Kristin A. Skinner

Telomerase reverse transcriptase expression is increased early in the Barrett’s metaplasia, dysplasia, adenocarcinoma sequence

Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector (TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14), and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.

Predicting axillary nodal positivity in 2282 patients with breast carcinoma.

AsbtractAxillary lymph node status continues to be the single most important prognostic variable for breast cancer survival despite significant progress in the molecular and genetic characterization of breast malignancies. All patients with invasive breast cancer who underwent axillary lymph node dissection as part of their treatment were evaluated by 11 clinical and pathologic factors, including the primary lesion’s T category (TNM staging system), whether the lesion was clinically palpable, the presence of lymphatic or vascular invasion, nuclear grade, estrogen and progesterone receptors, S-phase, age, HER2/neu overexpression, histology (infiltrating lobular or ductal), and ploidy. A total of 2282 axillary dissections were performed: 391 in patients with ductal carcinoma in situ (DCIS) [3 of which (0.8%) contained metastases] and 1891 in patients with invasive breast cancer [680 of which (36%) contained metastases]. Multivariate analysis of patients with invasive cancer identified four factors as independent predictors of axillary lymph node metastases: lymph/vascular invasion, tumor size, nuclear grade, tumor palpability. Among a group of 189 patients with nonpalpable, non-highgrade invasive lesions 15 mm or smaller without lymph/vascular invasion, only 6 (3%) had metastases to lymph nodes. If any three of the favorable factors were present, lymph node positivity was 6% or less. Clinical and pathologic feature of the primary lesions can be used to estimate the risk of axillary lymph node metastases. Such risk assessment can be used for the treatment decision-making process.

Breast Cancer: Do Specialists Make a Difference?

AbstractBackground: Many believe that breast cancer should be treated by specialists. We studied the effect of surgeon and hospital specialization on survival after breast cancer treatment in a large, well-defined patient population. Methods: The Cancer Surveillance Program database for Los Angeles County was reviewed. Between 1990 and 1998, 43,411 cases of breast cancer were diagnosed, of which 29,666 had complete data on surgeon, hospital, and staging information. Patients were stratified on the basis of surgeon and hospital specialization, as well as by age, race, stage, surgical procedure, and surgeon and hospital case volume. An analysis of survival and its dependence on these factors was performed. Results: Age, race, socioeconomic status, tumor size, nodal status, extent of disease, surgeon specialization, surgeon case volume, and hospital case volume were all associated with 5-year survival after diagnosis of breast cancer. Treatment at a specialty center did not affect survival. Multivariate analysis indicated that type of surgeon was an independent predictor of survival (relative risk, .77), as were both hospital and surgeon case volume. Conclusions: Treatment by a surgical oncologist resulted in a 33% reduction in the risk of death at 5 years. The effect of surgical specialization cannot be entirely attributed to volume effects.

High negative appendectomy rates are no longer acceptable

BACKGROUND A 10% to 20% negative appendectomy rate has been accepted in order to minimize the incidence of perforated appendicitis with its increased morbidity. We reviewed our experience with appendicitis in order to determine the incidence of negative appendectomies and perforation, and the role of delay in diagnosis or treatment. METHODS We reviewed 659 appendectomies performed over a 12-month period. Incidental and pediatric appendectomies were excluded. RESULTS Seventy-five percent of patients were male and 25% female. Nine percent had negative appendectomies and 28% had perforated appendicitis. Perforated appendicitis resulted in increased morbidity and length of stay. Delay in presentation greater than 12 hours after the onset of symptoms significantly increased the perforation rate. In-hospital delay did not affect perforation rate. CONCLUSIONS We have achieved a negative appendectomy rate lower than that in other reported series, while maintaining an acceptable perforation rate. In the majority of patients, perforated appendicitis is a result of late presentation.

Preoperative Twice-Weekly Paclitaxel With Concurrent Radiation Therapy Followed by Surgery and Postoperative Doxorubicin-Based Chemotherapy in Locally Advanced Breast Cancer: A Phase I/II Trial

PURPOSE Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready?

Gene expression profiling with breast carcinomas has allowed further classification of these tumors into 5 distinct subtypes (luminal A, luminal B, HER2-overexpression, basal-like, and normal-like) with unique clinical outcomes. Subsequent studies have shown that breast carcinomas can also be divided into 5 similar subgroups using immunohistochemical (IHC) analysis with a limited panel of molecular markers (including estrogen receptor, progesterone receptor, HER2, CK5/6, and epidermal growth factor receptor). These subgroups have distinguishing features closely associated with subtypes defined by gene expression profiling, including distinct clinical outcomes. This review aims to present the current data on molecular classification for breast carcinoma, and its clinical significance, with an emphasis on IHC-based studies and the pros and cons of these molecular classifications. We also propose a standardized IHC-based molecular classification, in the hope that it will promote more uniform large multicenter studies, and facilitate its clinical application.

