Feasibility of AC/EC followed by weekly paclitaxel in node-positive breast cancer in Japan.

UNLABELLED: The feasibility and efficacy of adriamycin or epirubicin in combination with cyclophosphamide followed by weekly paclitaxel (AC/EC-weekly PAC) as adjuvant chemotherapy for breast cancer was investigated. PATIENTS AND METHODS: Node-positive breast cancer was treated with AC/ EC-weekly PAC, namely AC at 60/600 mg/m(2) or EC at 90/600 mg/m(2) x4 at three-week intervals, followed by weekly PAC (80 mg/m(2)) x 12, namely four cycles of single weekly administration for three weeks followed by a one-week rest (3 x 4 PAC) or single weekly administration for 12 consecutive weeks (12 PAC). RESULTS: One hundred and three of 109 consecutive patients enrolled were analyzed, of whom 96 (93.2%) completed the regimen. Grade 3/4 neutropenia occurred in 52.4% receiving AC/EC, and 10.9% of 55 receiving 12 PAC but only 2.1% of 48 receiving 3 x 4 PAC. Neuropathy disorders occurred in more than half receiving PAC, which did not improve after one-week rest in 3 x 4 PAC. CONCLUSION: AC/EC-weekly PAC is feasible and without serious complications.

[Efficacy of low-dose CDDP and CPT-11 for patients with intestinal type of gastric adenocarcinoma].

BACKGROUND: Preclinical studies have shown that irinotecan (CPT-11) and cisplatin (CDDP) can act synergistically. Several chemotherapy regimens combining CPT-11 and CDDP for advanced gastric cancer have been reported to demonstrate high response rates and high incidence of severe toxicity. PURPOSE: We conducted a combination chemotherapy regimen of low-dose CDDP and CPT-11 to prolong the time to progression with less toxicity. PATIENTS AND METHODS: Seven patients with histologically-confirmed intestinal type of gastric adenocarcinoma were enrolled in this study. All patients were male, and their age at diagnosis ranged from 52 to 76 with a mean age of 64.8. Six patients received combination chemotherapy with CPT-11 and CDDP after the gastrectomy (stage I b: 1, II : 3, III b: 1, IV: 1). Only chemotherapy was administered in one patient because of a far advanced primary lesion and metastatic tumors. Low-dose CDDP (20 mg/body) and CPT-11 (65 mg/m(2)) were administered intravenously once every two weeks. RESULTS: The overall response rate was 43% including 1 complete response and 2 partial responses. One patient had grade 3 myelosuppression. Other adverse reactions were mild. CONCLUSION: The combination of low-dose CDDP and CPT-11 has mild therapeutic toxicities and may achieve a prolonged median survival time in patients with intestinal- type gastric adenocarcinoma.

False-positive and false-negative cases of fine-needle aspiration cytology for palpable breast lesions.

BACKGROUND: Fine-needle aspiration cytology (FNA) is less traumatic and technically easy to apply to small breast tumors. METHODS: A total of 382 cases of palpable breast lesions that had undergone fine needle aspiration and histopathologic diagnosis were reviewed with an emphasis on the rate of false positive diagnoses in benign breast lesions. RESULTS: A diagnosis of " malignant " was made in 98 of the 382 specimens (25.6%). The predictive value for malignancy was 97.9%. The sensitivity, specificity, and accuracy of FNA were 86.3%, 98.2%, and 93.2%, respectively, when the " suspicious " group was considered positive for malignancy. The histologic subtypes of the 4 false-positive cases were epithelial proliferative lesions, ductal or lobular hyperplasia. None of these 4 cases were definitely diagnosed as " malignant " by radiological studies. Four false-negative cases by FNA were suspicious for malignancy radiologically. There was no specific pathological subtype associated with false-negative status on FNA in this study. CONCLUSION: Palpable breast tumors can be definitively diagnosed based on a combination of physical examination, radiological studies and FNA, when the radiological studies concur with the diagnosis by FNA.

A case of lymphoepithelioma-like carcinoma of the colon with ulcerative colitis.

