Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17ß-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17ßHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17ßHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.

Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f, a microRNA targeting CYP19A1.

Aromatase inhibitors (AIs) are considered the gold standard of endocrine therapy for oestrogen receptor-positive postmenopausal breast cancer patients. AI treatment was reported to result in marked alterations of genetic profiles in cancer tissues but its detailed molecular mechanisms have not been elucidated. Therefore, we profiled miRNA expression before and after treatment with letrozole in MCF-7 co-cultured with primary breast cancer stromal cells. Letrozole significantly altered the expression profiles of cancer miRNAs in vitro. Among the elevated miRNAs following letrozole treatment, computational analysis identified let-7f, a tumour-suppressor miRNA which targeted the aromatase gene (CYP19A1) expression. Quantitative real-time PCR assay using MCF-7 and SK-BR-3 cells as well as clinical specimens of a neoadjuvant study demonstrated a significant inverse correlation between aromatase mRNA and let-7f expression. In addition, high let-7f expression was significantly correlated with low aromatase protein levels evaluated by both immunohistochemistry and the western blotting method in breast cancer cases. Results of 3'UTR luciferase assay also demonstrated the actual let-7f binding sites in CYP19A1, indicating that let-7f directly targets the aromatase gene. Subsequent WST-8 and migration assays performed in let-7f-transfected MCF-7 and SK-BR-3 cells revealed a significant decrement of their proliferation and migration. These findings all demonstrated that let-7f, a tumour suppressor miRNA in breast cancer, directly targeted the aromatase gene and was restored by AI treatment. Therefore, AIs may exert tumour-suppressing effects upon breast cancer cells by suppressing aromatase gene expression via restoration of let-7f.

Extrahepatic bile duct hepatocellular carcinoma due to recurrence of hematogenous metastasis 50 months after hepatectomy.

BACKGROUND: Recurrent hepatocellular carcinoma (HCC) in the extrahepatic bile duct is rare with most cases diagnosed after manifesting sudden obstructive jaundice. Here, we report an extremely rare case of recurrent HCC in the common bile duct due to hematogenous metastasis. CASE PRESENTATION: A 66-year-old man underwent an extended left hepatectomy for HCC in the medial segment of the liver. Fifty months later, he presented with sudden obstructive jaundice. Endoscopic retrograde cholangiography showed a space-occupying lesion in the common bile duct, which was suspected as cholangiocarcinoma. Therefore, he underwent extrahepatic bile duct resection and choledochojejunostomy with lymph node dissection. Macroscopically, a polypoid tumor and several nodular tumors were found in the common bile duct, which was obstructed by a tumor thrombus. Histopathologically, the tumors were diagnosed as metastases from the HCC resected 50 months before. Several distinct, nodular tumors were observed in the subepithelium of the common bile duct and had invaded some blood vessels. These findings support the conclusion that the HCC metastasized hematogenously to the extrahepatic bile duct. CONCLUSIONS: Recurrent HCC in the extrahepatic bile duct due to hematogenous metastasis is rare, and it is difficult to diagnose. Further similar cases should be accumulated for clarifying the pathological mechanism.

Heterogeneous expression of DNA-dependent protein kinase in esophageal cancer and normal epithelium.

Esophageal cancer tissues and adjacent normal mucosae in 13 patients with primary esophageal cancer were examined for quantitative differences in DNA-dependent protein kinase (DNA-PK) activity and for expressions of Ku70, Ku80 and DNA-PKcs proteins by Western blotting and immunohistochemistry. The tumor tissues showed higher DNA-PK activity than the normal mucosae. Protein levels of Ku70, Ku80 and DNA-PKcs correlated with DNA-PK activities in the tumor tissues. Immunohistochemical analysis revealed that Ku70, Ku80 and DNA-PKcs located predominantly in the nuclei in both the tumor tissues and normal mucosae. In the normal epithelium, Ku70, Ku80 and DNA-PKcs were expressed only in the nuclei of the basal cell layers and not in those of the lumenal cell layers. In the tumor tissues, the expressions of DNA-PK proteins showed intratumoral heterogeneity. The different portions in the same tumor showed different expression levels of DNA-PK proteins, and even each tumor cell showed different expression levels. These results suggest that cell differentiation and tumor progression affect cellular DNA-PK protein levels and its activity. Furthermore, the intratumoral heterogeneity of DNA-PK protein expression in esophageal cancer cells/ tissues also suggests the difficulty in prediction of radio- or chemo-sensitivity of the tumor through estimation of DNA-PK activity/protein levels in tumor specimens.

[Evaluation of service screening for breast cancer by clinical breast examination using regional cancer registry data].

