High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor α–negative (ERα–), Her2/Neu nonoverexpressing cells. In ERα+ cells, estradiol inhibited Notch activity and Notch-1IC nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERα–) cells, Notch-1 knockdown or γ-secretase inhibition decreased cyclins A and B1, causing G2 arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERα+) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, γ;-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERα+ breast cancers and that Notch signaling is a potential therapeutic target in ERα– breast cancers.

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Biliary tract brush specimens are fast becoming the method of choice in the evaluation of patients who present with biliary tract strictures. Although the specificity is high, sensitivity rates for the detection of malignancy are generally low on cytological sampling. New liquid-based preparations and ancillary tests have emerged with the intent of addressing this issue. This review focuses on the current schemata used in the diagnosis of biliary tract lesions and the current available modalities which aid in the diagnosis of cholangiocarcinoma.

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Bile aspiration during endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography has been used as a diagnostic tool in the evaluations of pancreatic and biliary tree strictures for the last two decades. However, recently biliary tract brush cytology has become the method of choice in evaluating pancreatic/biliary tract abnormalities. The aim of this study was to evaluate the accuracy of pancreatobiliary lesions by an endobiliary cytotechnique. From 1993-1999, 278 pancreatobiliary brushings were performed at our institutions. Cytologic material was air-dried for Diff-Quik stain or fixed in ethanol for Papanicolaou staining. The cytologic diagnoses were classified in three categories: 1) benign, 2) atypical/suspicious, or 3) malignant. Subsequent surgical biopsy was available in 87 (31%) patients. There were 150 males and 128 females with a mean age of 63 yr (range 22-97); 167 (60%) were benign cases. Follow-up surgical material was available in 39 cases, seven of which showed adenocarcinoma; 67 of all cases (24%) were atypical/suspicious cases. Follow-up surgical material was available in 31 cases, 17 (55%) of which showed adenocarcinoma; 32 cases (12%) were malignant cases. Follow-up surgical material was available in 15 cases. All 15 cases were in agreement with the cytologic diagnosis. Twelve (4%) cases were unsatisfactory for cytologic examination. Follow-up surgical material was available in two cases. One case showed mucinous cystadenoma of the pancreas. The other case showed benign duct epithelium. Our study shows a sensitivity of 68% and a specificity of 100%. Of the atypical cases, 55% were malignant on follow-up biopsy. Brush cytology of pancreatobiliary strictures is the most widely used technique in the diagnosis of carcinoma, with a high degree of specificity.

"Atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion (ASC-H)" is a new diagnostic category in the 2001 Bethesda nomenclature system for cervical cytology. The purpose of this 7-mo retrospective study (March 1, 2002-September 30, 2002) was to evaluate the significance of ASC-H on cervical Thin Prep Pap Tests. During this period, 25 (0.27%) of 9,214 Pap Tests were diagnosed as ASC-H, 22 of which resulted in either follow-up cervical biopsies and/or cervical cones, and which formed the basis of this study. Tissue specimens (22 cases) were negative in 5 cases (23%) and positive in 17 cases (77%). Of the positive specimens, there were 2 (12%) low-grade squamous intraepithelial lesions (LSIL) and 15 (88%) high-grade squamous intraepithelial lesions (HSIL). Of the 22 cases, ASC-H diagnoses included immature/atypical squamous metaplasia vs. a squamous intraepithelial lesion (SIL) in 19 (86%) cases, and tight clusters of small cells with a high nuclear to cytoplasmic ratio in 3 (14%) cases. The results of this study indicate that the reporting of ASC-H on cervical samples does lead to the detection of HSILs in a significant number of cases (68% in this study). Therefore, further evaluation of the patient is warranted.

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Cell blocks (CBs) are often prepared with fine-needle aspirates (FNAs) from multiple organs as an adjunct to smears in the diagnosis of aspirated lesions. However, the literature contains few reports on their utility with regard to specific organ sites. At our institution, CBs are made routinely on FNAs when there is sufficient material remaining after smear preparation, with thyroid representing the largest volume. The aim of this study was to determine the utility of CBs in the diagnosis of thyroid lesions. From January 2002 to April 2004, 546 thyroid FNAs were performed. Eighty-two (15%) cases, from 60 females and 20 males (age range, 17-88 yr; mean, 50 yr), had CBs and formed the basis of this study. Seventy-four (90%) of the cases were performed by the radiologist or the clinician and 8 (10%) by the pathologist, all of which had an immediate assessment for adequacy. One to 7 passes were performed with an average of 3/case. The needles were immediately rinsed in Hanks' Balanced Salt Solution after smear preparation. CBs were made on bloody specimens/those with tissue fragments. Cell-block slides were reviewed for the presence of cellular elements and classified into three categories: (1) contributory, (2) noncontributory, or (3) provides additional information. Of the 82 cases, 23 (28%) were neoplastic, 51 (62%) were nonneoplastic, and 8 (10%) were nondiagnostic. Fifteen of the neoplastic cases had confirmatory biopsies, 9 of which were papillary carcinoma. The overall cellularity of the CBs was low, varying from 0 to 2 follicular groups in the noncontributory CBs and 3 to 6 follicular groups or papillary formations in the contributory CBs. CBs were contributory in 25 (31%) cases: 5 neoplastic (1 follicular neoplasm, 3 papillary carcinoma, and 1 suspicious for papillary carcinoma), 18 nonneoplastic, and 2 nondiagnostic. CBs were noncontributory in 56 (68%) cases: 18 neoplastic (4 papillary carcinomas, 1 suspicious for papillary carcinoma, 4 Hürthle cell neoplasms, and 9 follicular neoplasms), 33 nonneoplastic, and 5 nondiagnostic. One case was categorized as provided additional information because the CB showed material that was not present on the slides; however, it was still nondiagnostic. In summary, CBs did not help in the majority of cases. They were contributory in only 25 (31%) of the 82 cases, and of the 23 neoplastic cases, only 5 (22%) CBs were contributory. The contribution of the CBs in the diagnosis of thyroid lesions was minimal because of the low cellularity. On-site assessment of specimen adequacy often results in fewer passes, thus contributing to the low cellularity present in cell-block preparations. Ancillary studies may require additional passes.