Follow-up colonoscopy of a 25-year-old Japanese man with ulcerative colitis (UC) who had undergone endoscopic mucosal resection twice for early colon cancers revealed the presence of a new 1.5-cm-diameter tumor in the sigmoid colon. It was diagnosed by preoperative biopsy as a poorly differentiated adenocarcinoma. Sigmoidectomy was performed, and the pathological findings revealed lymphoepithelioma-like carcinoma (LEC). In situ hybridization to detect Epstein-Barr virus (EBV)-encoded small RNAs showed positive signals in stromal lymphocytes, but weak signals in the tumor cells. The association between EBV and LEC was obscure in this case. Unlike typical UC-mediated colon cancers, the lesion was poorly differentiated, and negative for p53 signals immunohistochemically. These findings may hint at a novel mechanism of carcinogenesis in UC-mediated colorectal cancer.

Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells.

Matrilysin, MMP-7, is an important target for anti-metastasis therapy of colorectal cancer because it is a strong proteolytic factor secreted from the cancer cell itself and it induces tumor angiogenesis. In a previous report, we showed that matrilysin accelerated human umbilical vein endothelial cell (HUVEC) proliferation in low serum conditioned medium. In the present study, we show that matrilysin stimulation decreased VE-cadherin expression, induced accumulation of beta-catenin in the nucleus of the HUVEC, and up-regulated matrilysin mRNA expression. These results compel a hypothesis that matrilysin cleaves VE-cadherin and releases beta-catenin from the VE-cadherin/catenin complex; the free beta-catenin can activate T-cell factor (Tcf) DNA binding protein, which accelerates cell proliferation and matrilysin expression.

A multicenter phase II study of docetaxel 60 mg/m2 as first-line chemotherapy in patients with advanced or recurrent breast cancer.

PURPOSE: Docetaxel is an active agent as first-line chemotherapy in patients with advanced breast cancer at a dosage of 100 mg/m2. However, the efficacy of this agent as a first-line drug when used at a lower dosage is unclear. This study was performed to evaluate the clinical efficacy and safety of 60 mg/m2 docetaxel for the treatment of breast cancer. PATIENTS AND METHODS: This study enrolled 23 patients with advanced and/or metastatic breast cancer, who had not been treated with an anthracycline or taxane previously. Treatment with docetaxel was continued in patients showing a response until there was evidence of disease progression or unacceptable toxicity. RESULTS: Among 20 fully evaluated patients, the overall response rate was 50.0% and the median time to progression was 31 weeks. The most commonly observed adverse events were neutropenia (78.2%) and fatigue (60.9%). Fluid retention occurred in only 8.7% of the patients. Adverse events did not cause discontinuation of the treatment. CONCLUSION: Docetaxel achieved good disease control with mild adverse events in first-line treatment at a dosage of 60 mg/m2.

Evaluation of dynamic studies of MR mammography for the diagnosis of intraductal lesions with nipple discharge.

OBJECTIVES: We assessed the utility of dynamic magnetic resonance imaging (MRI) in differentiating benign from malignant lesions of the breast and then applied MRI to diagnose intraductal breast tumors with nipple discharge. METHODS: Gadolinium (Gd)-enhanced MR mammography was performed on 74 patients with breast tumors and 8 patients with nipple discharge. RESULTS: The steepest slopes of the contrast medium uptake (S slope) s from time-intensity curves were significantly different between malignant and benign lesions. At S slope threshold of 0.95% /second, malignancy was predicted with a sensitivity and specificity of 75% . Six of 8 cases with nipple discharge were successfully identified by MR ductography by injecting Gd-DTPA into discharging ducts. Among them, 2 non-invasive ductal carcinomas were differentiated from benign lesions by the S slope value. CONCLUSIONS: Dynamic MR mammography is an useful modality for differentiating breast lesions and has potential for evaluating intraductal lesions with nipple discharge.

Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray.

BACKGROUND: Brain metastases occur in 15% to 30% of breast cancer patients, usually as a late event. The patterns of metastases to different organs are determined by the tumor cell phenotype and interactions between the tumor cells and the organ environment. METHODS: We investigated the gene expression profile occurring in brain metastases from a breast cancer cell line. We used cDNA microarrays to compare patterns of gene expression between the mouse breast cancer cell line Jyg MC (A) and a subline that often metastasis to brain, (B). RESULTS: By Microarray analysis about 350 of 21,000 genes were significantly up-regulated in Jyg MC (B). Many candidate genes that may be associated with the establishment of brain metastasis from breast cancer were included. Interestingly, we found that the expression of astrocyte derived cytokine receptors (IL-6 receptor, TGF-beta receptor and IGF receptor) were significantly increased in Jyg MC (B) cells. These results were confirmed by RT-PCR. CONCLUSIONS: These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases from breast cancer cells.