MATERIALS: (1) Screening test: The study utilized data from a regional cancer-screening center from April 1, 1997, to December 31, 1998. A total of 51,700 women underwent screening at this center during this period. All incident cases of breast cancer in these women were derived from the files of the Yamagata Prefectural Cancer registry and sensitivity, specificity and positive predictive value were then estimated. False negative cases were defined as occurring in women who tested negative but were registered as having breast cancer in the cancer registry within 12 months after screening. (2) Effectiveness of screening: The target population comprised female cases with breast cancer registered in the Yamagata Prefectural Cancer Registry from January 1, 1989 to December 31, 1998. During this period, a total of 2,746 cases were registered. Survival probabilities for breast cancer cases were estimated according to method of detection using Kaplan-Meier method. Overall survival probability of the screen-detected group was compared with the not screen-detected group using the log-rank test. Point estimates of 5- and 9-year survival rates between groups were compared using z statistics. RESULTS: (1) Screening detected 27 breast cancer cases, while 31 false negative cases were identified. Sensitivity, specificity and positive predictive value were 46.6% (95% confidence interval (95% CI), 33.3-60.1%), 97.3% (95% CI, 97.2-97.5%) and 1.9% (95% CI, 1.3-2.8%), respectively. (2) Overall survival rate for the screen-detected group was significantly higher than that for the not screen-detected group (P<0.001), with 11.6% (95% CI, 8.0-15.2%) and 13.1% (95% CI: 5.3-20.8%) differences in 5-year and 9-year survival probabilities, respectively. CONCLUSION: Cancer screening by clinical breast examination in Yamagata has improved survival from breast cancer for females. However, the screening sensitivity is insufficient for effective mass screening purposes.

Comparison of screen-film and full-field digital mammography in Japanese population-based screening.

PURPOSE: To investigate how the greater contrast of full-field digital mammography (FFDM) affects the detection of suspicious lesions in Japanese population-based screening. MATERIALS AND METHODS: Screen-film mammography (SFM) and FFDM were performed in 480 women aged 50 years or more. A set of mediolateral oblique views was obtained with each modality. All mammograms were independently double-read. The five-scale category assessment and type of finding using the Breast Imaging Reporting and Data system (BI-RADS) nomenclature were given. Intraobserver variance, recall rates, and positive predictive value were calculated. RESULTS: The findings between the two modalities were discordant. kappa-values for each reader were 0.619 and 0.385, respectively. Almost half of the microcalcifications were called with both modalities. The detection of masses was less concordant between the readers (27%). The masses were detected more frequently with FFDM (73%). Other findings were only detected with one modality. The recall rate was not significantly different (2.9% with SFM vs. 4.2% with FFDM; p=0.253). The positive predictive value was not significantly different (14% with SFM vs. 10% with FFDM; p=0.69), either. Two patients with breast cancer were detected with both modalities. CONCLUSION: Recall rates and positive predictive value were not significantly different between SFM and FFDM. Cancers were detected with both modalities.

A strategy for supraclavicular lymph node dissection using recurrent laryngeal nerve lymph node status in thoracic esophageal squamous cell carcinoma.

BACKGROUND: The desirability of supraclavicular lymph node (LN) dissection, which is the cervical part of three-field LN dissection, has been discussed for a long time. In this study, we examine the pattern of supraclavicular LN metastasis in esophageal cancer, with a particular focus on the correlation between recurrent laryngeal nerve (RLN) LN and supraclavicular LN metastasis. METHODS: In all, 220 cases of R0 resected T1 to T3 squamous cell carcinomas were retrospectively examined. All of these patients underwent bilateral RLN LNs dissection; none received cancer treatment before surgery. RESULTS: Of 21 upper esophageal cancer cases, 33.3% of the patients had metastasis in the supraclavicular LN. Every patient in whom supraclavicular LN metastasis developed had metastasis in the RLN LN. Of 141 cases of middle esophageal cancer, 19.1% had metastasis in the supraclavicular LN. Among the patients whose RLN LN metastasized, 38.3% had metastasis in the supraclavicular LN. A similar correlation between RLN LN and supraclavicular LN metastasis was observed in lower esophageal cancer cases, especially in T3 cases. When considering cancers of the esophagus and patients who had metastasis in the supraclavicular LN, our data demonstrated that RLN LN metastasis did not always lead to metastasis on the same side of the supraclavicular LN. CONCLUSIONS: The status of the RLN LN can be an indicator of supraclavicular LN dissection in upper esophageal cancer patients and advanced cases of middle and lower esophageal cancer patients. Bilateral supraclavicular LN dissection should be recommended even when only unilateral RLN LN metastasis occurs.