with colorectal cancer.