Breast cancer after augmentation mammoplasty.

Background:It is thought that implants interfere with breast cancer diagnosis and that cancers in women who have had breast augmentation carry a worse prognosis.Methods:A prospective breast cancer database was reviewed, comparing augmented and nonaugmented patients for details of histology, palpability, tumor size, nodal status, mammographic status, receptor status, nuclear grade, stage, and outcome.Results:Ninety-nine cancers in augmented women and 2857 cancers in nonaugmented women were identified. Among these women, mammography was normal in 43% of those who had had augmentation and in 5% of those who had not. Augmented women were more likely to have palpable cancers (83% vs. 59%) and nodal involvement (48% vs. 36%), and less likely to have ductal carcinoma in situ (DCIS) (18% vs. 28%). When comparing only women younger than 50, the differences in invasiveness and nodal status lost significance. Cancers diagnosed in the 1990s were more likely to be nonpalpable and noninvasive than those diagnosed in the 1980s. This trend was more pronounced in the augmented population.Conclusions:Augmented patients were more likely to have palpable cancers, although the overall stage and outcome were similar to those of nonaugmented women. Although there have been significant improvements in our ability to diagnose early breast cancer over the past two decades, mammography continues to be suboptimal in augmented women.

Folate Receptor α Associated With Triple-Negative Breast Cancer and Poor Prognosis

CONTEXT Folate receptor α (FRA) has been shown to be selectively expressed in several types of human cancer, including breast cancer. Currently, several FRA target therapies are under intensive study. OBJECTIVE To investigate the expression pattern of FRA in a large cohort of patients with breast cancer and analyze its relationship with different clinicopathologic features, with expression of several key biomarkers, and with clinical outcome. DESIGN Four hundred forty-seven cases of infiltrating ductal carcinoma diagnosed between 1997 and 2008 at the University of Rochester Medical Center were identified and reviewed, and 25 blocks of tissue microassays were constructed. The association between expression of FRA and clinicopathologic features; expression of estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67; and clinical outcome of these tumors were evaluated. RESULTS The expression of FRA was significantly associated with tumors with high histologic grade, higher nodal stages, ER/PR negativity, and high proliferative activity (Ki-67 ≥ 15%), and was independent of HER2/neu overexpression. In all, 74% of ER/PR-negative and 80% of triple-negative breast cancers expressed FRA. The expression of FRA was significantly associated with a worse disease-free survival. CONCLUSIONS Our data demonstrate that a significant subgroup of ER/PR-negative and triple-negative breast cancers express FRA, and its expression is associated with worse clinical outcome.

Palpable Breast Cancers Are Inherently Different From Nonpalpable Breast Cancers

AbstractBackground: We examined the clinicopathologic profile of T1 cancers to determine whether palpable cancers are different from nonpalpable cancers. Methods: A prospective database was reviewed. Palpable T1 cancers were compared with nonpalpable T1 cancers. Initial significance was determined by χ2 analysis. Factors found to be significant were then reanalyzed, controlling for tumor size by logistic or linear regression, as appropriate. Results: Of 1263 T1 cancers treated between 1981 and 2000, 857 (68%) were palpable and 401 (32%) were nonpalpable. Palpability correlated with pathologic tumor size, mitotic grade, nuclear grade, high S-phase, lymphovascular invasion, nodal positivity, and lack of extensive intraductal component, multifocality, and multicentricity. There was no significant difference in estrogen receptor, progesterone receptor or Her-2/neu status, ploidy, or DNA index. Breast cancer-specific survival was worse for patients with palpable cancers. Conclusions: Palpable cancers are inherently different from nonpalpable cancers, with a less diffuse growth pattern, higher metastatic potential, higher proliferative activity, more nuclear abnormalities, and a worse prognosis.

A lower Allred score for progesterone receptor is strongly associated with a higher recurrence score of 21-gene assay in breast cancer.

ABSTRACT Among the 77 infiltrating breast carcinomas, we found that progesterone receptor (PR) expression was inversely associated with recurrence score (RS, p < .0001). RS is also significantly associated with tubule formation, mitosis, and luminal B subtype. The equation of RS = 17.489 + 2.071 (tubal formation) + 2.926 (mitosis) –2.408 (PR) –1.061 (HER2) + 7.051 (luminal A) + 29.172 (luminal B) predicts RS with an R2 of 0.65. In conclusion, PR negativity, luminal B subtype, tubal formation, and mitosis are strongly correlated with a higher RS.