Cross-linked collagen C- and N-telopeptides for an early diagnosis of bone metastasis from breast cancer.

Bone resorption markers have become available for the diagnosis of bone metastasis. We evaluated cross-linked collagen C-and N-telopeptides (ICTP and NTx) in diagnosing bone metastasis from breast cancer. For a threshold of 4.5 ng/ml of 1CTP and 55.0 pmol BCE/micromol of NTx, bone metastasis could be predicted with an accuracy of 84% and 63%, respectively. All the patients who had metastatic lesions, but showed lower than 4.5 ng/ml of ICTP, had a solitary lesion of bone metastasis. Although ICTP is not sensitive enough to detect an early stage of bone metastasis, it is a better biochemical marker than NTx for detecting bone metastasis from breast cancer.

Locally advanced mucinous carcinoma of the breast with sudden growth acceleration: a case report.

We report a 35-year-old woman with locally advanced mucinous carcinoma of the breast with sudden growth acceleration. A pea-sized mass developed into an ulcerated large tumor within 1 month. After the combination of chemotherapy, radiation and hyperthermia, a radical mastectomy was performed, followed by repair of the skin defect by latissimus dorsi and rectus abdominis musculocutaneous flaps. Histological examination revealed a pure mucinous carcinoma with axillary lymph node involvement. Estrogen and progesterone receptors were not detected in the tumor. Twenty-five months after treatment, there is no sign of recurrent disease. Pure mucinous carcinoma generally has a less aggressive growth pattern as defined by tumor size, adherence to the overlying skin/bottom fasciae, estrogen and progesterone receptor positive and primary lymph axillary lymph node metastases. This case showed completely opposite features to all of these typical biological features of pure mucinous carcinomas.

VEGF receptor antisense therapy inhibits angiogenesis and peritoneal dissemination of human gastric cancer in nude mice.

The efficacy of a phosphorothioate antisense oligonucleotide (ASO) for KDR/Flk-1 (KDR/Flk-1-ASO), an endothelial cell-specific vascular endothelial growth factor (VEGF) receptor, was investigated on the peritoneal dissemination and angiogenesis of a human gastric cancer cell line in nude mice. Green fluorescent protein (GFP)-transduced NUGC-4 (NUGC-4-GFP) human gastric cancer cells were implanted into the peritoneal cavity of nude mice. KDR/Flk-1-ASO, -SO, or phosphate-buffered saline was administrated from days 7 to 14, 200 microg/mouse, once a day. The mice were sacrificed on day 28. Disseminated peritoneal tumor nodules expressing GFP were visualized by fluorescence microscopy. KDR/Flk-1-ASO significantly decreased the extent of peritoneal dissemination of the tumors. The number of cells undergoing apoptosis was significantly increased in the KDR/Flk-1-ASO-treated tumors. Microvessel density was significantly reduced in the KDR/Flk-1-ASO-treated tumor nodules. The KDR/Flk-1 antisense strategy, therefore, decreases tumor dissemination apparently by inhibiting angiogenesis.

MMP-7 (matrilysin) accelerated growth of human umbilical vein endothelial cells.

Matrix metalloproteinases (MMP) are considered to play important roles in angiogenesis. In angiogenic processes, endothelial cells secrete MMP-2 or MMP-1 to dissolve the basement membrane or connective tissue around the vessels. MMP-7 (matrilysin) is secreted from the neovasculars induced by cancer and is a metastatic factor of colorectal cancer. The effect of matrilysin on angiogenesis is still unclear, however. We therefore examined the effect of MMP-7 on the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro. Our results showed that recombinant MMP-7 (rMMP-7) accelerated the proliferation of endothelial cells dose-dependently, and did so for endothelial cells cultured not only on type IV collagen, but also on type I collagen. MMP-7 also upregulated MMP-1, -2 secretion, but did not stimulate vascular endothelial growth factor (VEGF) secretion. From this study, we conclude that MMP-7 directly induces angiogenesis, and that therefore MMP-7 would be a good target of cancer therapy.